George Wallace Jr., ‘Selma’ movie’s portrayal of my father is pure, unadulterated fiction

Tags

,

George-Wallace

Alabama Gov. George Wallace running for president in 1968

I (George Wallace, Jr.) realize more than anyone the legacy of my father and the feelings he engendered in so many for so long and how he still does today.

There was a time in his life when he supported segregation because as he said, “We were taught as children that a segregated society was best for both races, and anything other than that would bring about adverse relations between the races.” He believed that then, as did most southerners, and his acceptance of segregation was with no sense of ill feeling, malice, or hate toward black people.

His conscience eventually led him to believe that the South’s commonly held views on segregation were wrong, and he publicly renounced them. He even visited the Dexter Avenue Baptist church, where Martin Luther King once pastored, and asked the congregation for its forgiveness. I believe my father’s journey toward redemption helped lead the South and, indeed, much of the rest of the nation, along the path to reconciliation.

It is important to note that while support for segregation was part of his early life and career, he never advocated violence. He was defiant, charismatic, and energetic in his battle against what he saw as a threat from the central government to seek and control every aspect of our lives, but he was never violent.

The narrative pushed by his harshest critics that suggests he ordered the Alabama state troopers and Dallas County deputies to charge the marchers at the Edmund Pettus Bridge is simply untrue. That was the last thing he wanted. In fact, he ordered Col. Al Lingo and Dallas County Sheriff Jim Clark to protect the marchers if they crossed the bridge while he contacted President Johnson and requested federal help with their security throughout their 50 mile trek to Montgomery.

Unbeknownst to many people at the time, militant groups such as the Minute Men and others had vowed to have snipers in the wood line along Highway 80 to shoot the marchers. Not knowing if the the threats were true or not, my father’s desire was to protect the marchers, not attack them.

 photo GeorgeWallace_zpsc5bf57a4.jpg

His great effort to maintain peace at the University of Alabama before his Stand in the Schoolhouse Door is well documented by critics and supporters alike. He went on statewide television nightly and asked citizens to stay away from the campus while he raised Constitutional questions on their behalf. If he went to such great lengths to maintain peace at the University, why would he so drastically deviate in Selma?

Bob Ingram, a young reporter with the Montgomery Advertiser at the time, was in my father’s office when news of the violence at the Edmund Pettus Bridge was received. Ingram wrote that my father was enraged as he stormed around his office and said, “This is the last thing I wanted!” The fact is Lingo and Clark had lost their tempers, disobeyed his orders, and the rest is a painful and tragic part of our nation’s history.

I often think of my father’s many calls over the years to Congressman John Lewis, who had been beaten at the bridge, and how during those conversations he expressed sorrow at the violence that occurred at the foot of the bridge. Lewis has publicly acknowledged how deeply emotional my father became as he spoke of the incident.

SelmaThe movie “Selma” suggests that my father ordered troopers to beat participants in a nighttime civil rights march while television cameras were absent, which is pure, unadulterated fiction. Nor do I recall him ever making mention of a “mongrel” race that would result if segregation were ended. The truth and facts simply do not fit the image of my father that Oprah Winfrey and Brad Pitt wish to promote, so the producers needlessly changed history in order to tell what was an already compelling story in “Selma.”

There are those who will never find any redeeming qualities in my father, but he was a multi-faceted man who came to terms with much in his life. His forgiveness of the man who shot him and left him in such pain was a testament to his deep Christian faith. His later work both in office and in retirement to bring people of all races together in brotherhood and understanding is one of his greatest legacies, and one we could certainly emulate today.

For those who embrace the movie myth and refuse to believe the truth that he never advocated violence, I am reminded of lyrics from Don McLean’s “Vincent,” which say “They would not listen, they’re not listening still, perhaps they never will.”

George Wallace  Jr.George Wallace, Jr. is the son of two Alabama governors, George and his mother, Lurleen Wallace, and has previously held statewide office as state treasurer from 1987 to 1995 and as a member of the Public Service Commission from 1999 to 2007.

 

 

Controversy:

Film ‘Selma’ very real for Tallahassee eyewitness

The governor’s son, on the other hand, is not pleased with the portrait of his father, as played by Tim Roth, painted in “Selma.”

In an opinion piece written for http://www.al.com, George Wallace Jr. said of his father: “The narrative pushed by his harshest critics that suggests he ordered the Alabama state troopers and Dallas County deputies to charge the marchers at the Edmund Pettus Bridge is simply untrue.

“That was the last thing he wanted. … The fact is (Alabama High Patrolman) Col. Al Lingo and Clark had lost their tempers, disobeyed his orders, and the rest is a painful and tragic part of our nation’s history.”

Getting the Voting Rights Act passed was not only a societal matter for Range, but a family matter as well. Range’s father, Clifton Phillips Sr., fought in World War II, was wounded by the Japanese and returned to Selma with a Purple Heart medal.

“When he got home from serving his country, he couldn’t vote for the next president,” Range said, holding her father’s medal several days after the “Selma” screening. “He was not allowed in the voting booth.”

When asked if her father talked much about his military experience while fighting in the Pacific Theater, Range said, “No, but he had nightmares and would wake up screaming about ‘the trees.’ The Japanese were hiding in the trees. That’s the way the Japanese fought.”

Range also met King, as well as other civil-rights leaders such as Ralph Abernathy, Andrew Young and Jesse Jackson when they came to Selma for the marches.

“Dr. King took the time to meet all the children,” Range said. “I shook his hand. … At that time, you didn’t realize how famous they were. To a child, they were just people passing through your life.”

Though Range did not join the 8,000-strong march for the 52-mile walk on March 21, 1965, from her hometown to the Capitol in Montgomery, many of her classmates and her older brother did. She marched for about 15 miles before stopping, under direct orders from her father.

“I’m a daddy’s girl first and foremost,” Range said.

The Voting Rights Act was passed by Congress on Aug. 8, 1965, after American mainstream sympathies turned in favor of the marchers following televised images of children being beaten on Bloody Sunday.

“Bloody Sunday was the tipping point of the bottle,” Range said. “It changed everything.”

In 1967, Range graduated from R.B. Hudson High School, where she was a cheerleader and a member of the Future Teachers of America. Range attended Stillman College in Tuscaloosa, Ala., and graduated in 1971. She headed to North Florida the same year after marrying Nathan Lorenzo Hayes and moved to his hometown of Quincy. Hayes died in 1995 and she later re-married.

After teaching and coaching basketball at Havana Middle School for 35 years, Range also put in a stint at East Gadsden High before retiring. These days, she teaches reading at the PACE Center for Girls in Tallahassee.

Related:

George Wallace, Jr.: ‘Selma’ movie’s

Selma (2014) Movie

The Alabama Project: Nixon’s Assassination Team | lisa’s …

Distortions in ‘Selma’ make for richer discussions

George Wallace Jr. to Oprah: ‘Selma’ portrayal of my father …

Film ‘Selma’ very real for Tallahassee eyewitness

Activist says criticism of ‘Selma’ movie is misguided

 

 

California: New Survey Shows that Many Districts Are Not Evaluating Teachers by Student Scores

lisaleaks:

This is a big problem for “reformers,” constantly having to litigate against states and districts to force them to comply with invalid measures and policies that have negative consequences for students and teachers alike.

Originally posted on Diane Ravitch's blog:

The Los Angeles Times reports a new survey of 26 school districts showing that many of them are not complying with state law that requires them to evaluate teachers in part by student test scores. Apparently, the district leadership knows this is a flawed and invalid means of judging teacher quality.

Teresa Watanabe writes:

The review of 26 school districts serving more than 1.2 million students found that only Clovis Unified near Fresno and Sweetwater Union High School District in Chula Vista fully complied with the law. Two others, Upland Unified in the Inland Empire and San Ramon Valley Unified in Contra Costa County, were “blatantly in violation” of the law by expressly prohibiting the use of state standardized test scores in their teacher evaluations, the study said. The findings were disputed by both districts.

The other school systems surveyed — which included Long Beach, San Diego, Oakland and San…

View original 92 more words

Policing for Profit

Tags

, , , , ,

Civil Asset Forfeiture

Every year, federal and state law enforcement agents seize millions of dollars from civilians during traffic stops, simply by asserting that they believe the money is connected to some illegal activity and without ever pursuing criminal charges. Under federal law and the laws of most states, they are entitled to keep most (and sometimes all) of the money and property they seize.

Attorney General Eric Holder announced that, without evidence that a crime occurred, the Justice Department will end its practice of “adopting” Civil Asset Forfeiture cases brought to the department by state and local enforcement agencies.

In a move to check certain abuses inherent in the nation’s asset forfeiture law, Attorney General Eric Holder announced last Friday that the Justice Department would limit its practice of “adopting” state and local law-enforcement seizures of property for subsequent forfeiture to the government. Under the practice, to circumvent state laws that limit forfeitures or direct forfeited proceeds to the state’s general treasury, state or local officials who seize property suspected of being “involved” in crime ask the Justice Department to adopt the seizure, after which the proceeds, once forfeited pursuant to federal law, are then split between the two agencies, with 20 percent usually kept by Justice and 80 percent returned to the local police department that initiated the seizure.

If that sounds like “policing for profit,” that’s because it is! And the abuses engendered by this law’s perverse incentives are stunning. In Volusia County, Florida, police stop motorists going south on I-95 and seize amounts of cash in excess of $100 on suspicion that it’s money to buy drugs. New York City police make DUI arrests and then seize drivers’ cars. District of Columbia police seized a grandmother’s home after her grandson comes from next door and makes a call from the home to consummate a drug deal. Officials seized a home used for prostitution and the previous owner, who took back a second mortgage when he sold the home, loses the mortgage. In each case, the property is seized for forfeiture to the government not because the owner has been found guilty of a crime—charges are rarely even brought—but because it’s said to “facilitate” a crime. And if the owner does try to get his property back, the cost of litigation, to say nothing of the threat of a criminal prosecution, often puts an end to that.

assetSo bizarre is this area of our law—when lawyers first stumble on a forfeiture case they’re often heard to say “This can’t be right”—that a little background is necessary to understand how it ever came to be. American asset-forfeiture law has two branches. One, criminal asset forfeiture, is usually fairly straightforward, whether it concerns contraband, which as such may be seized and forfeited to the government, or ill-gotten gain, instrumentalities or statutorily determined forfeitures. Pursuant to a criminal prosecution, any proceeds or instrumentalities of the alleged crime are subject to seizure and, upon conviction, forfeiture to the government. Courts may have to weigh the scope of proceeds or instrumentalities. Or they may have to limit statutes that provide for excessive forfeitures. But forfeiture follows conviction, with the usual procedural safeguards of the criminal law.

Not so with civil asset forfeiture, where most of the abuses today occur. Here, law-enforcement officials often simply seize property for forfeiture on mere suspicion of a crime, leaving it to the owner to try to prove the property’s “innocence,” where that is allowed. Unlike in personam criminal actions, brought against the person, civil forfeiture actions, if they are even brought, are in rem, brought against “the thing,” on the theory that it “facilitated” a crime and thus is “guilty.”

Grounded in the “deodand” theories of the Middle Ages, when the “goring ox” was subject to forfeiture because it was “guilty,” this practice first arose in America in admiralty law. Thus, if a ship owner abroad and hence beyond the reach of an in personam action failed to pay duties on goods he shipped to America, officials seized the goods through in rem actions. But except for such uses, forfeiture was fairly rare until Prohibition. With the war on drugs, it again came to life, although officials today use forfeiture well beyond the drug war. And as revenue from forfeitures has increased, the practice has become a veritable addiction for federal, state and local officials across the country, despite periodic exposés in the media.

Thus, behind all of this is a perverse set of incentives, since the police themselves or other law-enforcement agencies usually keep the forfeited property—an arrangement rationalized as a cost-efficient way to fight crime. The incentives are thus skewed toward ever more forfeitures. Vast state and local seizures aside, Justice Department seizures alone went from $27 million in 1985 to $556 million in 1993 to nearly $4.2 billion in 2012. And since 2001, the federal government has seized $2.5 billion without either bringing a criminal action or issuing a warrant.

civil assetsThere will be some cases, of course, in which the use of civil asset forfeiture might be justified simply on the facts, as in the admiralty case just noted. Or perhaps a drug dealer, knowing his guilt, but knowing also that the state’s evidence is inconclusive, will agree to forfeit cash that police have seized, thereby to avoid prosecution and possible conviction. That outcome is simply a bow to the uncertainties of prosecution, as with any ordinary plea bargain. But the rationale for the forfeiture in such a case is not facilitation—it’s alleged ill-gotten-gain. By contrast, when police or prosecutors, for acquisitive reasons, use the same tactics with innocent owners who insist on their innocence—“Abandon your property or we’ll prosecute you,” at which point the costs and risks surrounding prosecution surface—it’s the facilitation doctrine they’re employing to justify putting the innocent owner to such a choice. In such cases, the doctrine is pernicious: it’s simply a ruse—a fiction—serving to coerce acquiescence.

Because it lends itself to such abuse, therefore, the facilitation doctrine should be unavailable to any law-enforcement agency once an owner challenges a seizure of his property. And once he does, the government should bear the burden of showing not that the property is guilty, but that the owner is and, therefore, his property may be subject to forfeiture if it constitutes ill-gotten-gain or was an instrumentality of the crime, narrowly construed (e.g., burglary tools, but not cars in DUI arrests or houses from which drug calls were made). In other words, once an owner challenges a seizure, criminal forfeiture procedures should be required. Indeed, “civil” asset forfeiture, arising from an allegation that there was a crime, is essentially an oxymoron in such cases. The government should prove the allegation, under the standard criminal law procedures, before any property is forfeited.

Short of such a fundamental reform, Holder’s move is welcomed, but it makes only a dent in the problem. As the Department’s press release said, “adoptions currently constitute a very small slice of the federal asset forfeiture program. Over the last six years, adoptions accounted for roughly three percent of the value of forfeitures in the Department of Justice Asset Forfeiture Program.” Moreover, the new policy does not apply to seizures resulting from joint federal-state task forces, joint investigations or coordination, or federal seizure warrants obtained from federal courts to take custody of assets originally seized under state law. And of course the reform does not limit the ability of state and local officials to seize assets under their state laws.

Regrettably, many if not most of the abuses today take place at the state level, yet changes in federal law, which often serves as a model for state law, can affect state law as well. In his recent statement, Holder said that “this is the first step in a comprehensive review that we have launched of the federal asset forfeiture program.” Members of Congress from both parties, already working on forfeiture reform, welcomed that news. Conceivably, then, this is one area in which the new Republican Congress can work with the administration to bring about further reforms. And in that, they would do well to study the course taken by the late Henry J. Hyde of Illinois, who paved the way for the Civil Asset Forfeiture Reform Act of 2000. That act made several procedural reforms, but it left in place the basic substantive problem—the “facilitation” doctrine. The abuses have thus continued, so much so that two former directors of the Justice Department’s civil asset forfeiture program recently wrote in the Washington Post that “the program began with good intentions but now, having failed in both purpose and execution, it should be abolished.”

Civil-Assets-seizedIf that is not possible, Congress should make fundamental changes in the program. In particular, if a crime is alleged, federal law-enforcement officials should have power to seize property for subsequent forfeiture under only four conditions: first, when the property is contraband; second, when in personam jurisdiction is not available, as in the admiralty example above; third, when, in the judgment of the officials, the evidence indicates that a successful prosecution is uncertain but there is a high probability that the property at issue is ill-gotten-gain from the alleged crime and the target does not object to the forfeiture, as in the drug-dealer example above; and fourth, when the property would be subject to forfeiture following a successful prosecution and there is a substantial risk that it will be moved beyond the government’s reach or otherwise dissipated prior to conviction—but such seizures or freezes should not preclude the availability of funds sufficient to enable the defendant to mount a proper legal defense against the charges, even though some or all of the assets may be dissipated for that purpose.

Those reforms would effectively eliminate the facilitation doctrine, except for a narrow reading of “instrumentalities,” and would largely replace civil forfeiture proceedings with criminal proceedings. Consistent with last Friday’s reform, however, Congress should put an end to the underlying incentive structure by requiring that forfeited assets be assigned to the federal treasury, rather than to the Justice Department, which should not be allowed, in effect, to “police for profit.” In 2013, the federal Asset Forfeiture Fund exceeded $2 billion, having more than doubled since 2008 and increased twenty-fold since it was created in 1986. Not coincidentally, the growth in civil asset forfeiture closely parallels the ability of law enforcement agencies to profit from their activities. In fact, a veritable cottage industry has arisen that instructs officers how to stretch their legal authority to the absolute limit and beyond. It’s a system that more resembles piracy than law enforcement.

At the least, if the reforms above are not made, Congress should require the government to show, if challenged, that the property subject to forfeiture had a significant and direct connection to the alleged underlying crime, not simply that it was somehow “involved” in the crime, as now. And the standard of proof should be raised from a mere preponderance of the evidence, again as now, to clear and convincing evidence. Similarly, a proportionality requirement should be imposed to ensure that the government does not seize property out of proportion to the offense. Congress should require officials to consider the seriousness of the offense, the hardship to the owner, the value of the property, and the extent of a nexus to criminal activity. If a son living in his parents’ home is convicted of selling $40 worth of heroin and officials try to take the home, as recently happened in Philadelphia, a proportionality requirement would ensure that prosecutors cannot take a home for a $40 crime.

IRSFinally, assuming that the facilitation doctrine is not eliminated, current law affords an innocent owner defense, but the burden is on the owner to prove his innocence by a preponderance of the evidence. Just as people enjoy the presumption of innocence in a criminal trial, property owners never convicted or even charged with a crime should not be presumed guilty in civil asset forfeiture proceedings. The burden of proof should be on the government to prove, by clear and convincing evidence, that the owner knew or reasonably should have known that the property facilitated a crime and he did nothing to mitigate the situation or that the property reflected the proceeds of a crime.

The Civil Asset Forfeiture Reform Act of 2000 has proven inadequate for curbing abuses, as countless Americans across the nation, having done nothing wrong, continue to lose their homes, businesses, and, sometimes, their very lives to the aggressive, acquisitive policing that this law encourages. There is broad agreement today that Congress should act quickly and decisively to fix a system that is badly in need of reform.

 

 

 

Related:

forfeiture legal definition of forfeiture

Forfeiture (law)

Nothing Civil About Asset Forfeiture

CIVIL ASSET FORFEITURE REFORM ACT OF 2000

Civil Asset Forfeiture | American Civil Liberties Union

Justice Department

U.S. Attorney General

Civil Forfeiture Laws And The Continued Assault On Private …

Guide to Equitable Sharing for State and Local Law …

Asset Forfeiture Policy Manual 2008 – US Department of …

On His Way Out, Holder Goes Big on Asset Forfeiture

F.E.A.R. Position Paper on forfeiture

 

 

Common Core OPT-OUT (Including opt-out form)

Tags

, ,

School_children_runningfromCommonCore01A rally sponsored by Citizens Against Common Core was held in Sacramento on the steps of the Capitol. What is Common Core? In a nutshell, it’s a new, top-down national educational program that California for students in grades K-12 to Higher Education.

The Common Core program to be administered in California is an educational plan orchestrated by representatives of the Council of Chief State School Officers, the National Governors Association, U.S. Chamber of Commerce Foundation – Bill & Melinda Foundation, and various members of the Obama administration and teachers’ union representatives.  Many parents object that Common Core will operate through computers that will collect private and personal information about students and their families. Teachers complain they are being forced to teach a program that has never been tested on public school students.  However, teachers have also been made aware that if they protest, they are in danger of losing their jobs.

