text:
Via Fox News:
Accusing Arizona of trying to “second guess” the federal government, the Justice Department on Tuesday filed a lawsuit challenging the state’s immigration policy — claiming the “invalid” law interferes with federal immigration responsibilities and “must be struck down.”
In the suit, which names the state of Arizona as well as Gov. Jan Brewer as defendants, the Justice Department claims the federal government has “preeminent authority” on immigration enforcement and that the Arizona law “disrupts” that balance. It urges the U.S. District Court in Arizona to “preliminarily and permanently” prohibit the state from enforcing the law, which is scheduled to go into effect at the end of the month.
“Arizonans are understandably frustrated with illegal immigration, and the federal government has a responsibility to comprehensively address those concerns,” Attorney General Eric Holder said in a written statement. “But diverting federal resources away from dangerous aliens such as terrorism suspects and aliens with criminal records will impact the entire country’s safety. Setting immigration policy and enforcing immigration laws is a national responsibility. Seeking to address the issue through a patchwork of state laws will only create more problems than it solves.”
The suit, which drew tough criticism from state lawmakers Tuesday, claimed the state law focuses only on getting rid of illegal immigrants and “ignores” other immigration objectives.
“The United States Constitution forbids Arizona from supplanting the federal government’s immigration regime with its own state-specific immigration policy,” the suit says. “A policy that, in purpose and effect, interferes with the numerous interests the federal government must balance.”
Of course, Republicans – and not just those in Arizona – are understandably not happy with this but some Arizona Democrats serving in the US House aren’t too pleased with the DOJ’s move, either. Rep. Harry Mitchell’s response:
“I am extremely disappointed that the Obama Administration has decided to file a lawsuit against Arizona to try to overturn our state’s new immigration enforcement law, SB 1070. This is the wrong direction to go. I urged President Obama and his administration against doing so because I strongly believe their time, efforts and resources should be focused on securing our border and fixing our broken immigration system. Arizona needs Washington to take action, but a lawsuit is definitely not the kind of action we need.
Illegal immigration didn’t occur overnight, and the situation cannot wait simply because folks choose to play politics. Illegal immigration affects our state more than it does any other — more than half of all illegal crossings over the U.S.-Mexico border happen in Arizona. The federal government has a responsibility to secure the border and fix our broken immigration system, but hasn’t done so, and Arizona continues to shoulder the burden.
According to the Washington Post, the Justice Department will be arguing ‘preemption’ — that enforcing immigration laws is a federal responsibility. While I’m glad that they agree that that this is a federal responsibility, the federal government has clearly failed to meet this responsibility — and a lawsuit won’t do anything to fix that. The only thing this lawsuit will do is demonstrate to Arizonans that Washington still doesn’t get it.
Rep. Gabrielle Giffords:
I am disappointed with the federal lawsuit against SB 1070 for the same reason I was disappointed when this bill became law: Neither will do anything to make Arizona’s border communities more secure.
Both the law and the lawsuit challenging the law are unnecessary distractions. Arizonans want our nation to control its borders and bring a halt to the violence, smugglers and drugs that threaten our way of life.
To fully appreciate the seriousness of what Arizonans are up against, President Obama should come to the border. The president should spend an afternoon with the ranchers of Cochise County and the retirees of Green Valley so he can see for himself that what we need are Border Patrol agents on the border, not lawyers in court.
Federal lawyers arguing with state lawyers will do nothing to strengthen border security or to fix our broken immigration laws.
The supreme irony of the lawsuit is its premise that SB 1070 intrudes on the federal government’s responsibility to enforce immigration laws. Had the federal government taken that responsibility seriously in the past, neither today’s lawsuit nor the state law that prompted it would be necessary.
Rep. Ann Kirkpatrick:
This lawsuit is a sideshow, distracting us from the real task at hand. A court battle between the federal government and Arizona will not move us closer to securing the border or fixing America’s broken immigration system. The legal fights and boycotts are drawing focus and attention away from what has to be a policy-driven, substantive debate.
Washington failed us on this issue again today, and Arizonans have had enough. The White House and Congress need to start developing a better approach to border security and immigration reform, working with us instead of against us. Our law enforcement and communities are at risk right now — this is a time for solutions, not new obstacles.
And last but not least, Republican Governor Jan Brewer’s response:
PHOENIX – “Today I was notified that the federal government has filed a lawsuit against the State of Arizona. It is wrong that our own federal government is suing the people of Arizona for helping to enforce federal immigration law. As a direct result of failed and inconsistent federal enforcement, Arizona is under attack from violent Mexican drug and immigrant smuggling cartels. Now, Arizona is under attack in federal court from President Obama and his Department of Justice. Today’s filing is nothing more than a massive waste of taxpayer funds. These funds could be better used against the violent Mexican cartels than the people of Arizona.
“The truth is the Arizona law is both reasonable and constitutional. It mirrors substantially what has been federal law in the United States for many decades. Arizona’s law is designed to complement, not supplant, enforcement of federal immigration laws. Despite the Department of Justice’s claims in paragraph 62 of today’s lawsuit, Arizona is not trying ‘to establish its own immigration policy’ or ‘directly regulate the immigration status of aliens.’ Arizona Revised Statutes § 11-1051(E) states that the federal government, along with local law enforcement officers authorized by the federal government, can only determine an alien’s immigration status. Subsection (L) of that same section goes on to state that the law ‘shall be implemented in a manner consistent with federal laws regulating immigration.’
“The irony is that President Obama’s Administration has chosen to sue Arizona for helping to enforce federal immigration law and not sue local governments that have adopted a patchwork of ‘sanctuary’ policies that directly violate federal law. These patchwork local ‘sanctuary’ policies instruct the police not to cooperate with federal immigration officials.
“The best thing government can do is to create a stable, predictable environment, governed by an easily understood set of rules or laws. We do not need to make this more complicated than it already is. We must first and foremost create a secure border. Enhanced trade, economic opportunity and freedom will surely follow.
“I am pleased that President Obama and the Department of Justice did not pursue the baseless claims of illegal racial profiling in the lawsuit. When signing S.B. 1070, I said, ‘My signature today represents my steadfast support for enforcing the law — both against illegal immigration AND against racial profiling.’ Arizona’s law expressly prohibits unconstitutional racial profiling. However, words are not enough. For this reason, I ordered the Arizona Peace Officer Standards and Training Board (AZPOST) to develop training on the new law for Arizona’s police officers. AZPOST has completed the training course and has published it for the all world to see at www.azpost.state.az.us/SB1070infocenter.htm . AZPOST has done its job professionally and served Arizona well.
“I will not stop fighting to protect the citizens of Arizona, and to defend Arizonans in federal court. I have set up a legal defense fund to pay the substantial legal fees that Arizona has been, and will be, forced to incur as a result of all of these lawsuits. Contributions to the Border Security and Immigration Defense Fund can be made at www.keepazsafe.com . My legal team will not hesitate to assert the rights of the State of Arizona in this matter. Arizona will ultimately prevail against the lawsuits – including this latest assault by the Obama Administration. Our laws will be found to be constitutional – because that is exactly what they are.”
DRJ at Patterico’s breaks down what’s to come in the next few weeks:
To obtain a preliminary injunction, the federal government must meet each part of a four prong test: (1) a substantial likelihood of success on the merits; (2) a substantial threat that failure to grant the injunction will result in irreparable injury; (3) that the threatened injury outweighs any damage that the injunction may cause the opposing party; and (4) that the injunction will not disserve the public interest. Just as Judge Feldman did in blocking Obama’s moratorium on offshore drilling, the Court in this Arizona case will balance the injury on the parties and consider the impact the injunction will have on “the public interest.”
Professor Jacobson at Legal Insurrection says the case has been assigned to U.S. District Judge Neil V. Wake. Because the Obama Administration is seeking a preliminary injunction, Judge Wake will give us an early view of his stand on this case when he rules on whether there is a “substantial likelihood” the Obama Administration will prevail on the merits.
Gird your loins.