Some objections focus on the literature portion of the Common Core program that reduces classic books from 80 percent of the school curriculum to only half.  Said Anthony Esolen, a professor of Renaissance English Literature at Providence College in Rhode Island:

“What appalls me most about the standards … is the cavalier contempt for great works of human art and thought, in literary form. It is a sheer ignorance of the life of the imagination. We are not programming machines. We are teaching children. We are not producing functionaries, factory-like. We are to be forming the minds and hearts of men and women.  Frankly, I do not wish to be governed by people whose minds and hearts have been stunted by a strictly utilitarian miseducation…. Do not train them to become apparatchiks in a vast political and economic system, but raise them to be human beings, honoring what is good and right, cherishing what is beautiful, and pledging themselves to their families, their communities, their churches, and their country.”

California experiments

ebonicsCalifornia has tinkered with many progressive education programs over the years, ranging from New Math to New New Math and Whole Language reading instead of phonics.  At one time, urban educators wanted to include the street-slang language Ebonics into the public-school classroom. There was also the infamous CLAS Test — the California Learning Assessment System that was kept secret from parents until it was introduced into the classroom and word leaked out that the program leaned more on opinion, not actual learning.

A controversial element of CLAS described a scene where students were to choose who would be offered a spot in a lifeboat after a passenger ship sunk.  With not enough room for every passenger to board the lifeboat, children were asked to choose who would board and who would not.  When it was learned the correct response was an older man should be cast off because he had already lived his life, parents objected, refused to permit their children to take the CLAS program and very quietly, CLAS exited the state.

Opposition

Parents now fear the national Common Core teaching program could return similar techniques to the classroom.  A protest movement has been launched across the country.  Many organizations are at work opposing Common Core, including TruthInAmericanEducation.comTwo Moms Against Common Core, Education Without Representation | lisa’s leaks and Hoosiers Against Common Core.

Former California school teacher Orlean Koehle taught speech, drama and journalism in the state’s classrooms for years.  After raising six children and returning to the classroom, she was shocked by the many reforms and changes.

That prompted her to write, “Common Core — A Trojan Horse for Education Reform.”   In it, she observes, “The federal government’s control over education can turn into something that has already been tried in other countries where our schools and universities are no longer centers for education, but now centers for propaganda and indoctrination.”

Yes, there ARE ways to stop Common Core!

Click Here to Download the Opt Out Form OptOutDownload

California Privacy Protection Opt-Out Form

Please take notice that pursuant to California Education Code §§ 51513, 60614, 60615 and 20 U.S.C. § 1232(h), my child is to be exempted and excused, for the current school year (see request date below), from the following activities:

1) Taking any and all statewide performance assessments, including but not by way of limitation to, academic, achievement and annual tests, and Common Core interim and formative assessments, administered pursuant to sections 60600, et seq. (Calif. Educ. §60615);

2) The administration of any test, questionnaire, survey, examination or evaluation containing any questions or items relative to my child, or my personal beliefs or practices in sex, family life, morality, or religion (Calif. Educ. §51513);

3) The administration of any test, examination, or assessment as part of a statewide pupil assessment program relative to my child, or my personal beliefs or practices in sex, family life, morality, or religion, or any question designed to evaluate personal behavioral characteristics, including, but not limited to, honesty, integrity, sociability, or self-esteem (Calif. Educ. §60614);

4) The administration of any survey, analysis or evaluation that reveals:

(1) political affiliations or beliefs of my child or me,

(2) mental or psychological problems of my child or his or her family,

(3) sexual behavior or attitudes,

(4) illegal, anti-social, self-incriminating, or demeaning behavior,

(5) critical appraisals of other individuals with whom respondents have close family relationships,

(6) legally recognized privileged or analogous relationships, such as those of lawyers, physicians, and ministers,

(7) religious practices, affiliations, or beliefs of my child or me, or

(8) income (other than that required by law to determine eligibility for participation in a program or for receiving financial assistance under such program.) (20 U.S. Code § 1232h)

Keep this signed, written notice on file in my child’s cumulative folder. This form supersedes all prior Opt-Out forms.
Child’s Name ________________________________ Grade Level ______ Date__________________
Parent/Guardian’s Name(s) _____________________________ ______________________________
Parent/Guardians(s) Address_____________________________________________________________
Parent/Guardian’s Signature(s) ____________________________ ______________________________
Daytime/Evening Phone Number(s) _________________________ ______________________________
School Name ________________________ School District _____________________________
Received by (Print Name) _____________________________________________________________
Date Received _______________________
http://www.PacificJustice.org

Instructions and Information on Using the California Privacy Protection Opt-Out Form

What to Do:
THE OPT OUT FORM MUST BE SUBMITTED EVERY YEAR
Applies to Public School K-12 Only
1) Make copies and share this California Privacy Protection Opt-Out Form with other parents.
2) Fill the form out to indicate that you do not allow your child to take any Common Core formative tests during the school year or a summative Common Core or other standardized test over any subjects at the end of the school year. Submitting this form for each student will help protect your child[ren]’s and family’s privacy.
3) Make two copies of the completed form. Then, sign and date each copy in ink.
4) Send the Opt Out form to the school Principal by Certified Mail Return Receipt Requested (the school’s signature serves as proof of receipt), or fax (with a fax transmittal sheet), or email, or other means which will show receipt by the school.
5) Keep one copy (with the proof of receipt) for your family and ask that the school keep a copy in your
child’s school records.
6) Make and give a copy to each of your child’s teachers. Keep a signed copy for yourself.
7) Ask to see your child’s records at least twice during the school year to monitor data being
collected and to verify that it is not being sent outside of the school district.
8) Educate your children to report to you attempts to collect personal information not related to
classwork.
9) Resubmit a copy of this Opt-Out form for each child when you enroll them for the next school year.
10) Follow steps 1 through 9 above at the beginning of each school year.
To download more copies of this California Privacy Protection Opt-Out Form at pji.org.

For more information about Common Core Standards, standardized testing, your parental rights and
data collection, please visit:
http://www.ConcernedParentsofCalifornia.com
http://www.ConcernedParentsofConejoValley.com

 

Resources:

California Privacy Opt Out Form – Pacific Justice

Institute

Instructions and Information on Using the California Privacy

Exercise parental rights: Opt out Daily Republic

California – Guide to Opting Out : Common Core Critics

Local Parent Groups – Concerned Parents of California

Californians United Against Common Core, California

20 U.S. Code § 1232h – Protection of pupil rights | LII / Legal

California: New Survey Shows that Many Districts Are Not …

CA Parents opposing national Common Core school

Concerned Parents of California

Concerned Parents of California Conejo Valley Unified …

Concerned Parents of California | Facebook

Orange County Voices : COMMENTARY ON EDUCATION ..

Common Core Curriculum and Agenda 21 | lisa’s leaks

Common Core has Sacrificed Special Education | lisa’s leaks

Education Without Representation | lisa’s leaks

Dismantling the School-to-Prison Pipeline | lisa’s leaks

Leaders, Laggards and the State of the Common Core

Tags

, , ,

 Leaders and LaggardsLead, Hunt, or Get Out of the Way?

New updated information about where each state is in, not only education reform, but Workforce training, 21st Century Teacher Force and more can be found at the U.S.Chamber Foundation’s website called Leaders & Laggards. (As a parent and teacher, I find the term “laggards” insulting to our kids. “Laggard” –  straggler, loiterer, lingerer, dawdler, sluggard, snail, idler, loafer; a person who makes slow progress and falls behind others).

uschamberpipeCommon Core’s famous for stating it can have our students ‘college ready’, now it claims ‘career ready’, too.

Since the Chamber is “so concerned” with a ‘talent pipeline’, here’s a resource you’ll definitely want to use in your state. It’s titled, Preparing Students for the World of Work: The Need for Career Readiness Data.” Wow, more need for our students data. Here’s how they are selling this angle, States have recognized the challenge and taken proactive measures to help students better prepare for their futures by adopting more rigorous college- and career-ready standards. Included in this mix are more than 40 states and the District of Columbia that have signed on to the Common Core State Standards, which “are designed to be robust and relevant to the real world, reflecting the knowledge and skills that our young people need for success in college and careers. Common Core provides the baseline for all students to be ready for careers or college, leading to their eventual participation in the workforce.”

Did you know that’s there has been a movement in recent years to have our states create legislation to ensure Common Core via Career Tech Education?! Yes, I found the evidence on the website for “Career Tech Education (CTE) Policy Watch.” (see: http://ctepolicywatch.typepad.com/ )

What you need to know:

From the 2013 document, “State Policies Impacting CTE, 2013″, the following excerpt, 2013 was a major year for career and technical education (CTE)! All but three states had legislative or regulatory action in the 2013 calendar year that impacted one or more elements of CTE. This level of engagement by state legislatures, state boards of education, governors’ offices and state agencies can be attributed to the growing awareness that CTE is key to engaging learners at all levels, closing the skills gap and bolstering America’s competitiveness advantage.”

Below is an image from the 2013 report highlighting the states’ action regarding embedding Common Core via CTE (Career Technical Education).

CTEWhy This Matters:

Many folks are under the impression, Common Core ends at 12th grade. But, I’ve repeatedly shown documents, facts, and research (as have others) that have proven post-secondary schools have been aligned ON PURPOSE with Common Core. This report details how each of the United States has greased the wheels legislatively to embed Common Core via Career Tech Ed. I urge you to look at any of the “Tech Thursday” posts to see the in-depth ties of CCSS (Common Core State Standards) to post-secondary CTE (Career Tech Education).

As an example, here’s what the state of residence in NC had accomplished up to 2013 in Common Core post-secondary moves legislatively.
“North Carolina  took some financial burden off of students who are seeking industry certifications and credentials. Under Senate Bill 402, students enrolled in public schools and in CTE courses are exempt from paying fees for one administration of an exam that leads to an industry certification or a credential. Also under this bill, schools will now receive one point per student (toward the School Achievement Score) enrolled in CTE coursework who earns a Silver, Gold or Platinum level on a national work readiness assessment, although this still needs to be reviewed by the General Assembly in collaboration with the Department of Public Instruction and is subject to change. The North Carolina State Board of Education approved a set of endorsements for their high school graduation requirements, first mandated under legislation that passed in early 2013. Specifically, students can earn the Career Endorsement, one of two College Endorsements and/or the Academic Scholars Endorsement. 

All four endorsements require students to complete the Future-Ready Core requirements in math (which are aligned to the Common Core State Standards) and earn at least a 2.6 GPA (which guarantees graduates’ placement into credit bearing courses at the state’s community colleges). Students earning a Career Endorsement must complete a CTE concentration, earn an industry-recognized credential and take a fourth year of math aligned to their post-high school plans. Students earning the first College Endorsement option must take a fourth year of math aligned to their post-high 12 school plans.”  You’ll need to see what your state did, ACTE-ASDCTEc_State_Policy_Review_2013

Click on the map below to see where your state ranks.

Leaders & Laggards: A State-by-State Report Card

report cardCA

CA repot cardCalifornia: Academic Achievement

Despite improvement since our last report, student performance in California is very weak. Fourth graders stand 9 percentage points below the national average in the percentage at or above the proficient level on the NAEP math exam. The national average is 42%.

Academic Achievement for Low-Income and Minority Students

California earns a failing grade on academic achievement for low-income and minority students. Only 13% of African-American 4th graders score at or above the proficient level on the NAEP reading exam.

Return on Investment

Student achievement in California is above average relative to state spending after controlling for cost of living.

Truth in Advertising: Student Proficiency

California posts mediocre marks on the credibility of its student proficiency scores. The grade is based on the difference between the percentage of students identified as proficient in reading and math on the 2011 state exams and the percentage identified as proficient on the 2011 NAEP reading and math tests.

Postsecondary and Workforce Readiness

California earns a high grade preparing its students for college and careers, with 27% of students passing an AP exam.

21st Century Teacher Force

California does a weak job of creating a strong teacher workforce. The Golden State does not effectively identify excellent teachers or remove ineffective ones.

Parental Options

California does a good job providing parents with strong school choice options. The state has a fairly strong charter school law, and information on school report cards and charter options is easy for parents to find.

Data Quality

California did not receive a grade for this metric because the state did not participate in the Data Quality Campaign study.

Technology

California receives a very poor grade employing technology to provide quality instruction and personalized learning. Its funding policies do not incentivize more digital options, and state infrastructure is not sufficient to support digital learning.

International Competitiveness

California earns a below average grade preparing its students to compete in a global economy, with only 23% of students proficient in reading and math compared with an international standard.

Fiscal Responsibility

California receives below average marks on fiscal responsibility. Only 77% of the state’s pension is funded, and its most recent pension contribution was 72%.

Download PDF

Lets see how the other states fared:

state report cardsstate report card1state report card2state reort card3state report card4state report card5

***

Here’s a short video from the Institute for a Competitive Workforce, titled Talent Pipeline Management.”

The above is a cutesy video to address the ‘skills gap.’ Somehow, Common Core aligned workers will solve this “dilemma.”

Related:

U.S. Chamber of Commerce President Calls for Cooperation in 2015

US Chamber of Commerce – Bill & Melinda Gates Foundation

State Chambers of Commerce Defend Common Core …

States and the (not so) new standards — where are they now?

The State of American Business 2014, Remarks by Thomas J.

Thomas J. Donohue | U.S. Chamber of Commerce Foundation

Dropout Nation » Jindal’s Anti-Common Core Fantasy

Leaders & Laggards – US Chamber of Commerce Foundation

Chamber of Commerce Spent Over $50 Million

Report Card | Leaders & Laggards: A State-by-State Report …

Common Core State Standards – National Center for …

Year 3 of Implementing the Common Core State Standards …

Business for Core | Common Core State Standards

Letter Regarding Chairman Paul Ryan’s FY 2015 Budget …

2015 Education Budget Proposal Dreams (and Spends) Big …

US Chamber of Commerce Threatens GOP

Aligned and Employed?! | commoncorediva

commoncorediva

Align4NCWorks | NC Community Colleges

California | Leaders & Laggards: A State-by-State Report …

CalChamber Reports – California Chamber of Commerce

Inside the Mammoth Backlash to Common Core

Rally for Excellent Education (NOT Common Core) Tomorrow

Why Does the U.S. Chamber of Commerce Love Common …

Chamber of Commerce Common Core

Common Core State Standards – Resources (CA Dept of …

Duncan Urges US Chamber of Commerce to Defend …

U.S. Chamber Foundation Releases Common Core Video …

Keep In Mind – The Establishment Political Class of The …

EXECUTIVE PROFILE: Elanna Yalow | U.S. Chamber of …

The Educational System May Not Only Miss Your Child’s …

Le Secret: Manna Machine

Tags

, ,

MannaThe basis of the Manna story should be known to almost everyone in the western world. The flight of the people of Israel out of Egypt and into the desert. The bible tells us, that the people of Israel hen wandered around in the desert for forty years, through the Sinai desert, one of the most arid regions of the earth. There is no natural water and nothing to eat, and after 15 days the Israelites had run out of food. They already saw their end in starvation, but then…

“13: In the evening quails came up and covered the camp; and in the morning dew lay round about the camp.
14: And when the dew had gone up, there was on the face of the wilderness a fine, flake-like thing, fine as hoarfrost on the ground.
15: When the people of Israel saw it, they said to one another, “What is it?” For they did not know what it was. And Moses said to them, “It is the bread which the LORD has given you to eat.
16: This is what the LORD has commanded: `Gather of it, every man of you, as much as he can eat; you shall take an omer apiece, according to the number of the persons whom each of you has in his tent.'”
17: And the people of Israel did so; they gathered, some more, some less.
18: But when they measured it with an omer, he that gathered much had nothing over, and he that gathered little had no lack; each gathered according to what he could eat.
19: And Moses said to them, “Let no man leave any of it till the morning.”
20: But they did not listen to Moses; some left part of it till the morning, and it bred worms and became foul; and Moses was angry with them.
21: Morning by morning they gathered it, each as much as he could eat; but when the sun grew hot, it melted.
22: On the sixth day they gathered twice as much bread, two omers apiece; and when all the leaders of the congregation came and told Moses,
23: he said to them, “This is what the LORD has commanded: `Tomorrow is a day of solemn rest, a holy sabbath to the LORD; bake what you will bake and boil what you will boil, and all that is left over lay by to be kept till the morning.'”
24: So they laid it by till the morning, as Moses bade them; and it did not become foul, and there were no worms in it.
25: Moses said, “Eat it today, for today is a sabbath to the LORD; today you will not find it in the field.

31: Now the house of Israel called its name manna; it was like coriander seed, white, and the taste of it was like wafers made with honey.

35: And the people of Israel ate the manna forty years, till they came to a habitable land; they ate the manna, till they came to the border of the land of Canaan.”
2. Mose 16

The mysterious substance “Manna” is still a riddle today. For hundreds of years experts have argued about its nature, but no satisfying explanation could be found. Modern interpretations say that Manna was a secretion of a scale insect living on the few acacias found on the Sinai. Some of the properties of this secretion would fit the description of the bible:

  • The secretion contains sugar and is white
  • It forms small grains and covers trees and bushes like white frost
  • Because of the sugar content it melts in the hot sun
  • It tastes a bit like honey

Contrasting points:

  • No one would call grains of sugary secretion “bread”
  • The Israelite were not a few nomads, they were “600.000 men at foot without the children”(2. Mose 12 v. 37). To get them fed from scale insect secretion the whole Sinai desert had to be covered by them. And where do these insects got their food from?

The Manna Machine

The English Authors Sassoon and Dale published a thesis in which they claim that manna was industrial produced food, produced by the tribe of Israel itself without knowing it. A secret machine, the so-called manna machine, also known as “Holy Grail,” produced algae which were then in several steps converted and baked to waffles.

The description in the “New Scientist”

Schema Manna-Maschine “At the top is a dew-still: a refrigerated, corrugated surface over which air is drawn, from which water condenses. This is fed to a container in the center of which is a powerful light-source for irradiating a culture, possibly of Chlorella-type algae. There are dozens of strains of Chlorella, and the balance of protein, carbohydrate, and fat in a chosen strain can be varied by choosing the appropriate conditions of growth for the culture.
This algal culture circulates through pipes which permit an exchange of oxygen and carbon dioxide with the atmosphere, and also dissipate heat. The Chlorella sludge is drawn off into another vessel where it is treated so that the starch is partially hydrolyzed to maltose, which is then burnt slightly to give the honey-and-wafers flavor….The dried material is then fed to two vessels. One is emptied daily to provide the day’s supply, and the other fills slowly during the week so that two days’ supply is available on the eve of the Sabbath….” George Sassoon and Rodney Dale, New Scientist, 1. April 1976

Manna Exodus

Exodus tells how manna rained down from heaven with the dew for 40 years, to feed the house of Israel in the desert.

According the Tanakh (The Torah), manna ”was like coriander seed, white and it tasted like wafers in honey . . . a fine and flaky substance, as fine as frost on the ground”.

The Israelites gathered it every morning, but if they tried to stockpile supplies it quickly rotted or became maggoty. Only the food collected on a Friday morning could be stored, so that no one had to break the Sabbath by hunting for food.

Rabbis have always regarded manna as a miraculous food. Two English engineers, George Sassoon & Rodney Dale, concluded a nuclear energy source would be required, a miniature power station. With enough heat, the algae would breed endlessly and generate enough sludge to be dried and distributed to all the tribe.

Because the mechanism was delicate, it was transported inside the Ark of the Covenant – hence the story that the Ark was actually God’s dwelling place. To the Israelites, a nuclear engine which produced free food must have been the image of God himself. But how did Moses acquire an atomic plant? And what became of it?

The answer, believe German brothers Johannes and Peter Fiebag lies in the medieval epic Parsifal. There are many versions, they explain in their book Die Ewigkeits-Maschine. Das Manna-Wunder, which has been published in English (translated by George Sassoon) as THE HOLY GRAIL – WHAT IS IT?

Parsifal has been retold many times, most famously by the French poets Chrétien de Troyes and Robert de Boron, and by the German story-tellerWolfram von Eschenbach.

MunsalvaescheThe hero is a knight who wanders across Europe, meets King Arthur, is led to the castle of Munsalvaesche by the ‘hand of God’, and heals a king there.
His journey is a quest for the Holy Grail, which Christian legend claims was a silver bowl which caught the blood of Jesus as he hung on the cross.
The Fiebags have a very different interpretation. They believe the Grail was the Othiq Yomin, the Ancient of Days.

Othiq YominWhile the textual description of the machine is extremely detailed, it is not immediately apparent that it is a technical service manual because the parts of the Othiq Yomin (originally translated as Ancient of Days, when the Transportable One of the Tanks would be more accurate) are designated with the terminology in use about 1000 B.C. For example, in the Zohar we read passages such as the following:

There are three upper heads; two, and one which contains them

And this is how von Eschenbach describes the Grail: ”A hundred squires were summoned, who respectfully took bread on white linen from the Grail . . . It came forth from the Grail, whenever one of them put out his hand to it . . . for the Grail was the fruit of the blessed ones, such a fullness of earthly sweetness, that it was like almost everything that might come from the Kingdom of Heaven.”

Can there have been two devices which, in different eras, magically produced sweet bread from the air? For our ancestors to have invented this machine once is beyond our comprehension – for it to have been built twice defies belief.
The brothers contend, of course, that our ancestors did not build it. It was given to them, just as the Israelites knew the Ancient of Days had been given to them by God. Von Eschenbach confirms it: ”Once upon a time it (the Grail) brought a troop, which flew back to the high stars, because their innocence drew them homewards.”

 

 

 

 

Related:

Manna Machine

The Ark of the Covenant and the Manna Machine

The Eternal Device – Mystical World Wide Web

Did Moses really invent the first nuclear engine?

Moses had nuclear powered machine!

Unearthly Disclosure: Timothy Good, The Lord Hill-Norton …

Cathar Slide Show: From ancient times to 1206

Images for The MANNA Machine

The manna machine / George Sassoon & RodneyDale …

The Eternal Device – Mystical World Wide Web

UFO AND RELATED PHENOMENA DIVULGATION LIST .

Peter Fiebag – Mysteria3000

Johannes Fiebag – Mysteria3000

Kaballah Decoded: Rodney Dale, George Sassoon

The Eternal Device – Mystical World Wide Web

Thomas Paine’s “Age of Reason” – Shaggybevo

On God and aliens – LabLit.com

On John Adams: “This Awful Blasphemy,” Extraterrestrials …

Alien Ideas | Center for Science and Culture

Bible and Technology

Anmerkungen:
[1] Johannes und Peter Fiebag; Die Ewigkeitsmaschine, Langen Müller 1998, p. 119
[2] ibid. p. 119
[3] May 2000: here (linked on the homepage of Peter Peter Fiebag -> PaleoSETI -> “Holy Grail – Chalice or Manna-Machine?”. A similar formulation can be found in the Ewigkeitsmaschine on p. 169

Ancient Aliens, Ancient Ufo and Alien Drawings

Tags

, ,

 

These drawings of ancient aliens are famous, and many of them are featured in museums and are also available to the general public through cave viewings. The depictions of aliens and UFOs are obvious, thinking that these pictures and artwork represent other things is possible.

One defining factor in many of these pictures is the Halo around the head of the alien. In my opinion and many others this means that they are Angelic, like Angels, meaning from Heaven, (heaven-the sky-or the heavens).

ufo-raysufo-rays-2

The above painting is by Carlo Crivelli (1430-1495) and is called “The Annunciation” (1486) and hangs in the National Gallery, London. A disk shaped object is shining a pencil beam of light down onto the crown of Mary’s head. A Blow up of the object is next to the painting.

moses-ufos.jpg (22158 bytes)

The above is a painting on wood drawer from furniture kept at the Earls D’Oltremond, Belgium. Moses is receiving the tablets and several objects in the sky are seen near by. Date and artist unknown. This supports the claims of many that many biblical events, can be further explained when ufos and aliens are taken into consideration, higher forms of technology could explain some of the events such as writing on stone with fire, parting the red sea, etc… higher forms of technology might explain how some of these feats were performed.

jesus-mary-ufo.jpg (14977 bytes)

The above picture depicts Jesus and Mary on what appear to be lenticular clouds. The painting is entitled “The Miracle of the Snow” and was painted by Masolino Da Panicale (1383-1440) and hangs at the church of Santa Maria Maggiore, Florence, Italy.

madonna-ufo.jpg (10078 bytes)

madonna-big.jpg (50179 bytes)

This painting is called “The Madonna with Saint Giovannino”. It was painted in the 15th century. The Palazzo Vecchio lists the artist as unknown although attributed to the Lippi school.Above Mary’s right shoulder is a disk shaped object. Below is a blow up of this section and a man and his dog can clearly be seen looking up at the object.

ufo-sighting-arabia.jpg (5376 bytes)

The above picture is from a book entitled Prodigiorum Ac Ostentorum Chronicon by Conrad Lycosthenes (1518-1561). Basel: Henricpteri, 1557. It depicts a UFO sighting in Arabia in 1479. The book is held at the Australian Museum Research Library.

ufo-fleet.jpg (81820 bytes)

The above image is entitled “The Assumption of the Virgin” by ANON. Painted c.1490. Once again notice the discoidal clouds.

jesus-rocket.jpg (26151 bytes)

This is a 15th century fresco from Kiev. Seems to show Jesus in a rocket type device.

aliens-in-ship.jpg (25750 bytes)

1660. The illustration depicts a sighting by two Dutch ships in the North Sea of an object moving slowly in the sky. It appeared to be made by two disks of different size. The source for this account is one of the books entitled :”Theatrum Orbis Terrarum” by Admiral Blaeu. These books were compilations of articles by different authors and consisted of detailed accounts of long engagements at sea, cartography information etc.

tapestry-ufos.jpg (54728 bytes)

This is a tapestry called Summer’s triumph and was created in Bruges in 1538. It now resides at the Bayerisches National Museum. You can clearly see several disc shaped objects in the top of the tapestry. Someone has speculated that they are islands, if so, then these islands are floating in the sky!

ancient aliens The Dropa Stones
The story of the Dropa for us begins in the same place, but the year is 1938. The mountains are the Baian-Kara-Ula mountains on the border that divides China and Tibet. An archaeological expedition, led by Chi Pu Tei, has trudged into the barely accessible mountain range, and has happened upon some caves that had obviously been occupied by a primitive people long ago.On the walls were carved pictograms of the heavens: the sun, the moon, the stars, and the Earth with lines of dots connecting them. Then the team made the most incredible discovery of all. Half-buried in the dirt floor of the cave was an odd stone disk, obviously fashioned by the hand of an intelligent creature. The disk was approximately nine inches in diameter and three-quarters of an inch thick. In the exact center was a perfectly round, 3/4″ hole, and etched in its face was a fine groove spiraling out from the center to the rim, making the disk look for all the world like some kind of primitive phonograph record.This one plate, dated to be between 10,000 and 12,000 years old , but the wonder was multiplied manifold. In all, 716 such plates were found. And each held an incredible secret. The groove, upon further inspection, was not a groove at all, but a continuous line of strange carved hieroglyphics – writing!

ancient aliens Dr. Tsum Um Nui , in 1962, painstakingly transcribed the characters from the disk to paper. The writing was so small he had to use a magnifying glass to see it clearly. But the stones were old – perhaps 12,000 years old, it was estimated – and much of the hieroglyphics were difficult to make out or had been worn away by time and the elements. As he worked, many questions nagged the professor. How did these primitive people fashion these precise stones? How did they manage the almost microscopic writing? Who were they and what was the purpose of these hundreds of stones? Once the characters were transcribed, Dr. Tsum Um Nui began the arduous task of trying to decode its message. Eventually, he began to make progress. A word emerged. Then another. A phrase became understandable, then an entire sentence. He had broken the code. He discerned that the messages on the stones were written by a people who called themselves the Dropa. But what they were saying to him 12,000 years later made no sense. What the Dropa had written must have been one of their cultural myths, or was part of some prehistoric religious ceremony.

Or was it? When he had completed the translation the professor wrote up a paper on his findings and presented it to the university for publication. Their reaction was swift and emphatic: the paper would not be published. The Academy of Prehistory expressly forbade him to publish or even speak of his findings. The world, the academy decided, should not know about the Dropa and their fateful journey to Earth.The Dropa disks tell the story of a space probe from a distant planet that crash-landed in the Baian-Kara-Ula mountains of the Himalayas. The occupants of the spacecraft – the Dropa – found refuge in the caves of the mountains.The stones go on to say how the Dropa were unable to repair their disabled spacecraft and could not return to their home planet, and so were stranded on Earth. If that’s true, have their descendents survived?

ancient aliens The Dogons
The Dogons are a people well known by their cosmogony, their esotericism, their myths and legends that interest foreigners at the highest point in search for culture or tourism.
The population is assessed to be about 300,000 people living in the South West of the Niger loop in the region of Mopti in Mali (Bandiagara, Koro, Banka), near Douentza and part of the North of Burkina (North west of Ouahigouya).
The Dogon’s (Mali, Africa) homeland has been designated a World Heritage site for its cultural and natural significance. They are also famous for their artistic abilities and vast knowledge about astrology, especially the Sirius star, which is the center of their religious teachings. The Dogons know that Sirius A, the brightest system in our firmament, is next to a small white dwarf called Sirius B, which was not identified by western scientists until 1978. The Dogons knew about it at least 1000 years ago. Sirius B has formed the basis of the holiest Dogon beliefs since antiquity.
Western astronomers did not discover the star until the middle of the nineteenth century, and it wasn’t even photographed until 1970.

The Dogons go as far as describing a third star in the Sirius system, called “Emme Ya” that, to date, has not been identified by astronomers. In addition to their knowledge of Sirius B, the Dogon mythology includes Saturn’s rings and Jupiter’s four major moons. They have four calendars, for the Sun, Moon, Sirius, and Venus, and have long known that planets orbit the sun.

How this Dogon’s Enigmatic Scientific Knowledge about Astronomy came from?
According to their oral traditions, a race people from the Sirius system called the Nommos visited Earth thousands of years ago. The Nommos were ugly, amphibious beings that resembled mermen and mermaids. They also appear in Babylonian, Accadian, and Sumerian myths. The Egyptian Goddess Isis, who is sometimes depicted as a mermaid, is also linked with the star Sirius. The Nommos, according to the Dogon legend, lived on a planet that orbits another star in the Sirius system. They landed on Earth in an “ark” that made a spinning decent to the ground with great noise and wind. It was the Nommos that gave the Dogon the knowledge about Sirius B !
(Picture: The original Dogon couple.This is one of the greatest symbols of the Dogon civilization. Sculpting represents spouses)

ufo_glyph.jpg (7126 bytes) ufo_glyph2.jpg (7404 bytes)

These ufo petroglyphs were created thousands of years ago by ancient Indians in the American Southwest. According to Indian folklore, two objects collided high in the sky and one crash-landed in the region of Death Valley. Some men arrived (presumably in another ship) and spent some time repairing the damaged Craft and were observed by the local Indians. The two images below may possibly depict the ship (left) used by the men who came to repair the damaged craft. In comparing the two images, the one on the right seems to depict structural damage around the edges and the bottom. Could it be the one that allegedly crashed? The images are stills taken from an old TV series entitled “In search of…” hosted by Leonard Nimoy.

ufos

This is an artistic reproduction of a relief found in a labyrinth on the island Jotuo in the Toengt’ing lake. An expedition took place in 1957 (two years before an earthquake in that region). The expedition was led by professor Tsj’i Pen-Lai. They found various reliefs showing “humans” in strange clothes which looked like astronaut suits (hose like objects attached to the clothes). They also found a painting which apparently resembled the solar system. The third and fourth circle (planet) were connected with a line. Also there were ten planets (excluding the sun as planet). This connects easily to the theories about Nibiru, planet X, etc.

ufos-flying.jpg (4966 bytes)

These are two cave paintings from Tanzania. Both are estimated to be up to 29,000 years old. The one on the left is located in Itolo and depicts several disc shaped objects. The other painting is from Kolo shows four entities surrounding a women. Notice also the entity looking down from inside some sort of box or object.

alien artwork

ancient ufo drawings alien-lifeform.jpg (9696 bytes)

This two images are from France, the cave of “Pech Merle” near “Le Cabrerets” c.17,000 – 15,000 BC. The scene depicts a landscape full of wildlife together with a number of saucer shaped objects. The objects seem totally out of context.

peru-glyphs.jpg (23543 bytes) peru-drawing.jpg (13545 bytes)

These two examples of rock art are from Toro Muerto,Peru 12-14,000 years old. Notice the beings have some sort of halo or covering over their heads (compare with the Val Camonica photo below). Also, in the right hand picture there is some sort of object left of the main being. Possibly a UFO ?

ancient aliens

This cave painting is c.10,000 BC and is from Val Camonica, Italy. It appears to depict two beings in protective suits holding strange implements.

big-alien-head.jpg (18335 bytes) weird-alien.jpg (11984 bytes)

Two images c.6000 BC from Tassili, Sahara Desert, North Africa. They do not look human do they ? Also notice the disk in the sky in left hand picture.

ancient aliens

This strange suited figure was found in Kiev and I believe its dated to 4,000 BC.

japan-ufos.jpg (9558 bytes)

This is a 7000 year petroglyph discovered in the province of Querato, Mexico in 1966. You can see 4 figures with their arms outstretched below a large oval object radiating what appear to be beams of light.

strange-aliens.jpg (13924 bytes)

More strange looking figures (aliens) this time from Sego Canyon , Utah. Estimated up to 5,500 BC.

halo-alien.jpg (4761 bytes)halo-grey-alien.jpg (5519 bytes)halotypealiens.jpg (6269 bytes)

These are illustrations from a book by Lt. Grey. “Journals of Two Expeditions of Discovery in North-West and Western Australia 1837, 1838, & 1839″. He led an expedition in the 19th century to some caves near the Glenelg River region of Kimberley, Northern Australia where he came across a series of cave paintings. The beings are called the Wandjina by the Aboriginies who painted them.

wandjina.jpg (83365 bytes)doublealien.jpg (14157 bytes)

many-aliens.jpg (17642 bytes)

More examples of Wandjina. These a images from Kimberley, Australia. Possibly 5,000 years old. Some people believe they may represent ET beings. Notice how the ones in the middle and on the left resemble the head size of grey aliens.

reptile-alien.jpg (12181 bytes)

The above photo is of a number of reptilian entities found in Iraq. They are dated at 5000-4500 BC. They are housed in the british museum.

alien-statuette.jpg (15133 bytes) statue-alien.jpg (21545 bytes)

alien-astronaut.jpg (13037 bytes)

These photos depict figures found in Equador. Notice they appear to be wearing space suits. You can see a comparison photo with an Apollo astronaut.

chinese-alien.jpg (91029 bytes)

This is an old Chinese illustration from a fictional book entitled “Illustrated Survey of Weird Countries” (c.1400 A.D.) and had the following original caption: “Ji Gung Land: The people could make flying cars that travelled far with a suitable wind. In Tarng’s day (c.1700 B.C.), Ji Gung people flying a car on a westerley reached Yew Jo. Tarng dismantled their car so it could not be demonstrated to the people … Later an east wind came on which he had them fly the car back to their own country [5,000 km] west pf our gateway.”

buddhist-alien.jpg (41544 bytes)

This artwork is alledgedly from the buddhist Dharamsala temple in Himachal Pradesh, India. This is where the Dalai Lama lives in exile. You can just make out six silvery saucer shaped objects.

saxons-ufo.jpg (84573 bytes)ufo-sax.jpg (20189 bytes)

These images of two crusaders date from a 12th century manuscript ” Annales Laurissenses” (volumes/books about historical and religion events)and refer to a UFO sighting in the year 776, during the siege on Sigiburg castle, France. The Saxons besieged and surrounded the French people. They both were fighting when suddenly a group of discs (flaming shields) appeared hovering over the top of the church. It appeared to the Saxons that the French were protected by these objects and the Saxons fled.

japan-fiery-ufo.jpg (31665 bytes)

This is an illustration depicting a sighting of a burning wheel in the year 900 over Japan.

vimana-ufo.jpg (48462 bytes)

saucer-vimana.jpg (34626 bytes)

The above image comes from the 10th Century Tibetan translation of the Sanskrit text “Prajnaparamita Sutra”, held at a Japanese museum. In the enlargement you can see two objects that look like hats, but why are they floating in mid air ? also one of them appears to have port holes on it. Indian Vedic texts are full of descriptions of Vimanas. The Ramayana describes Vimanas as a double decked, circular or cylindrical aircraft with portholes and a dome. It flew with “the speed of the wind” and gave forth a “melodious sound”.

french-ufo.jpg (21072 bytes)

This is an illustration of a sighting that occured in the french town of Angers in the year 842. I’m not sure when this illustration was done or who it was by however.

notre-dame-ufo.jpg (12693 bytes) burgandy-ufo.jpg (12729 bytes)

These two tapestries were created in the 15th century. Both depict the life of Mary. Hat shaped objects can be clearly seen in both tapestries.The one on the right is entitled “The Magnificat”. Both are located at the french basillica Notre-Dame in Beaune, Burgandy.

ball-ufo.jpg (21244 bytes)

This image cames from the french book “Le Livre Des Bonnes Moeurs” by Jacques Legrand. You can find this book in Chantilly Condé’s Museum ref 1338 ,297 part 15 B 8. Some people say that the sphere is a balloon but there was no balloon in france in 1338 …

christ-ufo.jpg (14419 bytes)

crucifixion-ufo.jpg (5500 bytes)spaceship-christ.jpg (5660 bytes)

The first picture shows a fresco entitled “The Crucifixion” and was painted in 1350. Two objects with figures inside can be seen in the top left and top right of the fresco. Two enlargements of these objects are shown above. The fresco is located above the altar at the Visoki Decani Monestary in Kosovo, Yugoslavia

red-ufo-saucer.jpg (13155 bytes)

The above painting is by Paolo Uccello (1396-1475) and is entitled “La Tebaide” (painted c.1460-1465). The blown up picture on the right shows a red saucer shaped UFO seen near Jesus. It hangs in the Academy of Florence.

roma-ufo.jpg (31875 bytes)

This is a renaissance illustration of a UFO sighting in Rome detailed in a book “Prodigiorum liber” by Roman historian Julio Obsequens – “Something like a sort of weapon, or missile, rose with a great noise from the earth and soared into the sky”.

cigar ufo

February 1465. The above illustration is from Notabilia Temporum by Angelo de Tummulillis. It describes a flaming girder seen in the sky during the reign of Enrico IV. , looks similar to the object in the Obsequens picture above.

nuremburg.jpg (15560 bytes)

The above image is of an actual sighting that occurred in Nuremburg on the 14th April 1561. It appeared in a local broadsheet and was a woodcut by Hans Glasser. The globes, crosses and tubes began to fight one another, and this went on for an hour. Then they all fell to earth, as if on fire, and faded slowly away producing a lot of steam. Afterwards a black spear-like object was seen, and the whole event was taken to be a divine warning. Held at the Wickiana Collection, Zurich Central Library.

swiss-ufo.jpg (17929 bytes)

This broadsheet picture by Samuel Coccius illustrates a UFO sighting over Basel, Switzerland in 1566. ‘Large black Globes’ appeared in the skies. It is held at the Wickiana Collection, Zurich Central Library.

eucharist.jpg (11419 bytes)

The above painting is by Bonaventura Salimbeni entitled “Glorification of the Eucharist”, painted in 1600. Notice the Sputnik satellite device. It hangs in the church of San Lorenzo in San Pietro. It is considered by some to be a stylised representation of the Earth but I have included it here as it still looks interesting.

ufo-coin.jpg (8662 bytes)

This is a French jeton minted in 1680, a coin-like educational tool that was commonly used to help people count money, or sometimes used as a money substitute for playing games. It is about the size of a U.S. quarter-dollar and similar to thousands of other jetons with different religious and educational designs that were produced and used in Europe during the 16th and 17th centuries. It appears to commemorate a UFO sighting of a wheel like object. Some researchers feel it represents the Biblical Ezekiel’s wheel. The Latin inscription ‘OPPORTUNUS ADEST’ translates as ‘It is here at an opportune time”.

ufo

ancient aliens

ancient ufo

This is a 17th century fresco and is located in the Svetishoveli Cathedral in Mtskheta, Georgia. Notice the two saucer shaped objects either side of Christ. In the two blow ups you can see they contain faces.

hamburg-ufos.jpg (24613 bytes)

More wheels! This picture shows a UFO sighting over Hamburg, Germany 4 November 1697. The objects were described as “two glowing wheels”.

ufo-baptism.jpg (17683 bytes)

This image is by flemish artist Aert De Gelder and is entitled “The Baptism of Christ” It was painted in 1710 and hangs in the Fitzwilliam Musuem, Cambridge. A disk shaped object is shining beams of light down on John the Baptist and Jesus.

ufosighting1742.jpg (30741 bytes)

sighting1742.jpg (5407 bytes)

This is a scan from vol. 42 of the Philosophical Transactions 1742 describing a sighting that occured on the 16th December 1742. Alongside is a contemporary reconstruction depicting the object with the colours described.

sightingufo.jpg (17517 bytes)

The above illustration depicts a sighting that occurred at 9.45pm on the evening of 18th August 1783 when four witnesses on the terrace of Windsor Castle observed a luminous object in the skies of the Home Counties of England. The sighting was recorded the following year in the Philosophical Transactions of the Royal Society. According to this report, witnesses observed an oblong cloud moving more or less parallel to the horizon. Under this cloud could be seen a luminous object which soon became spherical, brilliantly lit, which came to a halt; This strange sphere seemed at first to be pale blue in colour but then its luminosity increased and soon it set off again towards the east. Then the object changed direction and moved parallel to the horizon before disappearing to the south-east ; the light it gave out was prodigious; it lit us everything on the ground.; The image was captured in this by Thomas Sandby (a founder of the Royal Academy) and his brother Paul, both of whom witnessed the event.

ufo1803.jpg (25321 bytes)

This is an illustration from a book “Ume No Chiri (Dust of Apricot)” published in 1803. A foreign ship and crew witnessed at Haratonohama (Haratono Seashore) in Hitachi no Kuni (Ibaragi Prefecture), Japan this strange object. According to the explanation in the drawing, the outershell was made of iron and glass, and strange letters shown in this drawing were seen inside the ship.