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By March 20, employers will have completed H-1B Registrations but not everyone will be selected in the lottery. If you miss out on the H-1B lottery this year, does that mean you cannot hire foreign national employees for the rest of the year?
Luckily, employers have other choices when it comes to hiring nonimmigrant workers in the U.S. Depending on what country a candidate is from, perhaps an E-3 or TN visa will work. If you are transferring an employee from a foreign affiliate, the L-1 visa may be available.
WSM offers a series of webinars designed to train HR professionals and in-house counsel on the ins and outs of various immigration processes and requirements when sponsoring individuals for U.S. visas.
In this month’s webinar, we will provide an overview of several employment-based nonimmigrant visa categories. We will discuss: basic requirements of each nonimmigrant visa; timing; spouse work authorization, including updates on the H-4 EAD; and government adjudication trends.
Weaver Schlenger LLP is a recognized provider of recertification credits. HR Certification Institute® preapproved this program for 1 HR (General) credit towards aPHR™, aPHRi™, PHR®, PHRca®, SPHR®, GPHR®, PHRi™ and SPHRi™ recertification.
This program has also been approved for CA MCLE credit (1 hour) by the State Bar of California. If you require CA MCLE credit, please email your CA state bar # to email@example.com by March 25, 2020.

domain: law


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According to the results of the investigation, the prosecutor's office decided to charge the “Nerpa” captain Dmitry Lavrentiev (the captain of 1 rank) and foreman Dmitry Grobov. According to the investigators, it was the foreman Grobov who decided to press the fire button without authorization in order to suspect the watchman in such a strange way. Why Coffins could not take advantage of more adequate situations for the situation, and what generally led him to take this fatal step, the investigation and the prosecutor's office did not explain.
Captain 1 of rank Lavrentyev was accused of bringing an untrained crew to the test boat, in which, apparently, the most unprepared crew was identified as the foreman (bilge driver) Grobov. Moreover, Dmitry Lavrentiev was also blamed for the fact that he himself allegedly acted unprofessionally during an emergency on the “Nerpa”.
Already these arguments alone raised numerous questions.
First, by what criteria did the investigating authorities determine the crew’s unpreparedness, and even assuming that such unpreparedness of individual crew members could manifest itself, then for what purpose did the experienced Dmitry Lavrentyev use the services of these people on the boat? After all, the nuclear submarine cruiser is, it seems, if it is not a private stall, where shawarma is offered, and its owner is free to choose cooks at his own discretion ... And, therefore, the crew - what was ...
Secondly, as far as the inexperienced foreman Grobov needed to be, in order not to take advantage of the regular communication systems that were on board, in order to bring the watchman to him, but instead, excuse me, cut in the fire extinguishing system. If you believe the arguments of the investigation, then it turns out that the Grabs with the same "success" could try to beckoning the watchman, hitting the elements of ammunition with a hammer (if there was one on the submarine at the time) ... Grobov himself during court sessions denied the fact that He pressed the fire extinguishing system trigger button on the submarine.
Thirdly, how it happened that the launch of the fire protection system occurred at the touch of a button. After all, if the developers have foreseen just such a version of the fire extinguishing system, then, it turns out, the boat was not completely insured from its operation: for example, a button could be pressed for fatal randomness - everything happens in a limited space when a large number of people gather.
Fourthly, if even the fire extinguishing system worked, then why all this led to victims in general. It turns out that freon was used in the system, as mentioned in one well-known film, “the wrong system.” After all, if the fire extinguishing substance was suitable, and in addition the entire system also worked in normal mode, then you need to ask questions already to the developers and tankers: and what - if any fire protection system fires, the chances of surviving the crew will tend to to zero. Well, what is the difference between this fire extinguishing system and how someone would just let the water inside the submarine ... Sorry, but the effect with the number of victims would probably be the same.
And if we assume that the technicians were “screwing up” at the factory, then why only members of the submarine’s crew were in the dock. No, it is, of course, clear that the captain of the vessel should be responsible for everything that happens on this vessel, but it is unlikely to be blamed for the fact that the manufacturers could not have fulfilled all the elementary requirements, which led to the tragedy .
Such inconsistencies clearly did not find an explanation at the regular court hearing on this strange case that took place the other day. The jury decided that the actions of the captain of the 1 rank Dmitry Lavrentyev and the foreman Dmitriy Grobov did not contain any corpus delicti, and an acquittal was pronounced on the two accused sailors. At the same time, it is reported that the experts had carefully analyzed the recording of events on the Nerpa submarine, captured by the registrar on that fateful day, and the same specialists did not determine non-professional actions on the part of the submarine team. This added confidence to the jury that neither Lavrentiev nor the Sepulcher were guilty of the tragedy.
As it later turned out, this was not the end of the Nerpa case. Naval prosecutors believe that if the jury were competent in technical matters, their verdict would be the opposite of that rendered. The prosecutor's office is confident that the objective conclusion of the tragedy by the jury did not allow for the “complexity of technical nuances”, and in addition the defense “deliberately distorted the facts”, thereby misleading the jurors. Based on this, the prosecutor's office intends to appeal the verdict on appeal.
It should be noted that the acquittal verdict against Lavrentyev and Grobov is not passed for the first time. The first acquittal was announced a couple of years ago, and then the prosecuting authorities decided to appeal against it to the Supreme Court. The Supreme Court overturned the acquittal verdict handed down by the jury and referred the case to a new trial. The defense and then petitioned that the case be tried in a jury trial. The petition was granted, which immediately discouraged the prosecutors. Obviously, they were counting on the fact that the second time the court would pass without the participation of jurors, which would give more chances to the prosecution, but had to again hear the acquittal.
I wonder how many more court sessions will the prosecutors need to put an end to this matter? Or everything moves to the fact that appeals against sentences will go up until Lavrentiev and the Graves still do not appear behind bars. If so, this will be another oddity of the justice system in our country ...
It is noteworthy that, in addition to indirectly accusing jurors of incompetence (and no one obliges them to be competent in the technical nuances of nuclear submarines), the Military Prosecutor's Office decided to let off steam, accusing journalists as well. According to military prosecutors, information has passed in a number of media outlets that is distinguished by bias and also complete incompetence. At the same time, the main controversy spun around the recording made on January 8 2008 onboard the Nerpa submarine. Military prosecutors say that this is an audio recording from the registrar of the submarine, and journalists say that it is still a video. Although there is no fundamental difference in this, because the video recording of the audio recorder itself is difficult to fully call video recording, but, nevertheless, it is still a video. And the quality of the recording is such that to argue about whether it is proof of the guilt of the captain "Nerpa" or is not actually meaningless ...
Whatever it was, but the situation with the accident on the "Nerpa" continues to be in a "flooded" state. The persons really guilty of the tragedy are not clearly identified.


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Part 5 of The Sydney Science Fiction Film Festival IN CONVERSATION Series, hosted by Festival Director and Screen-Space Managing Editor, Simon Foster.
TIME TRAVEL 2 (Australia, Dir: Carma Sharon; 2.17 mins) T1 is still looking for Sarah Conor. Will he find her? Screening in The AUSTRALIAN SHORT FILM SHOWCASE on Saturday November 21 from 10.30am at Actors Centre Australia. Tickets: https://bit.ly/30vE3Py
SSFFF: What have been the science-fiction works – books, films, art of any kind – that have inspired your work and forged your love for the genre?
CARMA: Great question. When I was a kid I got to watch The Terminator with my brother on repeat. We were obsessed with that film! I think I watched T1 and T2 over 100 times. It was magical in every aspect of filmmaking and still is my favourite film of all time. But please don’t make me choose between them, not happening! Other than that, I've consumed a lot of philosophy and psychology books and I love how sci-fi explores alternative existence and solutions. It stimulates my mind
SSFFF: How did the original concept for your film take shape? What aspects of your film’s narrative and your protagonist’s journey were most important to you?
CARMA: My film is very short and very much inspired by the Terminator story. As for my protagonist’s journey...well, you will see for yourself [laughs] I can’t really say too much about it. My intention is to make people laugh and to create a fusion of sci-fi and comedy.
SSFFF: Does the ‘science-fiction’ genre have deep roots in the art and cultural history of your homeland? Were the resources, facilities and talent pool required to bring your film to life easily sourced?
CARMA: I live in Sydney and we love sci-fi over here, so it was very easily done. With zero budget [but] with lots of enthusiasm and great energy from the cast and crew. Adobe After Effects was very handy. too.
SSFFF: Describe for us the very best day you had in the life cycle of your film…
CARMA: Well, writing the script was great fun, I gave myself a giggle. And of course that very same day that we shot it [laughs] or more like those 4 hours in Newtown.
SSFFF: Having guided your film from idea to completion, what lessons and advice would you offer a young science-fiction filmmaker about to embark on a similar journey?
CARMA: The story is more important than anything else. Make sure you have a strong idea and script before you begin. Don’t rely on special effects and CGI to create a sci-fi film, it's not about that.
Content also available at Screen-Space

domain: artistic


text: This article outlines several volunteer-related research projects currently underway in the United Kingdom, initiated and funded by the government. There are as yet no findings to report, but e-Volunteerism feels the article will be useful to our readers as a model for how government research can support volunteer efforts. This is quite connected to the Points of View topic that appears elsewhere in this issue. The questions raised toward the end of the article for "future study" are provocative and we hope they will start other researchers thinking about additional ways to study issues of direct usefulness to practitioners. We will, of course, keep readers informed as the reports promised below become available.

domain: news


In the heightened awareness of domestic abuse and guns in the aftermath of the Jovan Belcher tragedy, news of some Terrell Suggs’ domestic issues has come to light. Last month, he and his girlfriend, Candace Williams, were involved in a custody dispute with the parties filing competing actions, and Suggs surrendered legally possessed firearms to authorities.
The article by the Baltimore Sun is not clear on the timeline, but there was also a protective order sought three years ago by Candace Williams. Among the allegations contained in a complaint (presumably, the one from three years ago, and not last month) were that Suggs threw a soap dispenser at her, hit her with his hand in the chest, and held a bottle of bleach over her and their infant son.
Obviously a very sensitive topic right now, and it is a positive, regardless of the truth of any of the underlying claims, that in this situation the guns have been removed. I will caution that since this case apparently arises out of competing interests in a custody situation, there are frequently allegations made by parties, and nothing has been adjudicated here.
[photo via USA Today Sports Images]


Russia's highest diplomat used his first meeting with Secretary of State Rex Tillerson to shame the U.S. for what he said was an unlawful attack against Syria.
Foreign Minister Sergei Lavrov was icy toward Tillerson Wednesday as they met for the first time. He said the Kremlin wanted to know the Trump administration's "real intentions," and sought clarity on "very ambiguous" and "contradictory" messages coming from Washington.
"We have seen very alarming actions recently with an unlawful attack against Syria," Lavrov said in reference to the missile strike last Thursday on a western Syria air base. "We consider it of utmost importance to prevent the risks of replay of similar action in the future."
The diplomats were photographed unsmiling as they shook hands Wednesday.
Tillerson became the first member of the Trump administration to visit the country, and the chilly reception came as the White House bashed Russia for its support of the Assad regime that runs Syria.


text:
If an item is not available through MNLINK, you may request that we try to obtain the item from libraries elsewhere in the United States. This request may be submitted by e-mail to firstname.lastname@example.org or by telephone at 651-501-6306. You may also make the request in person at any Saint Paul Public Library location.
There is a $5.00 fee per national search request. The $5.00 fee will be added to your patron account and is not refundable if we are unable to obtain the item. Please note that borrowing privileges are suspended for accounts owing more than $10 in fees. You may pay the fee in advance if making the request in person.

domain: library


text:
City of Vicksburg announces plans to open youth development center to help curb crime amongst young people
JACKSON, Miss. (WLBT) - Wednesday, city leaders in Vicksburg gathered inside the city auditorium to discuss ways to curb crime among the youth.
It’s troubling trend city leaders are determined to stop.
”We just believe we can save our youth,” said Mayor George Flaggs. “We believe that here’s hope, and we believe at the same time that if we give them a structure and a way to go up, they will go up.”
During Youth Ad Hoc Committee meeting, Mayor Flaggs unveiled the plans for a new youth development center.
City, county, school, church, and community leaders all coming together to bring some much-needed resources to offer to the youth.
The center will have a several resources geared towards the teens, teaching them a number of things such as Life and parenting skills, as well as mental health programs.
”We believe that we can staff that building in a way that we’ll be able to have resources available for our kids during the school hours and on weekends,” said Mayor Flaggs.
”It’s very important to have youth programs in the community,” said Vicksburg Police Chief Penny Jones. “It helps with mental health; it helps with teaching our kids how to be mentored or how to mentor to other kids. It helps them learn skills to teach them how to get a job, and not only that, gives them an opportunity to get scholarships to go to school and other places.”
As city leaders unveiled their plans for the youth center, they’re also hearing from the residents about other programs they’d like to see implemented.
”Mentorship is a key part of it,” said Dexter Jones, who’s a member of the Youth Ad Hoc Committee. “You’ve got to mentor young folks this day and age because a lot of them are on the wrong path and they need some help to get on the right path, so I think programs such as these that we are trying to implement is going to get them there, and ultimately, it boils down to them having a relationship with God.”
More than a dozen stakeholders from the city and county are coming together to work on the project.
At this time, there’s no date on when the youth center will open.
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Copyright 2023 WLBT. All rights reserved.