 

 

 

 

Related:

Ancient Aliens

Query3

Full text of “Collections historical & archaeological relating to …

How Bill Gates pulled off the Common Core Revolution

Tags

, , , , ,

trailofmoneyThe pair of “education advocates” had a big idea, a new approach to transform every public-school classroom in America. By early 2008, many of the nation’s top politicians and education leaders had lined up in support.

But that wasn’t enough. The duo needed money — tens of millions of dollars, at least — and they needed a champion who could overcome the politics that had thwarted every previous attempt to institute national standards.

So they turned to the richest man in the world.

On a summer day in 2008, Gene Wilhoit, director of a national group of state school chiefs, and David Coleman, an emerging evangelist for the standards movement, spent hours in Bill Gates’ sleek headquarters near Seattle, trying to “persuade” him and his wife, Melinda, to turn their idea into reality.

COLEMAN1_001Coleman and Wilhoit told the Gates that academic standards varied so wildly between states that high school diplomas had lost all meaning, that as many as 40 percent of college freshmen needed remedial classes and that U.S. students were falling behind their foreign competitors.

The pair also argued that a fragmented education system stifled innovation because textbook publishers and software developers were catering to a large number of small markets instead of exploring breakthrough products. That resonated with the man who led the creation of the world’s dominant computer operating system.

“Can you do this?” Wilhoit recalled being asked. “Is there any proof that states are serious about this, because they haven’t been in the past?”

Wilhoit responded that he and Coleman could make no guarantees but that “we were going to give it the best shot we could.”

After the meeting, weeks passed with no word. Then Wilhoit got a call: Gates was in.

What followed was one of the swiftest and most remarkable shifts in education policy in U.S. history.

The Bill and Melinda Gates Foundation didn’t just bankroll the development of what became known as the Common Core State Standards. With more than $200 million, the foundation also built political support across the country, persuading state governments to make systemic and costly changes.

Bill Gates was de facto organizer, providing the money and structure for states to work together on common standards in a way that avoided the usual collision between states’ rights and national interests that had undercut every previous effort, dating from the Eisenhower administration.

The Bill & Melinda Gates Foundation spread money across the political spectrum, to entities including the big teachers unions, the American Federation of Teachers (AFT) and the National Education Association (NEA), and business organizations such as the US Chamber of Commerce— groups that have clashed in the past but became vocal backers of the standards.

Money flowed to policy groups on the right and left, funding research by scholars of varying political persuasions who promoted the idea of common standards. Center for American Progress (CAP) and conservatives affiliated with the American Legislative Exchange Council who routinely disagree on nearly every issue accepted Gates money and found common ground on the Common Core.

One 2009 study, conducted by the conservative Thomas B. Fordham Institute with a $959,116 Gates grant, described the proposed standards as being “very, very strong” and “clearly superior” to many existing state standards.

Gates money went to state and local groups, as well, to help influence policymakers and civic leaders. And the idea found a major booster in President Barack Obama, whose new administration was populated by former Gates Foundation staffers and associates. The administration designed a special contest using “economic stimulus” funds to reward states that accepted the standards.

Obama-EdThe result was astounding: Within just two years of the 2008 Seattle meeting, 45 states and the District of Columbia had fully adopted the Common Core State Standards.

The math standards require students to learn multiple ways to solve problems and explain how they got their answers, while the English standards emphasize non-fiction and expect students to use evidence to back up oral and written arguments. The standards are not a curriculum but “skills” that students should acquire at each grade. How they are taught and materials used are decisions left to states and school districts.

The standards have become so pervasive that they also quickly spread through private Catholic schools. About 100 of 176 Catholic dioceses have adopted the standards because it is “increasingly difficult to buy classroom materials and send teachers to professional development programs that are not influenced by the Common Core,” Catholic educators said.

And yet, because of the way education policy is generally decided, the Common Core was instituted in many states without a single vote taken by an elected lawmaker. Kentucky even adopted the standards before the final draft had been made public.

States were responding to a “common belief system supported by widespread investments,” according to one former Gates employee who spoke on the condition of anonymity to avoid antagonizing the foundation.

The movement grew so quickly and with so little public notice that opposition was initially almost nonexistent. That started to change when local tea party groups began protesting what they viewed as the latest “intrusion by an overreaching federal government” — even though the impetus had come from the states. In some circles, Common Core became known derisively as “Obamacore.”

ObamacoreSince then, anti-Common Core sentiment has intensified, to the extent that it has become a litmus test in the Republican Party ahead of the GOP’s 2016 presidential nomination process. Former Florida governor Jeb Bush, whose nonprofit Foundations for Education Excellence has received about $5.2 million from the Gates Foundation since 2010, is one of the Common Core’s most vocal supporters. Indiana Gov. Mike Pence, who, like Bush, is a potential Republican presidential candidate, led a repeal of the standards in his state. In the past week, Oklahoma Gov. Mary Fallin, a Republican and former advocate of the standards, signed a law pulling her state out, days after South Carolina’s GOP governor, Nikki Haley, did the same.

Some liberals are angry, too, with a few teacher groups questioning Gates’ influence and motives. Critics say Microsoft stands to benefit from the Common Core’s embrace of technology and data — a charge Gates vehemently rejects.

gates-foundation-common-coreA group calling itself the “Badass Teachers Association,” citing opposition to what it considers market-based education reform, plans a June 26 protest outside the Gates Foundation’s headquarters in Seattle.

In an interview, Gates said his “role is to fund the research and development of new tools, such as the Common Core, and offer them to decision-makers who are trying to improve education for millions of Americans. It’s up to the government to decide which tools to use, but someone has to invest in their creation,” he said.

“The country as a whole has a huge problem that low-income kids get less good education than suburban kids get,” Gates said. “And that is a huge challenge. . . . Education can get better. Some people may not believe that. Education can change. We can do better.”

“There’s a lot of work that’s gone into making these [standards] good,” Gates continued. “I wish there was a lot of competition, in terms of [other] people who put tens of millions of dollars into how reading and writing could be improved, how math could be improved.”

Referring to opinion polls, he noted that most teachers like the Common Core standards and that those who are most familiar with them are the most positive.

Gates grew irritated in the interview when the political backlash against the standards was mentioned.

“These are not political things,” he said. “These are where people are trying to apply expertise to say, ‘Is this a way of making education better?'”

“At the end of the day, I don’t think wanting education to be better is a right-wing or left-wing thing,” Gates said. “We fund people to look into things. We don’t fund people to say, “Okay, we’ll pay you this if you say you like the Common Core.”

Whether the Common Core will deliver on its promise is an open question, except for the fact that it has proven to lower test scores.

Tom Loveless, a former Harvard University professor who is an education policy expert at the Brookings Institution, said the Common Core was “built on a shaky theory.” He said he has found no correlation between quality standards and higher student achievement.

“Everyone who developed standards in the past has had a theory that standards will raise achievement, and that’s not happened,” Loveless said.

Jay Greene, head of the Department of Education Reform at the University of Arkansas, says the Gates Foundation’s overall dominance in education policy has subtly muffled dissent.

“Really rich guys can come up with ideas that they think are great, but there is a danger that everyone will tell them they’re great, even if they’re not,” Greene said.

Testing2The first victory for Common Core advocates came on a snowy evening in Kentucky in February 2010, when the state’s top education officials voted unanimously to accept the standards.

“There was no dissent,” said Terry Holliday, Kentucky’s education commissioner. “We had punch and cookies to celebrate.”

It was not by chance that Kentucky went first

The state enjoyed a direct connection to the Common Core backers — Wilhoit, who had made the personal appeal to Bill and Melinda Gates during that pivotal 2008 meeting, is a former Kentucky education commissioner.

Kentucky was also in the market for new standards. Alarmed that as many as 80 percent of community college students were taking remedial classes, lawmakers had recently passed a bill that required Kentucky to write new, better K-12 standards and tests.

“All of our consultants and our college professors had reviewed the Common Core standards, and they really liked them,” Holliday said. “And there was no cost. We didn’t have any money to do this work, and here we were, able to tap into this national work and get the benefits of the best minds in the country.”

“Without the Gates money,” Holliday added, “we wouldn’t have been able to do this.”

Over time, at least $15 million in Gates money was directed both to the state — to train teachers in Common Core practices and purchase classroom materials — and to on-the-ground advocacy and business groups to help build public support.

Armed with $476,553 from Gates, the Kentucky Chamber of Commerce’s foundation produced a seven-minute video about the value and impact of the Common Core, a tool kit to guide employers in how to talk about its benefits with their employees, a list of key facts that could be stuffed into paycheck envelopes, and other promotional materials written by consultants.

The tool kit provided a sample e-mail that could be sent to workers describing “some exciting new developments underway in our schools” that “hold great promise for creating a more highly skilled workforce and for giving our students, community and state a better foundation on which to build a strong economic future.”

The chamber also recruited a prominent Louisville, Kentucky stockbroker to head a coalition of 75 company executives across the state who lent their names to ads placed in business publications that supported the Common Core.

“The notion that the business community was behind this, those seeds were planted across the state, and that reaped a nice harvest in terms of public opinion,” said David Adkisson, president and chief executive of the Kentucky chamber.

The foundation run by the National Education Association received $501,580 in 2013 to help put the Common Core in place in Kentucky.

Kentucky has since dropped out of Common Core.

Gates-backed groups built such strong support for the Common Core that critics, few and far between, were overwhelmed.

“They have so much money to throw around, they can impact the Kentucky Department of Education, the U.S. Department of Education, they can impact both the AFT and the NEA,” said Brent McKim, president of the teachers union in Jefferson County, Kentucky, whose early complaint that the standards were too numerous to be taught well earned him a rebuke by Holliday.

The foundation’s backing was crucial in other states, as well. Starting in 2009, it had begun ramping up its grant-giving to local nonprofit organizations and other Common Core advocates.

The foundation, for instance, gave more than $5 million to the University of North Carolina-affiliated Hunt Institute, led by the state’s former four-term Democratic governor, Jim Hunt, to advocate for the Common Core in statehouses around the country.

The grant was the institute’s largest source of income in 2009, more than 10 times the size of its next largest donation

With the Gates money, the Hunt Institute coordinated more than a dozen organizations — many of them also Gates grantees — including the Thomas B. Fordham Institute, National Council of La Raza, the Council of Chief State School Officers, National Governors Association, Achieve and the two national teachers unions.

The Hunt Institute held weekly conference calls between the players that were directed by Stefanie Sanford, who was in charge of policy and advocacy at the Gates Foundation. They talked about which states needed shoring up, the best person to respond to questions or criticisms and who needed to travel to which state capital to testify, according to those familiar with the conversations.

Common CoreThe Hunt Institute spent $437,000 to hire GMMB | Advertising, Political Consulting, Advocacy, a strategic communications firm owned by Jim Margolis, a top Democratic strategist and veteran of both of Obama’s presidential campaigns. GMMB conducted polling around standards, developed fact sheets, identified language that would be effective in winning support and prepared talking points, among other efforts.

The groups organized by Hunt developed a “messaging tool kit” that included sample letters to the editor, op-ed pieces that could be tailored to individuals depending on whether they were teachers, parents, business executives or civil-rights leaders.

Later in the process, Gates and other foundations would pay for “mock legislative hearings” for classroom teachers, training educators on “how to respond to questions from lawmakers.”

The speed of adoption by the states was staggering by normal standards. A process that typically can take five years was collapsed into a matter of months.

“You had dozens of states adopting before the standards even existed, with little or no discussion, coverage or controversy,” said Frederick Hess of the American Enterprise Institute, which has received $4 million from the Gates Foundation since 2007 to study education policy, including the Common Core. “People weren’t paying attention. We were in the middle of an economic meltdown and the health-care fight, and states saw a chance to have a crack at a couple of million bucks if they made some promises.”

The decision by the Gates Foundation to simultaneously pay for the standards and their promotion is a departure from the way philanthropies typically operate, said Sarah Reckhow, an expert in philanthropy and education policy at Michigan State University.

“Usually, there’s a pilot test — something is tried on a small scale, outside researchers see if it works, and then it’s promoted on a broader scale,” Reckhow said. “That didn’t happen with the Common Core. Instead, they aligned the research with the advocacy. … At the end of the day, it’s going to be the states [students and teachers] and local districts that pay for this.”

While the Gates Foundation created the burst of momentum behind the Common Core, the Obama administration picked up the cause and helped push states to act quickly.

There was so much cross-pollination between the foundation and the administration, it is difficult to determine the degree to which one may have influenced the other.

educationgraphicSeveral top players in Obama’s Education Department who shaped the administration’s policies came either straight from the Gates Foundation in 2009 or from organizations that received heavy funding from the foundation.

Before becoming education secretary in 2009, Arne Duncan was chief executive of the Chicago Public Schools, which received $20 million from Gates to break up several large high schools and create smaller versions, a move aimed at stemming the dropout rate.

As secretary, Duncan named as his chief of staff Margot Rogers, a top Gates official he got to know through that grant. He also hired Jim Shelton, a program officer at the foundation, to serve first as his head of innovation and most recently as the deputy secretary, responsible for a wide array of federal policy decisions.

Duncan and his team leveraged stimulus money to reward states that adopted common standards.

They created Race to the Top, a $4.3 billion contest for education grants. Under the contest rules, states that adopted high standards stood the best chance of winning. It was a clever way around federal laws that prohibit Washington from interfering in what takes place in classrooms. It was also a tantalizing incentive for cash-strapped states.

Heading the effort for Duncan was Joanne Weiss, previously the chief operating officer of the Gates-backed NewSchools Venture Fund.

As ‘Race to the Top’ was being drafted, the administration and the Gates-led effort were in close coordination.

An early version highlighted the Common Core standards by name, saying that states that embraced those specific standards would be better positioned to win federal money. That worried Wilhoit, who feared that some states would consider that unwanted — and possibly illegal — interference from Washington. He took up the matter with Weiss.

“I told her to take it out, that we didn’t want the federal government involvement,” said Wilhoit, who was executive director of the Council of Chief State School Officers. “Those kinds of things cause people to be real suspicious.”

The words “Common Core” were deleted.

The administration said states could develop their own “college and career ready” standards, as long as their public universities verified that those standards would prepare high school graduates for college-level work.

GEDPassrateStill, most states eying Race to the Top money opted for the easiest route and signed onto the Common Core.

The Gates Foundation gave $2.7 million to help 24 states write their Race to the Top application, which ran an average of 300 pages, with as much as 500 pages for an appendix that included Gates-funded research.

Applications for the first round of Race to the Top were due in January 2010, even though the final draft of the Common Core wasn’t released until six months later. To get around this, the U.S. Department of Education told states they could apply as long as they promised they would officially adopt standards.

Now six years into his quest, Gates finds himself in an uncomfortable place — countering critics on the left and right who question whether the Common Core will have any impact or negative effects, whether it represents government intrusion, and whether the new policy will benefit technology firms such as Microsoft.

Gates is disdainful of the rhetoric from opponents. He sees himself “as a technocrat trying to foster solutions to a profound social problem — gaping inequalities in U.S. public education — by investing in promising new ideas.”

bill-gatesEducation lacks research and development, compared with other areas such as medicine and computer science. As a result, there is a paucity of information about methods of instruction that work.

“The guys who search for oil, they spend a lot of money researching new tools,” Gates said. “Medicine — they spend a lot of money finding new tools. Software is a very R and D-oriented industry. The funding, in general, of what works in education … is tiny. It’s the lowest in this field than any field of human endeavor. Yet you could argue it should be the highest.”

Gates is devoting some of his fortune to correct that. Since 1999, the Gates Foundation has spent approximately $3.4 billion on an array of measures to try to improve K-12 public education, with mixed results.

It spent about $650 million on a program to replace large urban high schools with smaller schools, on the theory that students “at risk” of dropping out would be more likely to stay in schools where they forged closer bonds with teachers and other students. That led to a modest increase in graduation rates, an outcome that underwhelmed Gates and prompted the foundation to pull the plug.

Gates has said that one of the benefits of common standards would be to open the classroom to digital learning, making it easier for software developers — including Microsoft — to develop new products for the country’s 15,000 school districts.

Common Core-Aligned Tests and the New Pearson GED: Failure By Design

PearsonIn February, Microsoft announced that it was joining Pearson, the world’s largest educational publisher, to load Pearson’s Common Core classroom materials on Microsoft’s tablet, the Surface. That product allows Microsoft to “compete” for school district spending with Apple, whose iPad is the dominant tablet in classrooms.

Where does the money that goes to Pearson come from? It comes from school districts which are forced to buy their Common Core test, the PARCC test. (In the case of the GED test, the individual pays the full cost.) And the money to pay school districts comes from you and me, taxpayers. Essentially, our tax dollars go from our pocket to Pearson Publishing- We should bypass the legislature and just cut Pearson a check directly!

So, we have a government that is allowing a corporate monopoly to take over our schools and also it has allowed multinational corporations to not pay their taxes.

Gates dismissed any suggestion that he is motivated by self-interest.

“I believe in the Common Core because of its substance and what it will do to improve education,” he said. “And that’s the only reason I believe in the Common Core.”

Bill and Melinda Gates, Obama and Arne Duncan are parents of school-age children, although none of those children attend schools that use the Common Core standards. The Gates and Obama children attend private schools, while Duncan’s children go to public school in Virginia, one of four states that never adopted the Common Core.