domain: sociology


text:
Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis
Critical Care volume 10, Article number: 209 (2006)
In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin – administered even at low doses – with the therapeutic effects of antithrombin, and has confirmed – at the level of cellular mechanisms – a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.
Antithrombin is a vitamin K independent glycoprotein and an essential inhibitor of thrombin and other serine proteases such as factors Xa and IXa . Acquired antithrombin deficiency is more frequent than congenital deficiency and develops primarily through increased consumption or loss of antithrombin. The reduced plasma level in acquired deficiency is a strong predictor of a severe disease course, particularly in patients who have suffered trauma or severe sepsis. Increased consumption of antithrombin occurs primarily in disseminated intravascular coagulation (DIC) [2–8]. A diagnosis of DIC is made after taking into consideration the triggering disease, clinical picture, and unambiguous and striking hemostatic findings such as a drop in thrombocytes, loss of antithrombin activity, increased concentrations of D-dimers or fibrin monomers .
Based on the assumed inhibition by antithrombin of activated clotting factors in the circulating vascular system, concentrated human plasmatic antithrombin was administered in the setting of DIC in isolated cases [2, 4–6, 8], in animal experiments [6, 9–13], and in clinical studies [14–18] with the aim of interrupting the complex cycle of DIC and preventing multiple organ failure. In these studies the duration of DIC was significantly shortened and organ functions were improved, but no significant reduction in mortality in the antithrombin groups was achieved. Proof of reduced lethality from DIC with administration of concentrated human plasmatic antithrombin in prospective controlled clinical studies has not yet been reported.
The largest number of patients with acquired antithrombin deficiency treated with human plasmatic antithrombin in a prospective controlled clinical study can be found in the KyberSept trial . Patients with severe sepsis were recruited for this study independent of the cause or duration of sepsis and irrespective of the presence or absence of DIC. Therapeutic doses of heparin were not permitted because of the interaction of this agent with antithrombin and its anticoagulatory effects. In prophylactic doses, however, administration of heparin was permitted. Compared with placebo, treatment with high-dose antithrombin over 4 days had no significant effect on mortality at 28 days. Failure to demonstrate effectiveness of antithrombin may be due to the heterogeneity of the patient population investigated. Interaction between antithrombin and heparin was considered a possible reason, because antithrombin achieved a significant reduction in mortality at 90 days in a subgroup of patients who did not simultaneously receive prophylactic doses of heparin.
This review addresses the potential relevance of new knowledge on the mechanisms of action of antithrombin to the practising clinician.
Characteristics of antithrombin
The two basic endogenous anticoagulation principles that have an inhibitory effect on the coagulation cascade are the heparin–antithrombin and the protein C thrombomodulating mechanisms. Both of these inhibit serine proteases and cofactors/activated coagulation factors .
Antithrombin is a 58 kDa glycoprotein that is composed of a single amino acid chain with a plasma concentration of about 150–150 μg/ml (2–3 μmol/l). The total 432 amino acids carry four N glycosylated oligosaccharide chains and three disulfide bridges. In the presence of heparin, antithrombin strongly inhibits not only thrombin and factor Xa but also factor IXa, and it weakly inhibits factors XIa and XIIa, trypsin, plasmin, kallikrein and factor VIIa [15–17, 20, 21]. This broad spectrum of inhibition makes antithrombin the key regulator of the coagulation system. In addition, antithrombin appears to have anti-inflammatory properties that appear to be distinct in their mechanism from this effect on coagulation that is dependent on enzyme inhibition.
Two isoforms of antithrombin circulate in the plasma, namely the α and the β forms, which do not differ from each other in their thrombin inhibiting effect, but they differ in their affinity for heparin. Under normal conditions, 85–95% of circulating antithrombins are glycosylated at four of their asparagine molecules; these are of the α isoform. The remaining 5–15% of circulating antithrombins, of the β isoform, lack glycosylation at asparagine 135, which results in their 3- to 10-fold greater affinity for heparin .
Heparin exerts an anticoagulatory effect by binding to antithrombin and thereby alters its conformation in such a manner that it inhibits thrombin 1000-fold more strongly . It builds up a stoichiometric complex with thrombin, at a 1:1 ratio, over a reactive arginine-containing loop and a catalytic serine-containing interaction site. As soon as a thrombin–antithrombin (TAT) complex is formed, both molecules are inactivated (Fig. 1). The TAT complex has a short plasma half-life of only 5 min and is disposed of by its binding to the so-called low-density lipoprotein receptor-related protein of the liver [24, 25].
In order for thrombin to be inactivated by antithrombin, not only must heparin be bound to antithrombin but it must also accumulate on thrombin. Nonfractionated, high-molecular-weight heparins, which have several pentasaccharide sequences, can thus promote the antithrombin-dependent inactivation of thrombin. This bivalent interaction does not require the presence of antithrombin to inhibit other serine proteases, such as factor Xa or the contact factors. This explains why, compared with the other factors, thrombin is inhibited more weakly by low-molecular-weight heparins.
Proteoglycans, such as heparan sulfate proteoglycans (HSPGs), are expressed on the surface of vessel endothelium. It has been estimated that there are about 500,000 binding sites for antithrombin on each single endothelial cell on the inner surface of the blood vessels . If the heparin-binding capacity of circulating antithrombin is not blocked or exhausted by soluble heparin or by HSPG detached from the endothelium, the deposition of antithrombin on surface heparins of the endothelium can help antagonize the activated thrombin also deposited at the same sites of the endothelium in vessel injury . This mechanism might be of significance in the maintenance of microcirculation.
The anticoagulatory properties of antithrombin have been investigated relatively exhaustively and have been known for some time for their inhibitory effect on serine proteases. Since the late 1980s, additional results from several laboratories have shown that antithrombin also has strong anti-inflammatory properties that are independent of its anticoagulatory characteristics. These effects were first postulated by Taylor and coworkers [27, 28] based on their experiments on DIC in a monkey model. Infusions of antithrombin significantly reduced mortality in monkeys previously treated intravenously with lethal doses of Escherichia coli. The therapeutic effects on systemic blood pressure and organ failure, however, could not be explained on the basis of its direct effect on thrombin. These observations were supported by the fact that DEGR–factor Xa, a catalytically inactive factor Xa derivative that selectively blocks production of thrombin, also had no influence on organ failure in this model.
An early explanation for this anti-inflammatory effect of antithrombin presented itself when it was shown that antithrombin promotes the release of prostacyclin (prostaglandin I2) from the endothelium, which – both in vitro and in vivo – can interact with heparin-like glycosaminoglycans of the endothelium surface [29–31] (Fig. 2).
Endotoxin-induced damage to pulmonary blood vessels  as well as hepatic ischaemia/reperfusion lesions  can be decreased with antithrombin via induction of endothelial prostaglandin production. The protective effect could not be achieved with Trp49–antithrombin (a modified antithrombin) because, lacking affinity to heparin, it was unable to induce release of endothelial prostacyclin. In independent investigations conducted in a mesenteric ischaemia/reperfusion feline model, Ostrovsky and coworkers  showed that antithrombin exerts its protective effect by inhibiting rolling and adhesion of leucocytes on the endothelium. Hoffmann and coworkers  and Neviere and colleagues  later confirmed this effect in a rat model by intravital videomicroscopy of damage to the small intestine in endotoxinaemia. In both of these studies, the effect of antithrombin on the leucocyte–endothelium interaction could be abolished by indomethacin, which is an inhibitor of prostacyclin production. HSPGs (heparin-like glycosaminoglycans) are involved as mediators in the effect of antithrombin on the leucocyte–endothelium interaction. There are indications that syndecan-4 (an HSPG member of the syndecan family) mediates, as one of the antithrombin receptors on endothelial cells, these direct effects of antithrombin [36–38]. Antithrombin reduced the ischaemia/reperfusion induced renal or hepatic injury by inhibiting leucocyte activation, suggesting that therapeutic effects of antithrombin might be mainly mediated by prostacyclin released from endothelial cells through interaction of antithrombin with cell surface glycosaminoglycans [39, 40]. Organ systems protected by antithrombin in ischaemia/ reperfusion via such mechanisms may include those of the central nervous system [41, 42].
Syndecan-4 is expressed by leucocytes, and moreover antithrombin can regulate the migratory behaviour on the cell surface of neutrophils, monocytes, lymphocytes and eosinophiles [36, 38, 43]. In its highly conserved heparin sulfate ectodomains, syndecan-4 possesses pentasaccharide arrays that are recognized by the heparin-binding site of the antithrombin molecule [30, 44]. With reagents such as heparinase or natrium chlorate that degrade heparin sulfate, the effect of antithrombin on leucocyte migration could be abolished [36–38, 43]. In agreement with this is the observation that syndecan-4 deficiency in knockout mice increases mortality in endotoxinaemia . Even the smallest doses of heparin such as those used in thrombosis prophy-laxis can have a negative impact on the beneficial effect of antithrombin on microcirculatory disturbances in endotoxinaemia . This might be due to the fact that heparin competitively inhibits the binding of antithrombin to syndecan-4 or other HSPGs. It has been reported in human umbilical cord endothelial cells that, under static conditions, antithrombin inhibits endotoxin or cytokine induced signaling and adherence of neutrophils  (Fig. 2). Coincubation of antithrombin with a synthetic exogenous pentasaccharide or pretreatment of endothelial cells with heparinase or chondroitinase abolished the effect of antithrombin on neutrophil adherence. Based on these observations it was concluded that antithrombin has the capacity to block endothelial cell activation via activation of syndecan-4-dependent signal transduction.
In their investigations into the intracellular mechanisms that underlie the anti-inflammatory effects of antithrombin, Oelschläger and coworkers  confirmed that antithrombin inhibits activation of nuclear factor-κB (NF-κB) in cultured human monocytes and endothelial cells . The transcription factor NF-κB activates various genes that encode immune factors in reactions to inflammatory stimuli . That this mechanism is inhibited with antithrombin represents a plausible explanation for the anti-inflammatory effects described. This inhibition of NF-κB was observed in an in vitro concentration of antithrombin corresponding to its level in the plasma, a concentration required for therapeutic anti-inflammation in vivo  or for other effects described in vitro .
Additional in vitro findings on inhibition of β2 integrin expression in neutrophils and monocytes by antithrombin  suggest that direct molecular mechanisms underlie inhibition of leucocyte adhesion to the endothelium. Antithrombin inhibited the tumour necrosis factor (TNF)-α induced increase in E-selectin expression in endothelial cells by inhibiting the interaction of NF-κB with CBP/p300 through cAMP-dependent protein kinase A-induced CREB activation . This inhibitory activity of antithrombin probably also depends on its binding to heparin-like substances on the endothelial cell.
Because of the widespread expression of HSPGs, sites of action for antithrombin may not be restricted to endothelium and leucocytes but may well include additional targets. Evidence for this came from studies in ischaemic/reperfusion injury of the liver; antithrombin might increase hepatic tissue levels of prostacyclin via enhancement of hepatic injury induced activation of capsaicin-sensitive sensory neurones, thereby reducing liver injury in rats. In this process, calcitonin gene-related peptide-induced activation of both endothelial nitric oxide synthase and cyclo-oxygenase-1 might be critically involved . Because in such a scenario the site of action of antithrombin is within the interstitium, prior extravasation of circulating antithrombin would have to be a prerequisite for anti-inflammatory activity to be exerted. Of course, this also has implications for estimating dose–response relationships because it will be difficult to determine extravascular concentrations of antithrombin.
Interaction between antithrombin and heparin
It is clear that antithrombin has anti-inflammatory properties in addition to its anticoagulation ones. Because the anti-inflammatory effects are exerted via interaction between antithrombin and its heparin-binding domains and the heparin-like receptors on the surfaces of endothelial cells and leucocytes such as HSPG syndecan-4, it is not surprising that the antithrombin concentrations required for this differ from those for anticoagulation and lie in 'supraphysiological' region. In vitro and in animal models, low doses of unfractionated or low-molecular-weight heparin antagonized this HSPG-mediated effect, because the binding of antithrombin to the cellular HSPG was blocked by exogenous heparin  (Fig. 3). It was previously shown antithrombin–heparin treatment significantly attenuated the endotoxin-induced consumption of fibrinogen and completely prevented the increase in soluble fibrin in plasma; however, no significant effect of antithrombin III-heparin was observed on endotoxin-induced mortality and dysfunction in pulmonary gas exchange. We therefore conclude that a purified antithrombin–heparin complex inhibits thrombin effects and prevents development of DIC, but it fails to influence clinical outcome significantly in endotoxic shock in pig .
Therapy for severe sepsis, which in its initial phase is a proinflammatory, life-threatening disease, with antithrombin was evaluated in a randomized, controlled study (KyberSept) conducted in 2314 patients . Total mortality on day 28 after the start of therapy in patients in the intention-to-treat group (who received antithrombin) was no different from that in the placebo group (38.9% for antithrombin versus 38.7% for placebo). This finding was counter to the raised expectations stimulated by phase II trials [14–18, 21]. Concomitant – with the study medication, one subgroup of patients was given heparin for thrombosis prophylaxis. Because, according to subgroup analysis, antithrombin reduced 90-day mortality only in the group of patients who did not receive heparin at the same time, an interaction between antithrombin and heparin was postulated that probably offset the beneficial anti-inflammatory properties of the former [19, 57, 58].
Although prophylactic and therapeutic use of heparin in venous thromobosis and pulmonary embolism has been extensively investigated during the past 50 years, its employment in patients with sepsis has not yet been evaluated in prospective studies. In small studies a beneficial effect of heparin on survival of patients with sepsis could not be demonstrated . In the KyberSept study, administration of prophylactic doses of heparin was permitted by the protocol [19, 57]. Because the possibility of an interaction with antithrombin had not been excluded, the subgroup analysis was determined a priori, before the start of the study, although there was no stratification for heparin. Analyses of heparin were carried out post hoc in Kybersept, which distinguishes it from other retrospective calculations that were justifiably the subject of criticism .
The post hoc analyses of the effectiveness of antithrombin in – severe sepsis without concomitant administration of heparin  supported the hypothesis that prophylactic administration of heparin interferes with the therapeutic effect of antithrombin. Although definitive statistical proof is lacking, it is quite likely that the increasing loss of efficacy of antithrombin over the time course of the KyberSept trial is associated with increasing concomitant administration of heparin . In addition, the combination of antithrombin and heparin led to a significant increase in bleeding complications, even though no increase in mortality was shown to result from them. Conversely, antithrombin therapy without heparin did not result in an increase in the number of severe – thromboembolic events, which would suggest that withholding prophylactic heparin during antithrombin therapy does not present any new safety problems .
Further, rather less direct confirmation of the role of heparin as an unfavourable interaction partner with antithrombin in severe sepsis comes from another predefined subgroup analysis of the KyberSept trial. It was shown that, in KyberSept, those patients who failed to derive any benefit from antithrombin either were too ill to survive sepsis despite optimal therapy (predicted mortality >60%) or were too well to die in adequate numbers for the study conditions (predicted mortality <30%). In the group of patients with the 'right' degree of illness severity (predicted mortality between 30% and 60%), a statistically significant improvement in survival to day 90 of the observation period was seen in the antithrombin group, irrespective of whether the patients in this group concomitantly received heparin; if those patients who received heparin were excluded from the analysis, the therapeutic effect of antithrombin was even stronger .
Results of preclinical research carried out after the KyberSept study suggested the possibility of an undesirable drug interaction between antithrombin and heparin, and this – together with previous knowledge on this subject – provided the justification for re-analyses of the findings. The data support the assumption that if administration of heparin concomitantly with antithrombin is withheld, then the anti-inflammatory potential of the latter can be improved.
Disseminated intravascular coagulation and antithrombin-dependent inhibition of inflammation
DIC is a complex event both from diagnostic and from therapeutic perspectives. DIC can be triggered by numerous diseases that are quite independent from each other. It is not a disease entity in its own right but manifests as a consequence or complication of some severe underlying disease. Activation of coagulation within the context of such an underlying disease induces excessive intravascular coagulation that can manifest in various ways. It can lead to the formation and deposition of fibrin so that microthromboses develop in multiple organs (Fig. 4). The extensive and persisting activation of the coagulation system may also result in reduced levels of coagulation factors. Consumption of these factors is promoted by reduced synthesis in the liver, and their shortened half-life is dependent on activation of proteases. Consumption of coagulation factors and the subsequent thrombocytopenia can lead to the development of microthromboses and severe vascular complications.
DIC is among the most frequent complications of sepsis, which is almost always associated with hemostatic changes. Patients with septic shock who develop DIC exhibit higher mortality rates than do those without signs of DIC. With its ubiquitous microthrombosis, DIC plays an essential role in the development of organ dysfunction in septic shock, such that DIC can be considered a primary pathogenetic factor in multi-organ failure. In sepsis, laboratory data demonstrate not only changes in the number of leucocytes but also a reduction in the number of thrombocytes and antithrombin concentration.
Inflammation-dependent activation of coagulation
Increased levels of circulating cytokines follow a marked increase in the markers for thrombin formation (prothrombin fragments F1 and F2, and TAT complex) and for the conversion of fibrinogen to fibrin (fibrinopeptide A and fibrin monomers) . A similar activation of the coagulation system can be observed when TNF is injected into individuals . Concomitant administration of pentoxifyllin and endotoxin in chimpanzees blocked endotoxin-induced TNF expression, and also inhibited activation of coagulation . Thus, TNF is not only a central mediator in the cytokine cascade but also must be viewed as a decisive mediator of endotoxin-induced activation of the coagulation system.
Initial activation of the coagulation system in sepsis occurs primarily via the extrinsic system; that is, it is dependent on tissue factor (TF). In primates, infusions of high doses of E. coli were followed by strong expression of TF . Furthermore, in vitro studies showed that endotoxin and cytokine induced TF expression in monocytes and endothelial cells . TF binds to factor VIIa, resulting in a TF–factor VIIa complex, which is responsible for the conversion of factor X to factor Xa. In children with meningococcal sepsis, monocytes exhibit increased TF expression . One can assume that the TF-dependent system plays a predominant role in activation of coagulation in sepsis.
The coagulation system comprises several inhibitory systems that are of great importance, with antithrombin and protein C–protein S systems in the foreground. In sepsis, however, reduced activity of inhibitory systems has been measured in general . This further contributes to the development of a procoagulatory condition.
As a rule, the number of thrombocytes is reduced within the context of a septic event. This reduction is explained by their being used up in the region of fibrin deposits, by their adhesion to altered endothelial cells, and by pulmonary and hepatic sequestration. Generally speaking, there is a close correlation between lowering of thrombocyte numbers and mortality in patients. Disturbances in platelet function not only result from sepsis but can also arise in the context of antibiotic therapy, or they may be associated with sepsis-dependent uraemia.
Effects of antithrombin on monocytes and thrombocytes
Antithrombin binds to syndecan-4 in monocytes and thrombocytes, activates various signal transduction pathways, and thereby influences the functional behaviour of both of these blood cell types, which are so important in DIC [36, 37, 53, 69]. Signal transduction enzymes that are involved in monocytes in vitro include protein kinase C , Rho-GTP associated kinases , src tyrosine kinases  and sphingosine kinase .