Still, Gates said he wants his children to know a “superset” of the Common Core standards — everything in the standards and beyond.

“This is about giving money away,” he said of his support for the standards. “This is philanthropy. This is trying to make sure students have the kind of opportunity I had … and it’s almost outrageous to say otherwise, in my view.”

microsofttax

Related:

US Chamber of Commerce – Bill & Melinda Gates Foundation

CCSS | Common Core State Standards | Pearson k-12 …

Common Core revolution | Web …

How Pearson’s Common Core Tests Are Designed to Fail …

Pearson pays $7.7 million in Common Core settlement

Pearson, of course, wins huge Common Core testing contract

Melinda Gates Responds To Common Core Concerns …

U.S. Education Reform and National Security – Council on …

Common Core and the Pearson GED- Follow the Money to DC and Wall Street

Who is Behind Common Core? – Arizonans Against …

The Evolutionary Significance of Depression in Pathogen Host Defense

Tags

, , , , , ,

 depressionPathogen Host Defense (PATHOS-D) theory of depression:

(1) Depression should be associated with increased inflammation and inflammatory activation should induce depression.
(2) Allelic variants that increase the risk for major depressive disorder (MDD) should enhance host defense mechanisms in general and innate immune inflammatory responses in particular.
(3) Environmental risk factors for MDD should be associated with increased risk of infection and attendant inflammatory activation.
(4) On the whole, patterns of increased immune activity associated with MDD should have decreased mortality from infection in ancestral environments.
(5) Depressive symptoms should enhance survival in the context of acute infection and in situations in which risk of infection from wounding is high.

Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations.

These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia.

By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.

depressionMajor depression is so detrimental to survival and reproduction that it is hard to understand why allelic variants that promote the disorder have not been culled from the human genome, why in fact—far from being culled—genes that promote depression are so common and numerous and appear to have actually increased in prevalence during recent human evolution.1 To address this issue, we have developed a novel theoretical framework positing that risk alleles for depression originated and have been largely retained in the human genome because these alleles encode for an integrated suite of immunological and behavioral responses that promote host defense against pathogens. This enhanced pathogen defense is accomplished primarily via heightened innate immune system activation, which results in reduced death from infectious causes,2, 3, 4, 5 especially in infancy when selection pressure from infection is strongest,6 and the adaptive immune system is not yet fully operational.6, 7, 8, 9 A vast literature has associated depressive symptoms and/or major depressive disorder (MDD) with increased innate immune inflammatory responses,10 with meta-analyses reporting the most consistent findings for increased plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein and haptoglobin.11, 12, 13 Recent longitudinal studies extend these cross-sectional observations by reporting that increased inflammatory markers in nondepressed individuals predict the later development of depression.14, 15, 16 Because infection has been the primary cause of early mortality and hence reproductive failure across human evolution,9, 17, 18, 19, 20, 21 it would be expected that if depressive symptoms were an integral part of a heightened immunological response, allelic variants that support this response would have undergone strong positive selection pressure and thus would be both numerous and prevalent, as they appear to be. However, because the survival benefits of inflammatory processes are tempered by their costs in terms of increased mortality from septic shock,22, 23 pathogen manipulation,21, 24 long-term tissue damage and chronic disease,10 these alleles would not be predicted to go to fixation (that is, 100% prevalence) but would be expected to manifest an intermediate prevalence reflecting the benefit of enhanced host defense in any given environment minus attendant costs. Again, this is consistent with current findings in the genetics of depression.

It should be noted that this Pathogen Host Defense (PAThos HOSt Defense=PATHOS-D) hypothesis is not the first theory to associate depression with protection from infection. Indeed, similar to PATHOS-D, at least one previous hypothesis has envisioned depression as a behavioral response that helps the immune system combat existing infections while avoiding additional pathogen exposure.25 However, prior theoretical articulations have envisioned depressive symptoms as adaptive primarily because they compensate for various types of immune system vulnerabilities.25 PATHOS-D suggests something qualitatively different and more far-reaching; specifically that depressive symptoms were integral components of immune-mediated host defense against pathogens in the ancestral environment. In this model, depressive symptoms are inextricably intertwined with—and generated by—physiological responses to infection that—on average—have been selected as a result of reducing infectious mortality across mammalian evolution (Figure 1). Thus, it is proposed that the alleles for depression, rather than having coevolved with immunological alleles that support pathogen defense, are in fact one in the same as those alleles, and therefore genes associated with depression would be predicted to be the same genes that are associated with successful host immune responses.

PrintTo fully elaborate this hypothesis, this article is structured to evaluate the foundations of the PATHOS-D theory (Table 1) by first examining the immune relevance of previously identified depression risk alleles, followed by an exploration of relationships among environmental risk factors for depression, inflammation and pathogen host defense. The role of depression-associated immune changes in promoting survival during infection is reviewed next, followed by an examination of the potential utility of depressive symptoms in host defense. We conclude with a consideration of the potential limitations of—and challenges to— the PATHOS-D theory.

fundamentals-of-immunology-for-pharmacy-students-2-638Table 1 – Pathogen Host Defense (PATHOS-D) theory of depression: foundational hypotheses.

Risk alleles for MDD and host defense:

The failed promise of genome-wide association studies (GWASs) to unambiguously identify genetic risk variants for MDD has led increasingly to the suggestion that depression and other major psychiatric conditions arise not from common allelic variants with small effect sizes, but rather from an array of highly nonadaptive genetic variants too rare to be identified by GWASs that nonetheless have large effect sizes.26, 27 Confirmation of this would effectively preclude the possibility that depressive risk alleles conferred any selective advantage during human evolution.28 However, an alternative possibility is that differences in common allelic variants between depressed and nondepressed individuals might be more apparent/consistent if the unit of analysis was extended from single genes to groupings of genes that form functional units. In the context of the PATHOS-D theory, this suggests that small allelic differences between depressed and nondepressed groups should not be randomly distributed across the genome, but rather should be largely localized to genes with host defense functions, and that the effect sizes for differences in individual host defense alleles should be additive (that is, positive epistasis), so that large effect size differences should emerge when functionally related host defense-enhancing alleles are evaluated as a unit. Support for this possibility comes from a recent network analysis of candidate genes for MDD. Although this analysis only interpreted findings in terms of potential central nervous system (CNS) effects,29 from a PATHOS-D perspective, it is striking that pathways identified as central to the best-supported MDD gene networks all have well-documented inflammatory and/or anti-inflammatory effects.

To be fully consistent with the PATHOS-D theory, allelic risk variants should meet three criteria. They should (1) be located in genes with known immune effects; (2) increase signaling in inflammatory/host defense pathways; and (3) increase survival in the context of infection. Although a number of candidate gene studies have identified depression risk alleles that are associated with inflammatory processes,30, 31, 32, 33, 34 to evaluate in the most conservative manner whether putative risk alleles meet the three criteria above, we have limited our examination to candidate genes confirmed either by GWASs or meta-analysis and to alleles identified in meta-analyses of GWAS data.

Candidate genes confirmed by GWASs

Currently, only two candidate single-nucleotide polymorphisms (SNPs; rs12520799 in DCNP1 (dendritic cell nuclear protein-1) and rs16139 in NPY (neuropeptide Y)) and one candidate gene for MDD (TNF-α), smallest P-value for rs76917) have been confirmed by GWASs.35 It is striking that each of these genes plays an important role in processes central to host defense, including proinflammatory cytokine signaling (TNF), antigen presentation (DCNP1) and T helper type 1 cell differentiation and function (NPY). Of these SNPs, functionality has only been established for rs16139 in NPY. Although NPY has numerous and contrasting effects on innate and adaptive immune functioning, its primary actions appear to be anti-inflammatory in both the brain and periphery.36, 37, 38 Given this, the PATHOS-D theory predicts that MDD should be characterized by reduced NPY activity and that the depression risk T allele at rs16139 should be associated with reduced NPY production. Significant data support both predictions.39, 40, 41, 42, 43

Unlike NPY, the functionality of rs76917 in TNF is currently unknown. A clear prediction of PATHOS-D theory is that this SNP should be associated with increased TNF-α production, given that TNF-α is increased in MDD and appears to be especially relevant to enhanced survival from infection in the types of pathogen-dense environments that were normative during human evolution. A separate SNP (−308G/A) in the promoter region for TNF is worthy of comment in this regard. Although not found to be significant by GWASs,35 several studies have associated the high-production A allele at −308 (ref. 44) with depression and related states such as anger.33, 34, 45 As predicted by PATHOS-D theory, the −308A allele has also been associated with reduced risk for infection with a number of pathogens, including Mycobacterium tuberculosis, parvovirus B19 and hepatitis B virus (HBV),46, 47, 48 and with an increased likelihood of survival in critically ill hospitalized patients.49 On a population level, Canadian First Peoples who are highly susceptible to tuberculosis have a markedly reduced prevalence of the A allele compared with Caucasians.50

DCNP1 was initially considered to be unique to dendritic cells,51 although it has subsequently been identified in neurons.52 The rs12520799 T allele, which is associated with MDD, codes for a truncated version of the protein. No data are available regarding the effect of this allele on either inflammatory signaling or infection outcomes, but given strong patterns of comorbidity between asthma/atopy and MDD, it is intriguing that the allele has been associated with increased levels of immunoglobulin E for common specific antigens in individuals with asthma.53

Candidate genes confirmed by meta-analysis

Although findings on candidate genes for depression have proven remarkably difficult to replicate,35 a recent meta-analysis provides at least some additional support for several allelic variants being risk factors for MDD, including GNB3 825T, MTHFR 677T, APOE ε2, SLC6A3 40bpVNTR 9/10 genotype and SLC6A4 44bp ins/del short allele.54 Although not traditionally considered as primarily immune related, each of these genes has well-documented immunological effects and hence meets the first of the three criteria for consistency with the PATHOS-D theory. In addition, each to a varying degree has some evidence consistent with either the second or third criterion.

GNB3 825T produces a shortened splice variant of the guanine nucleotide-binding protein subunit β-3 (GNB3) that has enhanced signal transduction properties.55 Also, 825T has been reported to enhance in vitro cellular immune responses to recall antigens and IL-2 stimulation, to increase neutrophil chemotaxis in response to IL-8 and to increase both lymphocyte chemotaxis and the number of circulating CD4+ T cells.55, 56 These immune-enhancing effects come at the price of increased rates of microalbunemia, hypertension and cardiovascular disease in T allele carriers.57, 58 However, as predicted by the PATHOS-D theory, these effects also appear to translate into improved host defense, given associations between the T allele and reduced death from infection in infancy and evidence of positive selection for the T allele in geographical areas with high rates of infectious pathology.59, 60 Also consistent with enhanced host defense responses, the T allele is associated with improved antiviral responses following interferon-α (IFN-α) treatment for hepatitis C virus and highly active retroviral treatment for human immunodeficiency virus.61, 62, 63 In addition, following HBV booster vaccination, the T allele increases in vitro lymphocyte proliferative responses to HBV surface antigen.64

Total Homocysteine Figure_3 bigThe MTHFR 677T allele produces a version of the methylenetetrahydrofolate reductase (MTHFR) enzyme with reduced activity,65 leading to elevations in plasma concentrations of homocysteine and other markers of inflammation.66, 67, 68, 69, 70, 71, 72 Animal and human data suggest that this reduced MTHFR activity and concomitant increase in inflammatory tone may enhance host defense in at least some situations. For example, in a mouse model, MTHFR deficiency protects against cytomegalovirus infection,65 and in pregnant females, increased MTHF is associated with the presence of a sexually transmitted disease and bacterial vaginosis.73 Directly supporting a protective role for the T allele are data demonstrating that the allele protects against HBV infection in African populations.72 Moreover, the hyperhomocysteinemia associated with reduced MTHFR activity has been posited as protective against malaria and has been suggested as a selection factor for the T allele in sub-Saharan Africa.74 Interestingly, however, the prevalence of the T allele is actually far lower in sub-Saharan populations than in other ethnic/geographical groups despite these potential benefits, likely because homozygosity for the allele is lethal in situations of low folate availability such as pertain throughout much of the region.72 On the other hand, given the array of disease states that has been associated with MTHFR 677T,75, 76, 77, 78, 79, 80 as well as reduced fertility,81 its increased prevalence in environments of ready folate availability may reflect more substantial benefits for host defense than are currently recognized.

Apolipoprotein E (APOE), a glycoprotein central to lipid transport and metabolism, has been implicated as a risk and/or protective factor in a wide range of illnesses. The APOE gene has three primary alleles, termed ε2, ε3 and ε4, with ε3 being the most common worldwide, but with significant data suggesting that ε4 is the ancestral human allele.82, 83, 84, 85 APOE affects immune functioning in complex and apparently contradictory ways, with both immune-enhancing and immune-suppressing effects reported. The depression-protective ε2 allele does not appear to be associated with reduced inflammation per se, as PATHOS-D theory would predict, but may meet the third criteria required by PATHOS-D by being a risk factor for diseases known to have exerted significant selection pressure on humans, including tuberculosis and malaria.86 Conversely, the ε4 allele, which increases the risk for MDD when compared with ε2, is associated with increases in many measures of inflammation and related processes such as oxidative stress,82, 83, 84, 85 and has been reported to protect against the development of childhood diarrhea in high-pathogen environments.

Dopamine and serotonin are pivotal neurotransmitters in mood regulation, and yet like other factors linked to depression, these monoamines both affect, and are affected by, the immune system. The bulk of available evidence suggests that MDD is best characterized as a condition of low dopamine availability, at least in CNS regions linked to motivation and reward.87, 88, 89, 90 The possibility that reduced dopamine availability in MDD may serve host defense purposes is suggested by animal studies showing that hyperdopaminemia is associated with reductions in both innate and adaptive T helper 1-type cellular immunity, with resultant increased susceptibility to infection.91, 92 That dopamine transporter activity in particular may be important for host defense in humans is suggested by findings from two recent genome-wide linkage analyses of risk factors for tuberculosis in geographic areas in which the disease is endemic. Both studies localized a genetic protective factor to a locus of chromosome 15.93, 94 Fine mapping of this locus identified a SNP (rs250682) within the dopamine transporter gene (SLC6A3) as conferring the strongest protective effect.93 The G allele of rs250682 was found to be associated with reduced skin reactions to the tuberculin test, which predicts reduced risk of later active disease in endemic areas.93 However, no data were found indicating that rs250682 is in linkage disequilibrium with the SLC6A3 40bpVNTR that has been associated with MDD. Nor do any data address whether the 9 repeat allele of the VNTR has immunological effects that would enhance host defense. Indeed, even the question of whether this putative depression risk allele is a gain-of-function or loss-of-function variant for the dopamine transporter remains to be definitively clarified.95, 96

The SLC6A4 44bp ins/del polymorphism (often referred to as 5HTTLPR) is by far the most extensively studied, and debated, genetic risk factor for MDD. Significant data suggest that the ‘short’ allele of this serotonin transporter polymorphism (which is less efficient in the reuptake of serotonin) increases the risk for developing depression in response to psychosocial adversity, both during development and in adulthood. Less well known, but consistent with PATHOS-D predictions, the short allele has also been shown to protect against sudden infant death syndrome, a condition often associated with unrecognized infectious morbidity.97, 98, 99, 100 Given the PATHOS-D prediction that stress should activate inflammation as a prepotent protection against the risk of wounding (see below), it is intriguing that the 5HTTLPR short allele is associated with an increase in the ratio of circulating proinflammatory to anti-inflammatory cytokines (for example, IL-6/IL-10) following a psychosocial stressor.101 Further supporting a role for SLC6A4 in host defense is the recent finding that the gene might account for 10% of the correlation between depressive symptoms and circulating levels of IL-6 in a group of medically healthy adults.102 Finally, the prevalence of the short allele in cultures around the world is strongly correlated with historical burden of disease-causing pathogens in these cultures,103 consistent with the possibility that the short allele has undergone positive selection as a result of enhancing host defense.104

GWAS_Disease_allele_effectsAlleles identified by meta-analyses of GWAS data

Far less is known about the general functionality of alleles identified in GWASs, let alone which physiological effects may be relevant to MDD. Therefore, it should not be surprising that limited data are available regarding whether these potentially depressogenic SNPs affect immunity to enhance host defense. On the other hand, it is intriguing that associations with immune/inflammatory function or other aspects of host defense against pathogens have been demonstrated for 8 of the top 10 genes (or their very close homologs) identified in the largest GWAS meta-analysis of MDD conducted to date (Table 2).105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140 Many other depression-relevant genes identified in earlier large GWASs (as well as meta-analyses of these studies), including PBRM1, GNL3, ATP6V1B2, SP4, AK294384, LY86, KSP37, SMG7, NFKB1, LOC654346, LAMC2, ATG7, CUGBP1, NFE2L3, LOC647167, VCAN, NLGN1, BBOX1, ATF3, RORA, EIF3F, CDH13, ITGB1 and GRM8, have also been linked to immune system and/or host defense functions (see Supplementary Table S1 for additional information/relevant references).

Table 2 – Immune/host defense functions of single-nucleotide polymorphisms (SNPs) associated with major depression based on the largest meta-analysis of genome-wide association studies (GWASs) conducted to date for major depression (MDD).