Antithrombin enhances Tyr416 and inhibits Tyr527 phosphorylation of src tyrosine kinases; in combination with the chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted); however, it weakens the RANTES-enhanced phosphorylation of Tyr416 . These effects of antithrombin correspond to a large extent with the well known syndecan-4 induced signalling pathways . It can be assumed that antithrombin is also able to exert specific anticoagulatory and anti-inflammatory effects in thrombocytes via analogous biochemical mechanisms because it is known that syndecan-4 is also expressed by thrombocytes and that antisyndecan-4 antibodies can influence thrombocyte aggregation .
Antithrombin inhibits chemotaxis [36, 37] and expression of TF and cytokines  in monocytes. In activated thrombocytes, antithrombin inhibits CD40 ligand expression, syndecan-4 shedding, and release of adenosine diphosphate and adenosine triphosphate, together with inhibition of thrombocyte-regulated release of free radicals from neutrophils . Because all of these mechanisms play a role in activating thrombocytes in DIC patients, it can be assumed that antithrombin deficiency also contributes to the development of DIC via such direct cellular mechanisms, under the stipulation that the in vitro observations of functional regulation of thrombocytes are confirmed in vivo. The same applies for the possible relevance of direct antithrombin effects on monocytes.
Antithrombin therapy in acquired disseminated intravascular coagulation in sepsis
Post hoc analyses of the effectiveness of antithrombin in severe sepsis without concomitant administration of heparin supported the hypothesis of the KyberSept study that prophylactic heparin interferes with the therapeutic effects of antithrombin [57, 61]. Because antithrombin therapy without concomitant treatment with heparin was effective in the KyberSept trial, it appeared reasonable to investigate the same cohort of patients to find out whether the effectiveness of such therapy was dependent on the presence of DIC. Such an investigation was reported by Kienast and coworkers . A total of 563 patients who did not receive heparin concomitantly with antithrombin were evaluated (n = 277 for placebo; n = 286 for antithrombin). At the beginning of therapy, 40.7% of the patients (229/563) had DIC. In the placebo group DIC signified enhanced mortality due to sepsis (28-day mortality: 40.0% versus 22.2%; P < 0.01).
DIC patients treated with antithrombin exhibited an absolute reduction (14.6%) in 28-day mortality in comparison with placebo-treated patients (P = 0.02); in contrast, no such effects were noted among patients without DIC (0.1% reduction in mortality; P = 1.0). These analyses in a randomized study population confirmed that antithrombin therapy can have a favourable influence not only on the morbidity associated with severe sepsis but also on mortality if, in addition to withholding concomitant administration of heparin, substitution therapy is given, particularly to those patients with acquired antithrombin deficiency in whom acute DIC has been diagnosed .
Experimental studies have shown that high doses of antithrombin (>500 UI/kg body weight) elicit anti-inflammatory effects and most experimental studies used a high-dose pretreatment protocol, which is of little clinical relevance [2, 10, 11, 13, 27]. However, supranormal levels have not been achieved in human trials because the highest dose regimens could only induce 200–250% antithrombin activity. It is therefore unknown whether anti-inflammatory effects of high-dose antithrombin indeed play a clinical role in humans.
Timing of antithrombin administration in experimental and clinical studies may be another critical determinant of efficacy. Most experimental studies used a high-dose pretreatment protocol, which is of little clinical relevance. On the other hand, very early suppression of inflammation may exert adverse effects on the initial response to injury. In experimental acute lung injury induced by inhalation of Gram-negative bacteria, simultaneous intravenous administration of recombinant human antithrombin caused histologic damage, injury to the alveolar capillary barrier and increased permeability in rodents . These effects of inhibition of thrombin activation by antithrombin led to the hypothesis that there is a beneficial role of early coagulation activation in acute lung injury, and that inhibition of initial procoagulation is potentially dangerous.
Furthermore, biologically, the effect of antithrombin may be modified directly by bacterial endotoxins because porins (nonspecific channels of the bacterial outer membrane that allow transmembrane passage of nutrient molecules that are usually small and hydrophilic) not only enhanced thrombin activity but also inhibited the enhanced antithrombin activity resulting from antithrombin administration . The mechanisms of such inhibitory interaction of porins with antithrombin remain to be detailed; however, antithrombin's heparin-binding site may well be among the potential targets because affinity of porins to heparin-binding domains of matrix proteins was recently reported .
Finally, antithrombin may interfere with the cytotoxic effects of lymphocytes via its serine protease-inhibitory (SERPIN) action on granzymes, which are death-inducing proteases stored in the granules of cytotoxic lymphocytes that allow the immune system to eliminate intracellular pathogens and transformed cells rapidly . In severe sepsis, elevation of granzyme plasma levels correlates with disease severity . Whether this SERPIN activity of antithrombin is beneficial or deleterious is unknown.
On one hand, antithrombin research conducted during the past two decades has attempted to establish the effectiveness and safety of antithrombin substitution in cases of severe sepsis in accordance with the criteria of evidence-based medicine. On the other hand, plausible mechanisms of action of this drug were investigated in preclinical research to assess its therapeutic use. KyberSept , the first large-scale study conducted within the context of intensive care medicine, investigated use of high-dose antithrombin in severe sepsis, but it was unable to establish its effectiveness because of the highly heterogeneous nature of the patient population and a lack of clearly defined standard therapy . Results of preclinical research carried out simultaneously, however, demonstrated partial interference of heparin – administered even at low doses – with the therapeutic effects of antithrombin. They also confirmed, at the level of cellular mechanisms, the important role of antithrombin in DIC. This knowledge provides a biological background against which re-analyses of the results of the KyberSept study appear to be justified; such analyses suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent [79, 80]. Even though several new aspects regarding the biological role of antithrombin and it pharmacodynamcis have recently been discovered, knowledge is still incomplete. Final assessment of the drug's effectiveness must await the availability of positive, prospective, randomized and placebo-controlled studies.
DIC = disseminated intravascular coagulation
HSPG = heparan sulfate proteoglycan
NF-κB = nuclear factor-κB
TAT = thrombin–antithrombin
TF = tissue factor
TNF = tumour necrosis factor.
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Spannagl M, Hoffmann H, Siebeck M, Weipert J, Schwarz HP, Schramm W: A purified antithrombin III-heparin complex as a potent inhibitor of thrombin in porcine endotoxin shock. Thromb Res 1991, 61: 1-10. 10.1016/0049-3848(91)90163-Q
Hoffmann J, Wiedermann CJ, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Warren BL, Opal SM: Benefit/risk profile of high-dose antithrombin III in the treatment of severe sepsis without concomitant heparin. Thromb Haemost 2006, in press.
Opal SM, Kessler CM, Roemisch J, Knaub S: Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002, (Suppl):S325-S331. 10.1097/00003246-200205001-00024
Corrigan JJ, Jordan CM: Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970, 283: 778-782.
Sleight P: Debate: subgroup analyses in clinical trials: fun to look at but don't believe them! Curr Control Trials Cardiovasc Med 2000, 1: 25-27. 10.1186/CVM-1-1-025
Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Keinecke HO, Warren BL, Opal SM, for the KyberSept investigators: High-dose antithrombin III in the treatment of severe sepsis with a high risk of death: efficacy and safety. Crit Care Med 2006, 34: 285-292. 10.1097/01.CCM.0000194731.08896.99
van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A: Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990, 76: 2520-2526.
van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, van Deventer SJ, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990, 322: 1622-1627.
Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, van Deventer SJ, Hack CE, ten Cate JW, Rosenberg RD: Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994, 93: 114-120.
Drake TA, Cheng J, Chang A, Taylor FB Jr: Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993, 142: 1458-1470.
Nawroth PP, Stern DM: Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986, 163: 740-745. 10.1084/jem.163.3.740
Osterud B, Flaegstad T: Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 1983, 49: 5-7.
Martinez MA, Pena JM, Fernandez A, Jimenez M, Juarez S, Madero R, Vazquez JJ: Time course and prognostic significance of hemostatic changes in sepsis: relation to tumor necrosis factor-alpha. Crit Care Med 1999, 27: 1303-1308. 10.1097/00003246-199907000-00017
Feistritzer C, Mosheimer BA, Tancevski I, Kaneider NC, Sturn DH, Patsch JR, Wiedermann CJ: Src tyrosine kinase-dependent migratory effects of antithrombin in leukocytes. Exp Cell Res 2005, 305: 214-220. 10.1016/j.yexcr.2005.01.001
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Kaneider NC, Feistritzer C, Gritti D, Mosheimer BA, Ricevuti G, Patsch JR, Wiedermann CJ: Expression and function of syndecan-4 in human platelets. Thromb Haemost 2005, 93: 1120-1127.
Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Briegel J, Strauss R, Warren BL, Opal SM: Treatment effects of high-dose antithrombin III without concomitant heparin in patients with severe sepsis with and without disseminated intravascular coagulation. J Thromb Haemost 2006, 4: 90-97. 10.1111/j.1538-7836.2005.01697.x
Kipnis E, Guery BP, Tournoys A, Leroy X, Robriquet L, Fialdes P, Neviere R, Fourrier F: Massive alveolar thrombin activation in Pseudomonas aeruginosa -induced acute lung injury. Shock 2004, 21: 444-451. 10.1097/00024382-200405000-00008
Di Micco B, Di Micco P, Lepretti M, Stiuso P, Donnarumma G, Iovene MR, Capasso R, Tufano MA: Hyperproduction of fibrin and inefficacy of antithrombin III and α2 macroglobulin in the presence of bacterial porins. Int J Exp Pathol 2005, 86: 241-245. 10.1111/j.0959-9673.2005.00430.x
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Zeerleder S, Hack CE, Caliezi C, van Mierlo G, Eerenberg-Belmer A, Wolbink A, Wuillenmin WA: Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction. Clin Immunol 2005, 116: 158-165. 10.1016/j.clim.2005.03.006
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CW has received fees for speaking and funding of a research grant at the Medical University of Innsbruck, Austria (PI-Wiedermann) from ZLB Behring.
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Wiedermann, C.J. Clinical review: Molecular mechanisms underlying the role of antithrombin in sepsis. Crit Care 10, 209 (2006). https://doi.org/10.1186/cc4822
- Severe Sepsis
- Disseminate Intravascular Coagulation

domain: literature


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Family Matters: How does mom stop her baby from hitting?
Dear Diana: I’m a mom of a 16-month-old, and want to know how to deal with hitting at this age. He gets easily frustrated, sometimes hits me, and often hits kids at day care. His frustration may stem from not being able to communicate, with a vocabulary of about nine words. When he hits, I take his arms and hold them down by his side and say, “No, we do not hit.” He seems to understand, because he will try to kiss me or the boys he has just hit at day care.
When he hits me at home, I tell him if he does it again he will go in his time-out bouncy seat, which contains him until he calms down.
Do you have suggestions? I certainly don’t want him to be a bully at day care. I have told our day care provider she can tell him “no” and also put him in a time-out seat.
Dear Mom: It is fairly typical for little ones to experiment with hitting, but always distressing for their parents. In most cases there are underlying causes for a very young child to continue to hit. It is helpful to find the cause, and implement a consistent, effective teaching response.
Your son may hit as a result of his frustration due to his inability to communicate, as you have suggested. Hitting also is a learned behavior when it is modeled by siblings, family members, or children in day care. We know that children who are over-tired have a higher incidence of meltdowns and hitting. Over-stimulation or sensory overload also can cause a child to loose control. Keep a log to note time of day and situation, which will help determine contributing factors.
Timeout versus teaching: A timeout is not the most effective teaching method for a child under 2 1/2 years old, because he is not capable of making the necessary connections. Clear language with a replacement behavior is important. Say, “You may not hit” not, “We don’t hit” while holding his hand. Move his hand to gently touch the area where he hit, saying, “Soft and gentle. Sorry Mommy.” As his expressive language is limited, say those words for him. His receptive language far exceeds his verbal ability.
Say it, and then walk away, while keeping him in sight. If he cries, turn around saying, “Soft and gentle,” taking his hand again and placing it over the spot where he hit. Then, pick him up and say, “All better!” This is a clear two-step process which he can understand.
Focus on “soft and gentle” all the time. While holding a stuffed animal, pet it, whispering, “Soft and gentle.” During baths, wash his back with down strokes, whispering, “Soft and gentle.” Do the same when washing or combing his hair.
Questions to consider: Does your son seem to escalate in large or loud environments, doing better one-on-one? Does he have a high tolerance for pain, or discomfort with specific clothing item such as socks, shoes, tags, seams, or jeans? Does he have food temperature or texture preference (hot/cold, mushy/crunchy)? Does he complain about water temperature? Hitting can be a sensory seeking behavior. Provide regular, daily sensory activities. Teach him to squish, punch and pull Play-Doh. Dance along with musical. Rock in a rocking chair or swing on a swing.
Practice “zoo time” by hopping like a bunny and galloping like a horse. Blow bubbles. Fingerpaint with peanut butter. Find more information on Sensory Processing Disorder in my book, “Parenting with a Purpose.” Many parents have found that their children become calm when their sensory needs are satisfied.
Remember the phrase, “remove to remediate.” Remove him without talking to a quiet place. Noise or an “audience” can ignite frustration, making it difficult for a child to self-regulate. Take a closer look to identify triggers or frustrations which are causing your son to hit. Then, teach him what you do want, which is to be soft and gentle.
Diana Boggia, M.Ed., is a parenting coach. She is author of “Parenting with a Purpose.” Send your child-rearing questions to email@example.com or The Repository, c/o Family Matters, 500 Market Ave. S, Canton OH 44702. Find parenting resources at her website, www.yourperfectchild.com.

domain: psychology


|Title:||Director of Rental Services|
|Job Type:||Exempt (salaried)|
|Salary Range:||$75,000 to 111,990.75|
|Application Deadline:||Open until Filled|
Director of Rental Services
The Director of Rental Services will work in a regular, full-time (40 hours per week) position and is responsible for management of the Rental Services department, including eligibility and occupancy services, and directs efforts to serve the homeless in rural Nevada. This position is responsible for maintaining program integrity through compliance with various federal, state and local regulations and agency policy requirements. This position assists with implementation of department goals, objectives, policies and procedures.
The individual fulfilling this role shall be an enthusiastic, motivated self-starter and have a professional demeanor with the ability to build a good working rapport with all staff. The Director of Rental Services shall be effective, detail-oriented, team-oriented with the ability to work independently. The individual shall provide leadership of the department, oversee the services provided, provide consultation and advice relative to rental and homeless service programs including HUD Housing Choice Voucher program and NRHA’s senior management. The Director of Rental Services shall also identify and outline employees’ duties and responsibilities, outline program changes, provide training and adjustments relative to the departments needs and to provide compliance with regulatory change.
Essential Duties and Responsibilities:
Performance of these functions is the reason the job exists. Assigned job tasks/duties are not limited to the essential duties and responsibilities:
- Manage the day-to-day services and activities of the Rental Assistance Department
- Manages and participates in the development and implementation of goals, objectives, policies, procedures and priorities for assigned programs; Recommends and administers policies and procedures
- Plans, directs, coordinates and reviews the work plan for the department; Assigns work activities, projects and programs
- Compiles various reports for Department of Housing and Urban Development and state and federal programs.
- Manages annual renewal of PHA Plan, agency administrative plan, Section Eight Management Assessment Profile (SEMAP), Fair Market Rent (FMR) payment standards, rent reasonable, utility allowances, landlord and housing partner meetings
- Manages departmental audits for various state and federal programs
- Oversees rental assistance applicant waiting list, including federal preference and service area guidelines
- Assures NRHA received the highest possible SEMAP score to achieve High Performer status with HUD
- Reviews and evaluates work products, methods and procedures; Meets with staff to identify and resolve problems
- Monitors and evaluates the efficiency and effectiveness of department’s method and procedures; Recommends appropriate service and staffing levels
- Selects professional, technical, and support staff and ensures effective morale and productivity and provides recognition as needed; Implements disciplinary action as needed
- Manages departmental quality control, including inspections and client files
- Plans, organizes, administers, reviews and evaluates the activities of staff directly and through subordinate supervisors
- Encourages and provides for staff training and professional development
- Oversees and participates in the development and administration of the division budget; directs for forecast of funds needed for staffing, equipment, materials, and supplies; monitors and approves expenditures; implements adjustments
- Prepares clear and concise administrative and financial reports
- Supervises and oversees NRHA’s Rental Services Manager in all areas regarding the duties and responsibilities of all Rental Services operations and monitoring, on an on-going and routine basis
- Develops and/or oversees all contracts for rental assistance-related work to be performed and shall ensure that any and all additional approvals required by NRHA are obtained
- Implement and maintain budget and schedule controls
- Manages and participates in Shelter Plus Care and Supported Living Assistance programs
- Participates in Continuum of Care meetings and activities
- Manages and participates in homeless services
- Report significant issues in a timely manner to the Executive Director
- Ability to maintain relationships, to include governmental contacts, real estate agents, banking contacts, grantee contacts and other stakeholders
- Ability to communicate one-on-one, as well as to large groups
- Coordinates technology improvement needs
- Follows all Policies and Procedures, completes tasks correctly and timely, supports the organization’s goals and values
- Uses good judgment to solve work-related problems
- Adapts to changing situations and environments
- Follows complex oral and written instruction, including technical manuals
- Works effectively in both a team environment and individually
- Reads, writes and interprets written information, uses proper English and grammar in written and oral communications and displays a friendly demeanor when working with internal and external clients; Communicates clearly and effectively when sharing information, providing training, assisting with issues, meeting with management and co-workers, in research for development, etc.
- Identifies and resolves problems in a timely manner, gathers and analyzes information skillfully
- Punctual and dependable, arriving to work on time, and on a consistent basis, ensure duties are covered when absent, and arrives at meetings and appointments on time
- Follows instructions, responds to management direction, takes responsibility for own actions, and completes tasks on time
- Demonstrates accuracy and thoroughness, looks for ways to improve and promote quality, applies feedback to improve performance, monitors own work to ensure quality, maintains accurate files and records, and is detail oriented with repetitive tasks
- Observes safety and security procedures, reports potentially unsafe conditions, and uses equipment and materials properly
- Any combination of training, education and experience that would provide understanding of the required essential duties and expectations. A typical way to gain the required knowledge is to possess a bachelor’s degree from an accredited college or university with a major in Business, or related field, and a minimum of five (5) years-experience managing a Housing Choice Voucher program with increasing responsibilities as well as four (4) years management/supervisory experience
- Industry Certifications and memberships a plus
- Ability to travel locally and out of town for one (1) or more days to attend training classes, workshops, seminars, workshops, etc.; Some travel may be outside of normal business hours
- Knowledge of Department of Housing and Urban Development (HUD) and United States Department of Agriculture (USDA) Rural Development rules and regulations
- Knowledge of State and Federal housing regulations, including Americans with Disabilities Act (ADA), Section 504 and Fair Housing
- Supervisory techniques including organizing work flow, assigning and reviewing work, training, evaluating performance and disciplinary procedures
- Management skills to analyze programs, policies and operational needs
- Knowledge of computer applications, including agency-specific database, email, word processing, financial management systems and presentation software (Yardi, Outlook, Word, Excel and Power Point)
- Principles and practices of program development and administration
- Knowledge of the functions and organization of municipal government
- Federal and state laws related to non-profit organizations
- Principles and practices of budget administration
The work environment characteristics described here are representative of those an employee encounters while performing the essential functions of this job. Reasonable accommodations may be made to enable individuals with disabilities to perform the essential functions.
The Director of Rental Services works primarily indoors with varied travel outside of the office. The office environment consists of shared or isolated working space, with a desk located in a generally clean, climate-controlled environment with limited exposure to conditions such as dust, fumes, noise or odors. Interruptions to planned work activities occur frequently. The noise level in the work environment is typically moderate. When travel is required, an agency vehicle may be provided for local destinations, otherwise the use of personal vehicle may be approved. Any out of town travel shall be arranged by the Director of Rental Services, as approved by the Executive Director and/or Board approval during budget review. May require work in confined spaces. May occasionally require an adjusted work schedule such as evening/weekend hours in order to meet deadlines related to program requirements.
Physical and Mental Demands:
The physical and mental requirements described here are representative of those that must be met by an employee to successfully perform the essential functions of the job.
Employee must have the ability to appropriately handle stress and interact with others, including supervisors, coworkers, clients, and customers. Regular and consistent punctuality and attendance are required. Employee must possess the strength, dexterity, coordination, and vision to use a computer keyboard and video display terminal for prolonged periods, to bend, stoop, sit, and stand for long periods of time, to handle files, office supplies and single pieces of paper, to occasionally lift files, stacks of paper, office equipment, small/medium-sized boxes and other materials, and to reach, bend, squat and stoop to access items above and below desk level, and load in and out of vehicles, and the manual dexterity and cognitive ability to operate a personal computer, as well as office equipment, and to communicate effectively via telephone and through email. Employee must be able to lift items, materials, supplies, equipment of up to twenty-five (25) pounds, with or without the assistance of a hand truck or cart. There may be occasions that require climbing stairs while carrying materials, supplies, equipment or other items. An in-office elevator is always available for use.
In compliance with applicable disability laws, reasonable accommodations may be provided for qualified individuals with a disability who require and request such accommodations. Incumbents and individuals who have been offered employment are encouraged to discuss potential accommodations with the employer.