An exception to the general lack of knowledge regarding GWAS-identified depression risk alleles is provided by the rs1006737 SNP in the CACNA1C gene, which codes for the α1 subunit of the L-type voltage-gated calcium channel (Cav1.2).29 CACNA1C has been identified as a potential depression risk gene in several GWASs,105, 141, 142 and convergent validity for its role in depression is provided by data demonstrating that carriers of the risk A allele have changes in brain function and morphology relevant to MDD.143, 144, 145

An examination of the immune effects of CACNA1C highlights both the promise and complexities of a PATHOS-D perspective. Calcium signaling pathways play central and essential roles in multiple aspects of immune function, and the Cav1.2 channel in particular contributes to the function of a variety of immune cell types, including dendritic cells, CD4+ and CD8+ T cells, mast cells and macrophages.146, 147, 148, 149, 150, 151, 152, 153, 154 Consistent with an overall proinflammatory effect for Cav1.2, agents that block this calcium channel have been repeatedly observed to have anti-inflammatory properties.155 Given these findings, the PATHOS-D theory predicts that the depressogenic A allele at rs1006737 should be a gain-of-function variant with an overall proinflammatory effect. In support of this, the A allele has been associated with reduced activation of the anti-inflammatory intracellular messenger Akt,156 which is known from in vitro studies to downregulate TNF-α and inducible nitric oxide synthase production in response to challenge with bacterial endotoxin.157 Moreover, if Cav1.2 activation promotes host defense via activation of inflammatory processes, one would predict that the A allele should be associated with increased CACNA1C protein production. Although this has yet to be confirmed, data from post-mortem brain tissue indicate that carriers of the A allele have increased CACNA1C mRNA production in the CNS.144

These data suggest that the A allele of CACNA1C meets the first two criteria for consistency with a PATHOS-D perspective (that is, located in a gene with known immune effects and associated with increased signaling in inflammatory/host defense pathways). The finding that Cav1.2 activation is necessary for T-cell defense against Leishmania major infection is consistent with the third criteria,148 given that the A allele appears to be a gain-of-function variant. However, other lines of circumstantial evidence undermine any straightforward association between allelic variants that increase Cav1.2 function and enhanced host defense. In fact, the opposite appears to be the case, given that Timothy Syndrome, caused by a rare gain-of-function variant in CACNA1C,158 is associated with a strikingly increased risk of infection.154 Similarly, activation of Cav1.2 channels appears to actually impede host defense against M. tuberculosis by reducing the bactericidal activity of dendritic cell-activated T cells.149 These results appear paradoxical given that calcium influx into immune cells is essential for eradication of M. tuberculosis, and significant data indicate that L-type voltage-gated channels play an important role in this regard.150 However, conflicting data suggest that L-type calcium channels may actually downregulate overall calcium influx, given that blocking these channels increased calcium signaling and bactericidal activity in M. tuberculosis-infected macrophages.149 These findings are consistent with the observation that bacterial endotoxin acutely downregulates L-type calcium channel mRNA, as would be expected if Cav1.2 has an anti-inflammatory function.159

These considerations introduce a critically important complication into our discussion of the immune effects of depressogenic gene variants. Up to this point we have proceeded as though pathogen host defense is a monolithic process, which is a simplification exposed by the bivalent effects of L-type intracellular calcium signaling on infectious outcomes. Because calcium signaling activates multiple facets of the immune system, it is not surprising that this signaling has been shown to contribute to the antipathogen capacities of a variety of cell types. For example, macrophages rely on L-type calcium channel activation in response to Chlamydia pneumonia lipopolysaccharide to kill the microorganism.160 However, other microbes have evolved to manipulate this host defense system to their own benefit, such as Legionella pneumophila, which requires L-type calcium signaling to replicate within infected host cells.161 These examples demonstrate that the same physiological process can enhance host defense to one pathogen, while simultaneously increasing vulnerability to another.

signs_of_inflammationInfection, inflammation and environmental risk factors for MDD

If depressogenic alleles contribute to protection against pathogen invasion, the circumstances in which such invasion was likely or already a fait accompli should be especially potent activators of these genes, and hence especially likely to induce depression. Moreover, if these alleles heighten host defense in large part by increasing inflammation, inflammatory mediators released in response to environments rife with pathogen danger would be expected to induce depressive symptoms. These predictions are borne out by many studies demonstrating the depressogenic effects of inflammatory mediators,10, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 as well as the remarkably diverse array of conditions that activate inflammatory processes and also increase the risk for depression.174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221

Psychosocial stress may be especially relevant in this regard. Stress is a universal and powerful risk for the development of depression both during development and adulthood.222, 223, 224, 225 This squares nicely with social theories of depression, and at first glance appears to challenge host defense perspectives. But if we consider that the vast majority of stressors in mammals over evolutionary time boiled down to risks inherent in hunting, being hunted or fighting conspecifics in dominance hierarchies for reproductive access/status, it is not surprising that these states are also circumstances in which the risk of pathogen invasion—and subsequent death from infection—was greatly increased as a result of traumatic opening of the protective skin barrier from wounding.226 Such wounding is common in social species and was a significant source of morbidity and mortality among humans in the ancestral environment, and indeed well into the historical period.227, 228, 229 Given this, it is not surprising that—to quote Firdaus Dhabhar—‘stress perception by the brain may serve as an early warning signal to activate the immune system in preparation for a markedly increased likelihood of subsequent infection’.230 And although chronic stress is best known to suppress immune function,231 the types of acute and/or psychosocial stressors most likely to be associated with immediate risk of wounding and hence infection activate both innate and adaptive immunity.232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242 And while suppressing certain measures of adaptive immunity, chronic stress (whether experienced during childhood or as an adult) has been repeatedly associated with increased peripheral inflammatory biomarkers.233, 243, 244, 245, 246, 247, 248

From a PATHOS-D perspective, then, psychosocial stress may increase the risk for depression, at least in part, because it activates host defense mechanisms that reliably induce depressive symptoms. In ancestral environments, the association between stress perception and risk of subsequent wounding was reliable enough that evolution, operating by the so-called ‘smoke detector’ principle,249 favored organisms that prepotently activated inflammatory systems in response to a wide array of environmental threats and challenges (including psychosocial stressors), even if this activation was often in vain. This perspective provides a parsimonious explanation for why psychosocial stressors reliably induce depression, even though depressive reactions to stressors often appear so patently maladaptive. Across evolutionary time, the benefit that depressive symptoms (and their underlying physiology) conferred in terms of host defense in situations of high infectious danger (including most psychosocial adversities) outweighed their cost in terms of any social impairment they incurred in these same contexts. A clear prediction of this hypothesis is that genes promoting inflammatory responses to psychosocial stress should decrease in prevalence over time in human societies in which the association between stressors and subsequent infection has been weakened by factors such as modern health practices. Consistent with this possibility, the prevalence of the short allele of the serotonin transporter gene, which has been associated with increased inflammatory responses to psychosocial stress, is lower in societies with reduced rates of historical infectious mortality.104

In addition to providing a novel explanation for why stress is a primary risk factor for developing depression, the PATHOS-D theory offers a unifying perspective on why many other facets of modern life are also depressogenic, a perspective not readily provided by theories focused more exclusively on the social realm. Indeed, if the adaptive value of depression is to be found primarily in its effects on social functioning, it is hard to understand why so many risks for depression, including obesity, sedentary lifestyle, dietary factors, diminished sleep and smoking, are at least partially nonsocial in nature. On the other hand, these conditions are all associated with increased inflammation (for reviews see refs. 207, and 250, 251, 252), suggesting that they may be depressogenic because they tap into pathways that initially evolved to fight infection.

depressionPatterns of immune activation in MDD and protection from infectious mortality in ancestral environments

The hypothesis that patterns of immune activity associated with MDD should have decreased mortality from infection in ancestral environments appears to face a challenge from data indicating that depression worsens outcome in a number of infectious processes253, 254, 255, 256, 257, 258, 259, 260 and is associated with impairments in adaptive immune mechanisms important for protection against both viruses and bacteria.13, 261, 262 To address this challenge, we have first to inquire whether innate immune inflammatory processes that are increased in MDD produce the patterns of infectious vulnerability and adaptive immune impairment that are apparent in depression. Surprisingly, the answer is yes.263, 264 Although essential for activating adaptive immunity in response to pathogen invasion, chronic inflammation can actually suppress T- and B-cell function through various mechanisms.263, 264, 265, 266, 267, 268, 269, 270 Consistent with this, rates of infection are often increased—not decreased—in autoimmune conditions characterized by chronic inflammation.271 However, PATHOS-D theory requires only that across evolutionary time the survival benefits of enhanced inflammatory activity characteristic of depression outweighed any costs imposed by associated reductions in other aspects of immune functioning. Several lines of evidence support this possibility.

One such line of evidence comes from Ghana, a country in which some regions rely for drinking water on heavily contaminated rivers and other regions obtain clean water from boreholes. As would be expected, death rates from infection are higher in river-drinking regions than in areas where borehole-obtained water is available. Consistent with the prediction that increased inflammatory signaling is protective in the type of high-infection environments common during human evolution (and especially common since the origin of agriculture and the rise of cities),272 a haplotype of the IL-10 gene associated with increased inflammation was found to be significantly more prevalent in populations that relied on river water than in populations that drank from boreholes—suggesting positive selection driven by enhanced pathogen protection.2 Consistent with this possibility, during a 5-year follow-up period, the high-inflammation IL-10 haplotype was associated with increased survival in populations that drank from rivers, but reduced survival in individuals who drank from boreholes.2 These results are consistent with the observation that cytokine-stimulated production of TNF-α declines with age in the Netherlands, a country with a low infectious burden, but does not decline with age in Ghana, a country with high rates of infection (that is, 85% of Ghanan study participants were infected with malaria),273 again suggesting that increased proinflammatory cytokine production—as observed in MDD—promotes survival under conditions of high pathogen burden.274

Multiple facets of modernity have reconfigured our relationship with the microbial/parasitic world in ways that have reduced the benefits of inflammation and increased its costs.274, 275 Nonetheless, even in an environment so different from that in which humans evolved, multiple studies have identified associations between patterns of increased inflammation observed in MDD and improved outcome in the context of infection,3, 4, 5, 50, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290 as shown in Table 3.

Survival-promoting elements of depressive/ sickness symptoms in response to infection

Microbial activation of the mammalian inflammatory response produces a highly regulated suite of symptoms known as sickness behavior that bears a striking resemblance to behavioral changes induced by stress in laboratory animals, as well as to the symptoms of MDD in humans.10, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173 Many of these symptoms can be ameliorated by antidepressants in animal models,291, 292, 293, 294, 295 further suggesting that cytokine-induced behavioral changes are either closely aligned with, or identical to, MDD in humans. Studies report that 20–70% of patients undergoing chronic immune activation as a result of treatment with the cytokine IFN-α meet symptom criteria for MDD, providing additional evidence in this regard.164, 296 Moreover, IFN-α-induced depression shares symptom homology with idiopathic MDD,297 and responds to treatment with antidepressants.164, 298, 299, 300, 301 In addition to a remarkable symptom overlap, sickness and depression during cytokine exposure also appear to be causally linked, given the strong association between sickness in the first week of treatment with IFN-α and the development of cognitive/emotional symptoms of depression over the ensuing 6 months of therapy.302 Finally, peripheral inflammatory activation induces many—if not all—of the most replicated CNS and neuroendocrine abnormalities observed in MDD (Figure 1).303, 304, 305, 306, 307, 308, 309, 310

The PATHOS-D theory asserts that depressogenic alleles are common not because depression is adaptive in managing social negotiations, but because these alleles promote symptoms and behaviors that decreased mortality from infectious causes across mammalian evolution. However, from an evolutionary perspective, there is no a priori reason why these antipathogen effects should overlap with the depressogenic effects of these risk alleles. That they do so is powerful evidence, we would suggest, for the primacy of immune defense in the pathogenesis of depression, regardless of the environmental adversity that initiates the disorder in individual cases. In keeping with this perspective is the possibility that some of the symptoms of depression promote survival in response to infection.

Fever and hypoferremia

Although once viewed as a maladaptive consequence of immune activation,311 several decades of research have produced a consensus that sickness behavior is an adaptive central motivational state evolved to promote survival and necessitated to a large degree by the metabolic costs of mounting a fever.163, 169, 311, 312, 313, 314 Fever, in turn, has been shown to enhance resistance to both viral and bacterial pathogens, over and above other antipathogen effects of the inflammatory mechanisms by which fever is induced. In addition to retarding pathogen replication/spread,315, 316, 317, 318 febrile range temperatures have multiple stimulatory effects on the immune system relevant to host defense.319, 320, 321, 322, 323, 324, 325

Because these effects are enhanced in conditions of low iron availability, it should not be surprising that in addition to causing fever, inflammatory cytokines deplete bodily iron stores.326 Nor should it be surprising that sickness is associated with hypoferremia,327, 328 which—after fever—is probably the feature of sickness that has been best established as of adaptive value.329, 330, 331 For example, low bodily iron stores protect against infection in children in the developing world,332 and multiple studies suggest that iron supplementation worsens an array of infection-related health outcomes and increases infectious mortality.333, 334, 335, 336, 337

If depressive symptoms aid in pathogen defense and if fever and hypoferremia are important in this regard, one would expect that MDD should be associated with elevated body temperature and reduced bodily iron stores, even in individuals with no evidence of an infectious process. In this regard, it is surprising, given the centrality of fever to the adaptive function of sickness behavior,163, 169, 315 that so little attention has been paid to the fact that MDD appears to be reliably characterized by an elevation in body temperature into the range known to be maximally protective in the context of infection.338, 339, 340, 341, 342, 343, 344, 345 As with elevated body temperature, a number of studies have reported that depressive symptoms are associated with reductions in various measures of bodily iron stores.346, 347, 348, 349, 350

Because fever and hypoferremia are central to the adaptive purposes of sickness, their presence in depression is mandated from a PATHOS-D perspective, and their absence would strongly argue against the validity of this approach. On the other hand, their presence in depression is not parsimoniously explained by theories that focus on potential social benefits of depression. Similarly, if depression is simply a nonadaptive phenomenon, why would such ancient, highly conserved and highly complex physiological responses be a hallmark of the disorder?

stressConservation-withdrawal

Proinflammatory cytokines induce a behavioral state of conservation-withdrawal,351 characterized by depressed mood, anhedonia, psychomotor retardation, fatigue, social avoidance and anorexia.163, 252, 352, 353 This state is an integral component of depressive disorders and has been widely considered to develop in the context of infection and/or tissue injury as a means of marshalling limited metabolic resources for the expensive tasks of immune activation, fever generation and tissue repair.311 In addition to energy allocation, conservation-withdrawal symptoms may have also proved adaptive by reducing interpersonal contact and thereby limiting infectious exposure.25 Because ancestral humans typically lived in small coalitional groups of genetically related individuals, the logic of inclusive fitness suggests that social withdrawal might have been adaptive for an individual’s genes by reducing the risk of infection in kin, even if such withdrawal limited the provision of much needed care from others and thus reduced individual survival.354, 355 As would be predicted from this line of reasoning, acute exposure to an inflammatory mediator has been shown to induce feelings of social isolation/withdrawal in humans,356 and increased neural sensitivity to social rejection (indexed by changes in activity in dorsal anterior cingulate and anterior insula cortices) is associated with increased inflammatory responses to psychosocial stress.357 However, in addition to potential benefits related to kin selection, significant data demonstrate that viral infections promote aggressive immune responses to bacterial superinfections that can greatly increase mortality;358, 359, 360, 361, 362, 363, 364 therefore, any decrement in survival from loss of social aid might have been more than offset by reduced risk of exposure to other pathogens while in a vulnerable state due to a pre-existing infection. Moreover, social withdrawal and reduced environmental exploration might also have promoted individual survival by limiting a sick person’s contact with immunologically dissimilar out-group members who potentially harbored pathogens against which the sick person would have had reduced immunity compared with pathogens endemic in the home group.354, 365

Hypervigilance

Although withdrawal-conservation-type behavior is prominent in MDD, depressed individuals also often manifest metabolically expensive symptoms more consistent with behavioral activation, including anxiety/agitation and insomnia.366, 367, 368, 369, 370 By siphoning energy away from immune activity, these symptoms would be expected to impair host defense and hence to argue against a PATHOS-D perspective. However, sickness behavior—although of benefit for surviving infection—carries its own survival and reproduction costs as a result of increased risk for predation and reduced ability to care for one’s young, as well as potential loss of status in a social species and/or loss of breeding territory.371 Therefore, evolutionary logic dictates that inflammatory processes—especially when chronic—might promote hypervigilant behavior that, while shunting energy away from fighting infection, would nonetheless serve adaptive purposes by protecting against environmental dangers engendered by sickness. In fact, significant data demonstrate that chronic cytokine activation reliably produces hypervigilant behaviors/symptoms, including anxiety/agitation, insomnia and anger/irritability.305, 353, 372 Neurobiological substrates for the mixture of withdrawal-conservation and behavioral activation/hypervigilance symptoms that is common to chronic inflammation/medical illness and MDD have been recently identified, including the effects of cytokines on both the basal ganglia (withdrawal-conservation) and the dorsal anterior cingulate cortex (hypervigilance) (Figure 1).303, 309, 357, 373, 374, 375, 376

Anorexia

As suggested above, anorexia may enhance survival during infection by redirecting energy away from food procurement to the metabolic demands of immune activation/fever, while also limiting the exposure to food-borne pathogens. But the metabolic requirements of fighting infection make the anorexic response a paradox in need of a more robust adaptive explanation. Although it remains unclear whether food restriction protects against the development of infection,377 animal data indicate that force feeding rodents once they are infected increases mortality.378 Similarly, the provision of total parenteral nutrition in animal models and to critically ill patients has been associated with increased risk for infection and subsequent mortality.379, 380, 381, 382 Interestingly, rats injected with lipopolysaccharide consume proportionately more carbohydrates—as do depressed individuals with hyperphagia383—even though more energy is available from ingesting lipids. This suggests that lipid consumption may be counterproductive during an infection. Several observations are consistent with this possibility. For example, preclinical data demonstrate that lipid consumption increases infectious mortality,384 and a meta-analysis of total parenteral nutrition use found that infected patients provided lipids in their feedings had higher complication rates than those receiving total parenteral nutrition without lipids.385 Finally, omega-3 fatty acids have been shown to activate peroxisome proliferator-activated receptor-γ signaling in dendritic cells, with a resultant downregulation of CD1a receptor expression.129 These receptors play an essential role in activating T-cell responses to pathogens, as demonstrated by the ability of Leishmania donovani to survive in host cells by downregulating these receptors.386 Moreover, CD1a expression in dendritic cells is also crucial for the presentation of M. tuberculosis antigens to cells of the adaptive immune system.387

Potential limitations of, and challenges to, PATHOS-D theory

In this article we have focused our analyses on allelic variants associated with phenotypic variability. Many genetic features contributing to MDD may have swept to fixation over evolutionary history and by becoming nonpolymorphic remain invisible to genetic association studies. It is possible that such sequences are preferentially associated with species-typical social, rather than immunological, factors. Were this to be the case, our analyses may have overestimated immune risk factors for depression at the cost of universal depressogenic risk alleles maintained as a ‘price of being human’.

It should also be noted that inflammatory biomarkers are not elevated in all individuals with MDD. Whether patients with increased inflammation represent a biologically and evolutionary distinct subset of MDD is an area of active research.388 If this turns out to be the case, it may be that selection for enhanced host pathogen defense is relevant primarily to these individuals (and their allelic variants) and is thus only one adaptive factor driving the persistence of depressogenic alleles. Prior theorists have posited a variety of potentially fitness-enhancing psychosocial effects of low mood and/or depression not obviously related to host defense functions (that is, abandoning unattainable goals, yielding in dominance struggles and so on),389, 390, 391 and it may be that these types of psychosocial benefits are promoted by allelic variants retained in the human genome independently of variants maintained as a result of conferring pathogen host defense benefits. If both immune and nonimmune etiological pathways contribute to MDD, the next question is how they combine. One hypothesis consistent with the general absence of documented epistatic interactions among MDD risk alleles is that inflammation/immune alleles provide one hit and social/stress factors provide a second (biologically distinct) hit, which together sum to exceed an MDD symptom threshold. If distinct social and immune-related genetic risk factors were identified, statistical analysis of epistasis could help distinguish intrinsic interactions between pathways from a simple additive model.

On the other hand, findings from patients undergoing treatment with IFN-α suggest a more inclusive scenario for the role of pathogen defense in the evolution/persistence of depressogenic alleles. Specifically, although standardized dosages of IFN-α are employed, a wide range of behavioral responses are observed during treatment, from mild neurovegetative/sickness symptoms, such as fatigue, to completed suicide in response to catastrophic major depression. Individuals who develop significant depressive symptoms evince changes in CNS and neuroendocrine functioning that are also observed in idiopathic MDD,305, 306, 307, 308, 309, 310 but that are not observed to a significant degree in patients on IFN-α who do not develop depression. These findings raise the possibility that depression reflects a state of immune response element amplification, such that for any given amount of inflammatory input, depressed individuals react with enhanced downstream CNS/neuroendocrine activity. If so, depressogenic alleles that do not promote an increase in inflammatory biomarkers may nonetheless have undergone positive selection because they enhanced host pathogen defense via sensitization of downstream CNS/neuroendocrine pathways that themselves promote survival during infection. Some evidence for this hypothesis comes from the finding, noted above, that individuals who develop depression during IFN-α manifest enhanced sickness behavior at the start of treatment, which may aid in acutely clearing pathogens from the body during infection.302 Moreover, a clear prediction of PATHOS-D theory is that changes in CNS/neuroendocrine function that typically accompany MDD should enhance survival in the context of acute infection. To date, few data support this possibility, although it is intriguing to note that glucocorticoid resistance, which is common in MDD392 and is associated with the development of depressive symptoms during IFN-α treatment (Raison et al., unpublished observations), has been associated with improved T-cell function in HIV infection,393 and that enrichment paradigms known to enhance glucocorticoid sensitivity in animal models increase mortality in response to Escherichia coli infection.394

These two possibilities (that is, distinct additive social and immunological risks vs inflammatory mediation of social risk) might be genetically discriminated based on their contrasting implications for the functional relationship between social–environmental precipitants and immune-related genetic risks for MDD. In the former model, one would expect to find largely additive effects of social risk factors and immune-related genetic risk alleles, whereas the meditational model would suggest a product-term interaction (that is, a social stimulus shows larger depressogenic ‘gain’ in the context of a sensitizing genotype). This approach could be extended to use an instrumental variables analysis (for example, a Mendelian randomization study) to determine whether inflammatory signals function as mediators of, moderators of, or functionally independent additional additive influences with respect to, social precipitants of MDD.