A member of the ever-influential 90s legends Pavement, Christopher Scott's Spiral Stairs project is an eclectic mix of alt. rock. His latest album We Wanna Be Hyp-No-Tized is unsurprisingly hypnotising with its swirling guitar riffs and big hook-y choruses.
Presented by Eat Your Own Ears & Primary Talent.
This is an 18+ event.


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The La Mesa Historical Society is holding their 6th annual Historic Home Tour on Saturday, November 5, from 10-3 pm. Cost of the tour is $18.00 if tickets are purchased by October 29. They are $20.00 the day of the event. You can save some dinero if you become a member of the La Mesa Historical Society with the purchase of a ticket. The cost is reduced to $15.00 for members. Joining the historical society is inexpensive, only $10.00 for a single person and $15.00 for a family!
The tour this year features homes that are located in the lesser known areas of Grossmont and Mount Helix. These homes are located on c. 1913 roads and sites and it is recommended that you use The Old Town Trolley shuttle buses provided at the Women’s Club at 5220 Wilson Street to tour the homes. For more information download this flyer.

domain: history


Rectus Poland is one of the leaders in the pneumatics business.
It is an international company offering the products of such global brands as: Rectus, Talkob, Tema, Pneumax, Omal, ACL, M&M, Nycoil, Faster.
Rectus Poland’s strength resides in the state-of-the-art, high-quality products, continuously and robustly growing production of finished goods, and competitive prices. Pneumatic solutions find their applications in a number of industrial disciplines. Rectus Poland’s product offering covers a broad range of quick-fit connections, RQS pneumatic accessories, Nicoil polyamide and polyurethane (PA/PU) cables, ACL solenoid valves and M&M TURBO dedusting system components. Rectus Poland also offers industrial valves by Omal Automation and Dansk Ventil Centrer, as well as CEAP foot-operated gates, M&M angular valves, AKO pinch valves, Rifox steam separators and Purtorq blade pneumatic drives. To meet the expectations of its customers, Rectus Poland expanded its offering to add hydraulic products. It comprises connections with Conexa clamping ring, Pi.effe.ci pipe holders, Tema and Faster quick-fit connections. Relying on its long track record, the company offers premium instrumentation products, such as DK-LOK connections and valves, pipes, O-Bien racks and shields, Serto connections and valves, as well as Tescom reducers and valves.
We also encourage you to visit the manufacturer’s websites:


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Police in Centralia are investigating an attempted rape after a 16-year-old girl reported a man pulled her into his car and tried to pull off her pants.
The incident occurred near Fort Borst Park at about 6:45 p.m. Tuesday, according to police. The suspect was described as a white man in his 20s wearing a black hat and dark hooded sweatshirt.
The teen said she was walking at Pioneer Way and Mt. Vista Road when she was followed by the man in a late-1990s Nissan passenger car. The man confronted her, grabbed her and pulled her into his car, trying to pull her pants off her once she was in the car.
According to the teen, she was able to escape after she kicked the suspect. She then fled to her home a few blocks away.


Orange Business Services (OBS) and Sorin Group have joined forces to launch devices that allow healthcare professionals to monitor data from heart patients remotely.
The SMARTVIEW cardiac rhythm management (CRM) devices provide information and alerts with the support of Sorin's PARADYMTM RF technology even when a patient is at home.
It is thought that the CRM devices will offer improved diagnostic capabilities and allow for earlier detection of disease progression.
A help desk from OBS and the medical device firm will also be launched to help with the installation of the monitoring system. This is designed to remove the installation burden from healthcare professionals.
Thierry Zylberberg, executive vice-president at Orange and general director of Orange Healthcare, said: "In the expanding area of remote patient care, Orange Business Services has developed significant expertise in the development and deployment of e-health platforms that facilitate the remote monitoring and measurement of chronic illnesses."
He added: "We are extremely proud to have been able to work with Sorin and to apply our dual expertise as a solutions integrator and network operator to the development and launch of SMARTVIEW."


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Published at Tuesday, 12 December 2017. Islands. By Ancil Verdier.
Materials: Now that you‘ve decided to build a kitchen island, materials are something to consider. There are many materials available to build your island with such as: wood and stainless steel as well as a wide variety of countertop options like quartz or granite that will give your kitchen island an original design. Your materials should be selected to match the rest of your kitchen. A kitchen island should complement the space without overwhelming it or sticking out. Wood can give a kitchen a rustic, chic feel while natural stones like granite and quartz offer your new surface durability and timeless elegance. Stainless steel is a great surface to use for cooking and creating edible masterpieces and marble could be another alternative to a traditional design, depending on your budget.
Jagged coastline. This kitchen counter design offers you a variety of designs such as indefinable, crescent shaped, or wavy. If it suits your kitchen, budget, and taste, builds the kitchen counter that want. With a unique design, it will be the toast of internet.
Shape and Size: Since the kitchen cart also needs to be stored somewhere in the kitchen temporarily, you need to keep the space of your kitchen in mind while choosing the right Stainless Kitchen Island for yourself. There are numerous shapes and sizes of kitchen carts and islands available in the market including the custom sizing options, so that you can choose the perfect one for yourself.
Any content, trademark’s, or other material that might be found on the Goolor website that is not Goolor’s property remains the copyright of its respective owner/s. In no way does Goolor claim ownership or responsibility for such items, and you should seek legal consent for any use of such materials from its owner.
Copyright © 2018 Goolor. All Rights Reserved.

domain: design


text:
River Region Federal Credit Union of Lutcher, Louisiana has been a member-owned institution for more than 54 years. It is designated as a primarily chemical industry common bond.
Checking services include no cost share drafts, share certificates with low minimum balance requirements, bill pay services, overdraft protection and overdraft lines of credit. Debit cards, ATMs with no surcharges and prepaid debit cards are available.
Besides boat, RV, and car loans and other kinds of lending, River Region FCU can do real estate loans. Employees can help you with check cashing and low-cost wire transfers. River Region FCU members may also benefit from student scholarships.
Available electronic access includes Internet banking, automated telephone access and wireless phone apps. Remotely, you can take out a loan, look at your balance, order share drafts, pay your loan, view transactions, transfer money, pay bills and download your account history.
Special offer to credit union members. See your instant credit report.
Free credit report for Canada residents.
Monitor your credit and protect against identity theft! Who checked your credit report recently, and what did they see?
Also see our daily credit union news page.
Online newspapers and TV stations serving Lutcher and Louisiana: WWL - CBS, USA Today, or view a national listing of newspapers.
Thinking of buying a car? See Louisiana car dealers listed alphabetically by city.

domain: finance