Thus far, we have focused on the possibility that risk alleles promote depressive symptoms primarily as a result of increasing activity in inflammatory and/or immune-relevant downstream physiological pathways (that is, gene right arrow immune effects right arrow depression). However, many of the associations cited in this review could be equally well accounted for by the hypothesis that alleles directly influence CNS functioning to increase MDD risk, and that MDD subsequently affects immune function (that is, gene right arrow depression right arrow immune effects). This possibility is especially likely for genes such as NPY, which we have described in immune terms, but that also has well-documented effects on CNS functioning relevant to depression. In addition to downstream immune effects, such genes may also have enhanced host defense in ancestral environments by promoting behavioral patterns likely to reduce the risk of becoming infected, spreading infection to kin or of dying once an infection had commenced.395, 396 Just such effects have been proposed for the short allele of the serotonin transporter, which has been associated with collectivistic social behavior relevant to host defense.104

Immune changes associated with MDD are not only specific but also occur in other severe mental disorders, including bipolar disorder and schizophrenia. Although the high prevalence of depression in these conditions is consistent with a PATHOS-D perspective, it is hard to imagine that other behavioral states associated with these diseases, including mania and psychosis, are adaptive for pathogen host defense. Indeed, the impaired decision-making characteristic of both states and the social isolation/reduced access to resources that is common in psychosis would be expected to increase vulnerability to pathogen exposure. Given overlapping genetic risk factors for these conditions and MDD, it is possible that they are best understood as purely maladaptive states supported at relatively low levels in the human population, at least in part, because their genetic antecedents enhanced host defense in carriers of immune-relevant risk alleles who responded to infectious challenges with enhanced immune activation and sickness behavior/depression without developing the full disease phenotype. Another possibility is that very severe disorders such as bipolar disorder and schizophrenia have been maintained in the human genome because immune benefits accrued to afflicted individuals that counteracted the fitness-reducing behavioral profiles (including increased risk of infection) associated with these diseases. This scenario would suggest that immune changes seen in schizophrenia and bipolar disorder should be more robust than those seen in depression, because they would have to be large enough to offset behavioral costs not present in depression. Although not entirely consistent,397 some data support this possibility.398, 399, 400

Summary

By shifting the adaptive context of depressogenic alleles from any purported benefit of depressive symptoms on relations with conspecifics to the potential benefits of sickness behavior (and its attendant physiology) on relations with the microbial world, the PATHOS-D hypothesis provides a straightforward explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates suggesting an adaptive function. Across vertebrate evolution, innate immune inflammatory responses were essential for effective host defense against pathogens. In humans, these responses are especially relevant during the first several years of life when infectious mortality was highest and adaptive immunity was not yet fully functional. Given these considerations, it is not surprising that the immune system alterations most frequently observed in MDD are proinflammatory in nature, and that the best characterized MDD risk alleles appear to generally produce a proinflammatory phenotype. However, we should not infer from this that any given depressogenic allele will uniformly increase innate immune function or enhance host defense against all microbes. Rather, what PATHOS-D suggests is that depressogenic alleles—and the physiological processes they promote—can be understood as reflecting a summation of the most successful pathogen defense mechanisms against the wide array of pathogens encountered during human evolution, with all the imperfections and tradeoffs this has entailed. Moreover, knowing the effects of depressogenic alleles on outcomes following infection with specific pathogens may cast light on the relative importance of each pathogen for driving human evolution, because the high price imposed by depressogenic alleles mandates a compensatory high payoff in terms of pathogen defense. If confirmed in future studies, this perspective raises the intriguing possibility that gaining a better understanding of how genes promote MDD may significantly advance the field of immunology and that—conversely—a better understanding of the ongoing evolutionary ‘arms race’ between pathogens and their human hosts may suggest novel theoretical paradigms and treatment strategies for MDD.

Conflict of interest

The authors declare no conflict of interest. Charles L Raison serves as a consultant for Pamlab, Biolex Therapeutics and Bristol Myers Squibb. Andrew H Miller has served as a consultant for Abbott Laboratories, AstraZeneca, GlaxoSmithKline, Lundbeck Research USA, F. Hoffmann-La Roche, Schering-Plough Research Institute and Wyeth/Pfizer and has received research support from Centocor, GlaxoSmithKline and Schering-Plough Research Institute

References

  1. Crespi B, Summers K, Dorus S. Adaptive evolution of genes underlying schizophrenia. Proc Biol Sci 2007; 274: 2801–2810. | Article | PubMed | CAS |
  2. Kuningas M, May L, Tamm R, van Bodegom D, van den Biggelaar AH, Meij JJ et al. Selection for genetic variation inducing pro-inflammatory responses under adverse environmental conditions in a Ghanaian population. PLoS One 2009; 4: e7795. | Article | PubMed |
  3. van Dissel JT, van Langevelde P, Westendorp RG, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351: 950–953. | Article | PubMed | ISI | CAS |
  4. Bermejo-Martin JF, Martin-Loeches I, Rello J, Anton A, Almansa R, Xu L et al. Host adaptive immunity deficiency in severe pandemic influenza. Crit Care 2010; 14: R167. | Article | PubMed |
  5. Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–173. | Article | PubMed | ISI | CAS |
  6. McDade TW. Life history theory and the immune system: steps toward a human ecological immunology. Am J Phys Anthropol 2003 (Suppl 37): 100–125.
  7. Pedron B, Guerin V, Cordeiro DJ, Masmoudi S, Dalle JH, Sterkers G. Development of cytomegalovirus and adenovirus-specific memory CD4 T-cell functions from birth to adulthood. Pediatr Res 2011; 69: 106–111. | Article | PubMed | ISI |
  8. Nwachuku N, Gerba CP. Health risks of enteric viral infections in children. Rev Environ Contam Toxicol 2006; 186: 1–56. | PubMed |
  9. Chen LC, Rahman M, Sarder AM. Epidemiology and causes of death among children in a rural area of Bangladesh. Int J Epidemiol 1980; 9: 25–33. | Article | PubMed |
  10. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741. | Article | PubMed | ISI | CAS |
  11. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186. | Article | PubMed | ISI | CAS |
  12. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457. | Article | PubMed | ISI | CAS |
  13. Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 2001; 15: 199–226. | Article | PubMed | ISI | CAS |
  14. Gimeno D, Kivimaki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med 2008; 39: 1–11.
  15. van den Biggelaar AH, Gussekloo J, de Craen AJ, Frolich M, Stek ML, van der Mast RC et al. Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age. Exp Gerontol 2007; 42: 693–701. | Article | PubMed | ISI | CAS |
  16. Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 2010; 197: 372–377. | Article | PubMed | ISI |
  17. Finch CE. Evolution in health and medicine Sackler colloquium: Evolution of the human lifespan and diseases of aging: roles of infection, inflammation, and nutrition. Proc Natl Acad Sci USA 2010; 107(Suppl 1): 1718–1724. | Article | PubMed |
  18. Dobson AP, Carper ER. Infectious diseases and human population history. Biosci 1996; 46: 115–126. | Article |
  19. Wolfe ND, Dunavan CP, Diamond J. Origins of major human infectious diseases. Nature 2007; 447: 279–283. | Article | PubMed | ISI | CAS |
  20. Lovel H. Targeted interventions and infant mortality. Trans R Soc Trop Med Hyg 1989; 83: 10–18. | Article | PubMed |
  21. Kavaliers M, Colwell DD, Choleris E. Parasites and behavior: an ethopharmacological analysis and biomedical implications. Neurosci Biobehav Rev 1999; 23: 1037–1045. | Article | PubMed | ISI |
  22. Goncalves GM, Zamboni DS, Camara NO. The role of innate immunity in septic acute kidney injuries. Shock 2010; 34(Suppl 1): 22–26. | Article | PubMed | ISI |
  23. Oberholzer A, Oberholzer C, Moldawer LL. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 2001; 16: 83–96. | Article | PubMed | ISI | CAS |
  24. Klein SL. Parasite manipulation of the proximate mechanisms that mediate social behavior in vertebrates. Physiol Behav 2003; 79: 441–449. | Article | PubMed | ISI |
  25. Kinney DK, Tanaka M. An evolutionary hypothesis of depression and its symptoms, adaptive value, and risk factors. J Nerv Ment Dis 2009; 197: 561–567. | Article | PubMed | ISI |
  26. Gershon ES, Alliey-Rodriguez N, Liu C. After GWAS: searching for genetic risk for schizophrenia and bipolar disorder. Am J Psychiatry 2011; 168: 253–256. | Article | PubMed | ISI |
  27. Licinio J, Dong C, Wong ML. Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Arch Gen Psychiatry 2009; 66: 488–497. | Article | PubMed | ISI | CAS |
  28. Keller MC, Miller G. Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behav Brain Sci 2006; 29: 385–404; discussion 405–452. | Article | PubMed | ISI |
  29. Detera-Wadleigh SD, Akula N. A systems approach to the biology of mood disorders through network analysis of candidate genes. Pharmacopsychiatry 2011; 44(Suppl 1): S35–S42. | Article | PubMed | ISI |
  30. Wong ML, Dong C, Maestre-Mesa J, Licinio J. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008; 13: 800–812. | Article | PubMed | ISI | CAS |
  31. Cerri AP, Arosio B, Viazzoli C, Confalonieri R, Vergani C, Annoni G. The −308 (G/A) single nucleotide polymorphism in the TNF-alpha gene and the risk of major depression in the elderly. Int J Geriatr Psychiatry 2010; 25: 219–223. | Article | PubMed |
  32. Clerici M, Arosio B, Mundo E, Cattaneo E, Pozzoli S, Dell’osso B et al. Cytokine polymorphisms in the pathophysiology of mood disorders. CNS Spectr 2009; 14: 419–425. | PubMed | ISI |
  33. Jun TY, Pae CU, Hoon H, Chae JH, Bahk WM, Kim KS et al. Possible association between -G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Psychiatr Genet 2003; 13: 179–181. | Article | PubMed | ISI |
  34. Pae CU, Lee KU, Han H, Serretti A, Jun TY. Tumor necrosis factor alpha gene-G308A polymorphism associated with bipolar I disorder in the Korean population. Psychiatry Res 2004; 125: 65–68. | Article | PubMed | ISI |
  35. Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D et al. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 2011; 16: 516–532. | Article | PubMed | ISI |
  36. Wheway J, Herzog H, Mackay F. NPY and receptors in immune and inflammatory diseases. Curr Top Med Chem 2007; 7: 1743–1752. | Article | PubMed | ISI |
  37. Ferreira R, Xapelli S, Santos T, Silva AP, Cristovao A, Cortes L et al. Neuropeptide Y modulation of interleukin-1{beta} (IL-1{beta})-induced nitric oxide production in microglia. J Biol Chem 2010; 285: 41921–41934. | Article | PubMed | ISI |
  38. Wheway J, Herzog H, Mackay F. The Y1 receptor for NPY: a key modulator of the adaptive immune system. Peptides 2007; 28: 453–458. | Article | PubMed | ISI |
  39. Heilig M, Zachrisson O, Thorsell A, Ehnvall A, Mottagui-Tabar S, Sjogren M et al. Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism. J Psychiatr Res 2004; 38: 113–121. | Article | PubMed | ISI |
  40. Sjoholm LK, Melas PA, Forsell Y, Lavebratt C. PreproNPY Pro7 protects against depression despite exposure to environmental risk factors. J Affect Disord 2009; 118: 124–130. | Article | PubMed | ISI |
  41. Mickey BJ, Zhou Z, Heitzeg MM, Heinz E, Hodgkinson CA, Hsu DT et al. Emotion processing, major depression, and functional genetic variation of neuropeptide Y. Arch Gen Psychiatry 2011; 68: 158–166. | Article | PubMed | ISI | CAS |
  42. Morales-Medina JC, Dumont Y, Quirion R. A possible role of neuropeptide Y in depression and stress. Brain Res 2010; 1314: 194–205. | Article | PubMed | ISI |
  43. Kallio J, Pesonen U, Kaipio K, Karvonen MK, Jaakkola U, Heinonen OJ et al. Altered intracellular processing and release of neuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Y in humans. FASEB J 2001; 15: 1242–1244. | PubMed | ISI | CAS |
  44. Wilson AG, di Giovine FS, Blakemore AI, Duff GW. Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1992; 1: 353. | Article | PubMed | CAS |
  45. Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG. Labile anger during interferon Alfa treatment is associated with a polymorphism in tumor necrosis factor alpha. Clin Neuropharmacol 2010; 33: 191–197. | Article | PubMed | ISI |
  46. Correa PA, Gomez LM, Cadena J, Anaya JM. Autoimmunity and tuberculosis. Opposite association with TNF polymorphism. J Rheumatol 2005; 32: 219–224. | PubMed | ISI | CAS |
  47. Kerr JR, McCoy M, Burke B, Mattey DL, Pravica V, Hutchinson IV. Cytokine gene polymorphisms associated with symptomatic parvovirus B19 infection. J Clin Pathol 2003; 56: 725–727. | Article | PubMed | ISI |
  48. Chen DQ, Zeng Y, Zhou J, Yang L, Jiang S, Huang JD et al. Association of candidate susceptible loci with chronic infection with hepatitis B virus in a Chinese population. J Med Virol 2010; 82: 371–378. | Article | PubMed | ISI |
  49. Surbatovic M, Grujic K, Cikota B, Jevtic M, Filipovic N, Romic P et al. Polymorphisms of genes encoding tumor necrosis factor-alpha, interleukin-10, cluster of differentiation-14 and interleukin-1ra in critically ill patients. J Crit Care 2010; 25: 542 e541–548. | Article | PubMed |
  50. Larcombe LA, Orr PH, Lodge AM, Brown JS, Dembinski IJ, Milligan LC et al. Functional gene polymorphisms in Canadian aboriginal populations with high rates of tuberculosis. J Infect Dis 2008; 198: 1175–1179. | Article | PubMed | ISI |
  51. Masuda M, Senju S, Fujii Si S, Terasaki Y, Takeya M, Hashimoto Si S et al. Identification and immunocytochemical analysis of DCNP1, a dendritic cell-associated nuclear protein. Biochem Biophys Res Commun 2002; 290: 1022–1029. | Article | PubMed | ISI | CAS |
  52. Zhou T, Wang S, Ren H, Qi XR, Luchetti S, Kamphuis W et al. Dendritic cell nuclear protein-1, a novel depression-related protein, upregulates corticotropin-releasing hormone expression. Brain 2010; 133: 3069–3079. | Article | PubMed | ISI |
  53. Kim Y, Park CS, Shin HD, Choi JW, Cheong HS, Park BL et al. A promoter nucleotide variant of the dendritic cell-specific DCNP1 associates with serum IgE levels specific for dust mite allergens among the Korean asthmatics. Genes Immun 2007; 8: 369–378. | Article | PubMed | ISI | CAS |
  54. Lopez-Leon S, Janssens AC, Hofman A, Claes S, Breteler MM, Tiemeier H et al. No association between the angiotensin-converting enzyme gene and major depression: a case-control study and meta-analysis. Psychiatr Genet 2006; 16: 225–226. | Article | PubMed | ISI |
  55. Virchow S, Ansorge N, Rosskopf D, Rubben H, Siffert W. The G protein beta3 subunit splice variant Gbeta3-s causes enhanced chemotaxis of human neutrophils in response to interleukin-8. Naunyn Schmiedebergs Arch Pharmacol 1999; 360: 27–32. | Article | PubMed | ISI | CAS |
  56. Lindemann M, Virchow S, Ramann F, Barsegian V, Kreuzfelder E, Siffert W et al. The G protein beta3 subunit 825T allele is a genetic marker for enhanced T cell response. FEBS Lett 2001; 495: 82–86. | Article | PubMed | ISI | CAS |
  57. Romundstad S, Melien O, Holmen J. The G protein beta3 subunit C825T polymorphism is associated with microalbuminuria in hypertensive women and cardiovascular disease in hypertensive men. Am J Hypertens 2010; 23: 1114–1120. | Article | PubMed | ISI |
  58. Holmen OL, Romundstad S, Melien O. Association between the G protein beta3 subunit C825T polymorphism and the occurrence of cardiovascular disease in hypertensives: The Nord-Trondelag Health Study (HUNT). Am J Hypertens 2010; 23: 1121–1127. | Article | PubMed | ISI |
  59. Hauge Opdal S, Melien O, Rootwelt H, Vege A, Arnestad M, Ole Rognum T. The G protein beta3 subunit 825C allele is associated with sudden infant death due to infection. Acta Paediatr 2006; 95: 1129–1132. | Article | PubMed | ISI |
  60. Bagos PG, Elefsinioti AL, Nikolopoulos GK, Hamodrakas SJ. The GNB3 C825T polymorphism and essential hypertension: a meta-analysis of 34 studies including 14,094 cases and 17,760 controls. J Hypertens 2007; 25: 487–500. | Article | PubMed | ISI | CAS |
  61. Ahlenstiel G, Nischalke HD, Bueren K, Berg T, Vogel M, Biermer M et al. The GNB3 C825T polymorphism affects response to HCV therapy with pegylated interferon in HCV/HIV co-infected but not in HCV mono-infected patients. J Hepatol 2007; 47: 348–355. | Article | PubMed | ISI |
  62. Sarrazin C, Berg T, Weich V, Mueller T, Frey UH, Zeuzem S et al. GNB3 C825T polymorphism and response to interferon-alfa/ribavirin treatment in patients with hepatitis C virus genotype 1 (HCV-1) infection. J Hepatol 2005; 43: 388–393. | Article | PubMed | ISI |
  63. Brockmeyer NH, Potthoff A, Kasper A, Nabring C, Jockel KH, Siffert W. GNB3 C825T polymorphism and response to anti-retroviral combination therapy in HIV-1-infected patients–a pilot study. Eur J Med Res 2005; 10: 489–494. | PubMed | ISI |
  64. Lindemann M, Barsegian V, Siffert W, Ferencik S, Roggendorf M, Grosse-Wilde H. Role of G protein beta3 subunit C825T and HLA class II polymorphisms in the immune response after HBV vaccination. Virology 2002; 297: 245–252. | Article | PubMed | ISI |
  65. Fodil-Cornu N, Kozij N, Wu Q, Rozen R, Vidal SM. Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection. Genes Immun 2009; 10: 662–666. | Article | PubMed | ISI |
  66. Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T et al. Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers. Metabolism 2010; 59: 728–733. | Article | PubMed | ISI |
  67. Fujimaki C, Hayashi H, Tsuboi S, Matsuyama T, Kosuge K, Yamada H et al. Plasma total homocysteine level and methylenetetrahydrofolate reductase 677C>T genetic polymorphism in Japanese patients with rheumatoid arthritis. Biomarkers 2009; 14: 49–54. | Article | PubMed | ISI |
  68. Dedoussis GV, Panagiotakos DB, Pitsavos C, Chrysohoou C, Skoumas J, Choumerianou D et al. An association between the methylenetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease. Int J Cardiol 2005; 100: 409–414. | Article | PubMed | ISI |
  69. Chen AR, Zhang HG, Wang ZP, Fu SJ, Yang PQ, Ren JG et al. C-reactive protein, vitamin B12 and C677T polymorphism of N-5,10-methylenetetrahydrofolate reductase gene are related to insulin resistance and risk factors for metabolic syndrome in Chinese population. Clin Invest Med 2010; 33: E290–E297. | PubMed | ISI |
  70. Hammons AL, Summers CM, Woodside JV, McNulty H, Strain JJ, Young IS et al. Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1. Clin Immunol 2009; 133: 132–137. | Article | PubMed | ISI |
  71. Lu ZY, Morales M, Khartulyari S, Mei M, Murphy KM, Stanislawska-Sachadyn A et al. Genetic and biochemical determinants of serum concentrations of monocyte chemoattractant protein-1, a potential neural tube defect risk factor. Birth Defects Res A Clin Mol Teratol 2008; 82: 736–741. | Article | PubMed |
  72. Bronowicki JP, Abdelmouttaleb I, Peyrin-Biroulet L, Venard V, Khiri H, Chabi N et al. Methylenetetrahydrofolate reductase 677T allele protects against persistent HBV infection in West Africa. J Hepatol 2008; 48: 532–539. | Article | PubMed | ISI | CAS |
  73. Simhan HN, Himes KP, Venkataramanan R, Bodnar LM. Maternal serum folate species in early pregnancy and lower genital tract inflammatory milieu. Am J Obstet Gynecol 2011; 205: 61. e1–e7.
  74. Chillemi R, Zappacosta B, Simpore J, Persichilli S, Musumeci M, Musumeci S. Hyperhomocysteinemia in acute Plasmodium falciparum malaria: an effect of host-parasite interaction. Clin Chim Acta 2004; 348: 113–120. | Article | PubMed | ISI |
  75. Maeda M, Yamamoto I, Fukuda M, Motomura T, Nishida M, Nonen S et al. MTHFR gene polymorphism is susceptible to diabetic retinopathy but not to diabetic nephropathy in Japanese type 2 diabetic patients. J Diabetes Complications 2008; 22: 119–125. | Article | PubMed | ISI |
  76. Khandanpour N, Willis G, Meyer FJ, Armon MP, Loke YK, Wright AJ et al. Peripheral arterial disease and methylenetetrahydrofolate reductase (MTHFR) C677T mutations: a case-control study and meta-analysis. J Vasc Surg 2009; 49: 711–718. | Article | PubMed | ISI |
  77. Ferrara F, Novo S, Grimaudo S, Raimondi F, Meli F, Amato C et al. Methylenetetrahydrofolate reductase mutation in subjects with abdominal aortic aneurysm subdivided for age. Clin Hemorheol Microcirc 2006; 34: 421–426. | PubMed | ISI |
  78. Pollex RL, Mamakeesick M, Zinman B, Harris SB, Hanley AJ, Hegele RA. Methylenetetrahydrofolate reductase polymorphism 677C>T is associated with peripheral arterial disease in type 2 diabetes. Cardiovasc Diabetol 2005; 4: 17. | Article | PubMed | CAS |
  79. Chen J, Ma J, Stampfer MJ, Palomeque C, Selhub J, Hunter DJ. Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics 2002; 12: 339–342. | Article | PubMed | ISI | CAS |
  80. Movva S, Alluri RV, Venkatasubramanian S, Vedicherla B, Vattam KK, Ahuja YR et al. Association of methylene tetrahydrofolate reductase C677T genotype with type 2 diabetes mellitus patients with and without renal complications. Genet Test Mol Biomarkers 2011; 15: 257–261. | Article | PubMed |
  81. Reyes-Engel A, Munoz E, Gaitan MJ, Fabre E, Gallo M, Dieguez JL et al. Implications on human fertility of the 677C right arrow T and 1298A right arrow C polymorphisms of the MTHFR gene: consequences of a possible genetic selection. Mol Hum Reprod 2002; 8: 952–957. | Article | PubMed | ISI | CAS |
  82. Gerdes LU. The common polymorphism of apolipoprotein E: geographical aspects and new pathophysiological relations. Clin Chem Lab Med 2003; 41: 628–631. | Article | PubMed | ISI |
  83. Urosevic N, Martins RN. Infection and Alzheimer’s disease: the APOE epsilon4 connection and lipid metabolism. J Alzheimers Dis 2008; 13: 421–435. | PubMed | ISI |
  84. Mahley RW, Rall Jr SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000; 1: 507–537. | Article | PubMed | ISI | CAS |
  85. Jofre-Monseny L, Minihane AM, Rimbach G. Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 2008; 52: 131–145. | Article | PubMed | ISI | CAS |
  86. Wozniak MA, Maude RJ, Innes JA, Hawkey PM, Itzhaki RF. Apolipoprotein E-epsilon2 confers risk of pulmonary tuberculosis in women from the Indian subcontinent–a preliminary study. J Infect 2009; 59: 219–222. | Article | PubMed | ISI |
  87. Roy A, Karoum F, Pollack S. Marked reduction in indexes of dopamine metabolism among patients with depression who attempt suicide. Arch Gen Psychiatry 1992; 49: 447–450. | Article | PubMed | ISI |
  88. Meyer JH, Kruger S, Wilson AA, Christensen BK, Goulding VS, Schaffer A et al. Lower dopamine transporter binding potential in striatum during depression. NeuroReport 2001; 12: 4121–4125. | Article | PubMed | ISI | CAS |
  89. Lambert G, Johansson M, Agren H, Friberg P. Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry 2000; 57: 787–793. | Article | PubMed | ISI | CAS |
  90. Klimek V, Schenck JE, Han H, Stockmeier CA, Ordway GA. Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry 2002; 52: 740–748. | Article | PubMed | ISI | CAS |
  91. Kavelaars A, Cobelens PM, Teunis MA, Heijnen CJ. Changes in innate and acquired immune responses in mice with targeted deletion of the dopamine transporter gene. J Neuroimmunol 2005; 161: 162–168. | Article | PubMed | ISI |
  92. Alaniz RC, Thomas SA, Perez-Melgosa M, Mueller K, Farr AG, Palmiter RD et al. Dopamine beta-hydroxylase deficiency impairs cellular immunity. Proc Natl Acad Sci USA 1999; 96: 2274–2278. | Article | PubMed | CAS |
  93. Cobat A, Gallant CJ, Simkin L, Black GF, Stanley K, Hughes J et al. Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med 2009; 206: 2583–2591. | Article | PubMed | ISI |
  94. Stein CM, Zalwango S, Malone LL, Won S, Mayanja-Kizza H, Mugerwa RD et al. Genome scan of M. tuberculosis infection and disease in Ugandans. PLoS One 2008; 3: e4094. | Article | PubMed |
  95. Mill J, Asherson P, Browes C, D’Souza U, Craig I. Expression of the dopamine transporter gene is regulated by the 3′ UTR VNTR: evidence from brain and lymphocytes using quantitative RT-PCR. Am J Med Genet 2002; 114: 975–979. | Article | PubMed | ISI |
  96. van de Giessen E, de Win MM, Tanck MW, van den Brink W, Baas F, Booij J. Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med 2009; 50: 45–52. | Article | PubMed | ISI | CAS |
  97. Opdal SH, Vege A, Rognum TO. Serotonin transporter gene variation in sudden infant death syndrome. Acta Paediatr 2008; 97: 861–865. | Article | PubMed | ISI |
  98. Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N. Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics 2001; 107: 690–692. | Article | PubMed | ISI | CAS |
  99. Weese-Mayer DE, Berry-Kravis EM, Maher BS, Silvestri JM, Curran ME, Marazita ML. Sudden infant death syndrome: association with a promoter polymorphism of the serotonin transporter gene. Am J Med Genet A 2003; 117A: 268–274.
  100. Prandota J. Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants. Am J Ther 2004; 11: 517–546. | Article | PubMed |
  101. Fredericks CA, Drabant EM, Edge MD, Tillie JM, Hallmayer J, Ramel W et al. Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions. Brain Behav Immun 2010; 24: 350–357. | Article | PubMed | ISI |
  102. Su S, Zhao J, Bremner JD, Miller AH, Tang W, Bouzyk M et al. Serotonin transporter gene, depressive symptoms, and interleukin-6. Circ Cardiovasc Genet 2009; 2: 614–620. | Article | PubMed | ISI | CAS |
  103. Murray DR, Schaller M. Historical prevalence of infectious diseases within 230 geopolitical regions: a tool for investigating origins of culture. J Cross Cult Psychol 2010; 41: 99–108. | Article |
  104. Chiao JY, Blizinsky KD. Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene. Proc Biol Sci 2010; 277: 529–537. | Article | PubMed |
  105. Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR et al. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned. Mol Psychiatry 2012; 17: 36–48. | Article | PubMed |
  106. Cattaneo M, Otsu M, Fagioli C, Martino S, Lotti LV, Sitia R et al. SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. J Cell Physiol 2008; 215: 794–802. | Article | PubMed | ISI |
  107. Schelhaas M, Malmstrom J, Pelkmans L, Haugstetter J, Ellgaard L, Grunewald K et al. Simian Virus 40 depends on ER protein folding and quality control factors for entry into host cells. Cell 2007; 131: 516–529. | Article | PubMed | ISI | CAS |
  108. Oresic K, Ng CL, Tortorella D. TRAM1 participates in human cytomegalovirus US2- and US11-mediated dislocation of an endoplasmic reticulum membrane glycoprotein. J Biol Chem 2009; 284: 5905–5914. | Article | PubMed | ISI |
  109. Ban Y, Taniyama M, Tozaki T, Yanagawa T, Tomita M. SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases. Thyroid 2001; 11: 335–338. | Article | PubMed | ISI |
  110. Song J, Duncan MJ, Li G, Chan C, Grady R, Stapleton A et al. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. Plos Pathog 2007; 3: e60. | Article | PubMed | CAS |
  111. Abera AB, Sales KJ, Catalano RD, Katz AA, Jabbour HN. EP2 receptor mediated cAMP release is augmented by PGF 2 alpha activation of the FP receptor via the calcium-calmodulin pathway. Cell Signal 2010; 22: 71–79. | Article | PubMed | ISI |
  112. Klempan TA, Rujescu D, Merette C, Himmelman C, Sequeira A, Canetti L et al. Profiling brain expression of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene in suicide. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 934–943.
  113. Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 2006; 7: 156–164. | Article | PubMed | ISI | CAS |
  114. Koehn J, Huesken D, Jaritz M, Rot A, Zurini M, Dwertmann A et al. Assessing the function of human UNC-93B in Toll-like receptor signaling and major histocompatibility complex II response. Hum Immunol 2007; 68: 871–878. | Article | PubMed | ISI |
  115. Pifer R, Benson A, Sturge CR, Yarovinsky F. UNC93B1 is essential for TLR11 activation and IL-12-dependent host resistance to Toxoplasma gondii. J Biol Chem 2011; 286: 3307–3314. | Article | PubMed | ISI | CAS |
  116. Crozat K, Vivier E, Dalod M. Crosstalk between components of the innate immune system: promoting anti-microbial defenses and avoiding immunopathologies. Immunol Rev 2009; 227: 129–149. | Article | PubMed | ISI |
  117. Lang R, Kofler B. The galanin peptide family in inflammation. Neuropeptides 2011; 45: 1–8. | Article | PubMed | ISI |
  118. Matkowskyj KA, Danilkovich A, Marrero J, Savkovic SD, Hecht G, Benya RV. Galanin-1 receptor up-regulation mediates the excess colonic fluid production caused by infection with enteric pathogens. Nat Med 2000; 6: 1048–1051. | Article | PubMed | ISI | CAS |
  119. McDonald AC, Schuijers JA, Gundlach AL, Grills BL. Galanin treatment offsets the inhibition of bone formation and downregulates the increase in mouse calvarial expression of TNFalpha and GalR2 mRNA induced by chronic daily injections of an injurious vehicle. Bone 2007; 40: 895–903. | Article | PubMed | ISI |
  120. Su Y, Ganea D, Peng X, Jonakait GM. Galanin down-regulates microglial tumor necrosis factor-alpha production by a post-transcriptional mechanism. J Neuroimmunol 2003; 134: 52–60. | Article | PubMed | ISI |
  121. Christiansen SH, Olesen MV, Wortwein G, Woldbye DP. Fluoxetine reverts chronic restraint stress-induced depression-like behaviour and increases neuropeptide Y and galanin expression in mice. Behav Brain Res 2011; 216: 585–591. | Article | PubMed | ISI |
  122. Wardi Le Maitre T, Xia S, Le Maitre E, Dun XP, Lu J, Theodorsson E et al. Galanin receptor 2 overexpressing mice display an antidepressive-like phenotype: possible involvement of the subiculum. Neurosci 2011; 190: 270–288. | Article |
  123. Davidson S, Lear M, Shanley L, Hing B, Baizan-Edge A, Herwig A et al. Differential activity by polymorphic variants of a remote enhancer that supports galanin expression in the hypothalamus and amygdala: implications for obesity, depression and alcoholism. Neuropsychopharmacology 2011; 36: 2211–2221. | Article | PubMed | ISI |
  124. Rauch I, Lundstrom L, Hell M, Sperl W, Kofler B. Galanin message-associated peptide suppresses growth and the budded-to-hyphal-form transition of Candida albicans. Antimicrob Agents Chemother 2007; 51: 4167–4170. | Article | PubMed | ISI |
  125. Ikegami K, Sato S, Nakamura K, Ostrowski LE, Setou M. Tubulin polyglutamylation is essential for airway ciliary function through the regulation of beating asymmetry. Proc Natl Acad Sci USA 2010; 107: 10490–10495. | Article | PubMed |
  126. Chen C, Han YH, Yang Z, Rodrigues AD. Effect of interferon-alpha2b on the expression of various drug-metabolizing enzymes and transporters in co-cultures of freshly prepared human primary hepatocytes. Xenobiotica 2011; 41: 476–485. | Article | PubMed | ISI |
  127. Crossland H, Constantin-Teodosiu D, Greenhaff PL, Gardiner SM. Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle. J Physiol 2010; 588: 1333–1347. | Article | PubMed |
  128. Palomer X, Alvarez-Guardia D, Rodriguez-Calvo R, Coll T, Laguna JC, Davidson MM et al. TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res 2009; 81: 703–712. | Article | PubMed | ISI |
  129. Zapata-Gonzalez F, Rueda F, Petriz J, Domingo P, Villarroya F, Diaz-Delfin J et al. Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR(gamma):RXR heterodimers: comparison with other polyunsaturated fatty acids. J Leukoc Biol 2008; 84: 1172–1182. | Article | PubMed | ISI | CAS |
  130. Nawa Y, Kawahara K, Tancharoen S, Meng X, Sameshima H, Ito T et al. Nucleophosmin may act as an alarmin: implications for severe sepsis. J Leukoc Biol 2009; 86: 645–653. | Article | PubMed | ISI |
  131. Sarek G, Jarviluoma A, Moore HM, Tojkander S, Vartia S, Biberfeld P et al. Nucleophosmin phosphorylation by v-cyclin-CDK6 controls KSHV latency. Plos Pathog 2010; 6: e1000818. | Article | PubMed |
  132. Johnson JS, Samulski RJ. Enhancement of adeno-associated virus infection by mobilizing capsids into and out of the nucleolus. J Virol 2009; 83: 2632–2644. | Article | PubMed | ISI | CAS |
  133. Lee JJ, Seah JB, Chow VT, Poh CL, Tan EL. Comparative proteome analyses of host protein expression in response to Enterovirus 71 and Coxsackievirus A16 infections. J Proteomics 2011; 74: 2018–2024. | Article | PubMed | ISI |
  134. Zeng Y, Ye L, Zhu S, Zheng H, Zhao P, Cai W et al. The nucleocapsid protein of SARS-associated coronavirus inhibits B23 phosphorylation. Biochem Biophys Res Commun 2008; 369: 287–291. | Article | PubMed | ISI |
  135. Fankhauser C, Izaurralde E, Adachi Y, Wingfield P, Laemmli UK. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. Mol Cell Biol 1991; 11: 2567–2575. | PubMed | ISI | CAS |
  136. Lymberopoulos MH, Bourget A, Abdeljelil NB, Pearson A. Involvement of the UL24 protein in herpes simplex virus 1-induced dispersal of B23 and in nuclear egress. Virology 2011; 412: 341–348. | Article | PubMed | ISI |
  137. Garcia MA, Meurs EF, Esteban M. The dsRNA protein kinase PKR: virus and cell control. Biochimie 2007; 89: 799–811. | Article | PubMed | ISI | CAS |
  138. Burrows JF, McGrattan MJ, Johnston JA. The DUB/USP17 deubiquitinating enzymes, a multigene family within a tandemly repeated sequence. Genomics 2005; 85: 524–529. | Article | PubMed | ISI | CAS |
  139. Burrows JF, McGrattan MJ, Rascle A, Humbert M, Baek KH, Johnston JA. DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation. J Biol Chem 2004; 279: 13993–14000. | Article | PubMed | ISI | CAS |
  140. Chen R, Zhang L, Zhong B, Tan B, Liu Y, Shu HB. The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling. Cell Res 2010; 20: 802–811. | Article | PubMed | ISI |
  141. Liu Y, Blackwood DH, Caesar S, de Geus EJ, Farmer A, Ferreira MA et al. Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Mol Psychiatry 2011; 16: 2–4. | Article | PubMed | ISI |
  142. Green EK, Grozeva D, Jones I, Jones L, Kirov G, Caesar S et al. The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry 2010; 15: 1016–1022. | Article | PubMed | ISI | CAS |
  143. Erk S, Meyer-Lindenberg A, Schnell K, Opitz von Boberfeld C, Esslinger C, Kirsch P et al. Brain function in carriers of a genome-wide supported bipolar disorder variant. Arch Gen Psychiatry 2010; 67: 803–811. | Article | PubMed | ISI |
  144. Bigos KL, Mattay VS, Callicott JH, Straub RE, Vakkalanka R, Kolachana B et al. Genetic variation in CACNA1C affects brain circuitries related to mental illness. Arch Gen Psychiatry 2010; 67: 939–945. | Article | PubMed | ISI |
  145. Perrier E, Pompei F, Ruberto G, Vassos E, Collier D, Frangou S. Initial evidence for the role of CACNA1C on subcortical brain morphology in patients with bipolar disorder. Eur Psychiatry 2011; 26: 135–137. | Article | PubMed | ISI |
  146. Suzuki Y, Inoue T, Ra C. L-type Ca2+ channels: a new player in the regulation of Ca2+ signaling, cell activation and cell survival in immune cells. Mol Immunol 2010; 47: 640–648. | Article | PubMed | ISI |
  147. Badou A, Jha MK, Matza D, Mehal WZ, Freichel M, Flockerzi V et al. Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function. Proc Natl Acad Sci USA 2006; 103: 15529–15534. | Article | PubMed | CAS |
  148. Matza D, Badou A, Kobayashi KS, Goldsmith-Pestana K, Masuda Y, Komuro A et al. A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation. Immunity 2008; 28: 64–74. | Article | PubMed | ISI | CAS |
  149. Gupta S, Salam N, Srivastava V, Singla R, Behera D, Khayyam KU et al. Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis. PLoS One 2009; 4: e5305. | Article | PubMed |
  150. Radermacher AN, Crabtree GR. Monster protein controls calcium entry and fights infection. Immunity 2008; 28: 13–14. | Article | PubMed | ISI |
  151. Suzuki Y, Yoshimaru T, Inoue T, Ra C. Ca v 1.2L-type Ca2+ channel protects mast cells against activation-induced cell death by preventing mitochondrial integrity disruption. Mol Immunol 2009; 46: 2370–2380. | Article | PubMed | ISI |
  152. Das R, Burke T, Van Wagoner DR, Plow EF. L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages. Circ Res 2009; 105: 167–175. | Article | PubMed |
  153. Matza D, Badou A, Jha MK, Willinger T, Antov A, Sanjabi S et al. Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis. Proc Natl Acad Sci USA 2009; 106: 9785–9790. | Article | PubMed |
  154. Liao P, Soong TW. CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency. Pflugers Arch 2010; 460: 353–359. | Article | PubMed | ISI | CAS |
  155. Das R, Plow EF. A new function for old drugs. Cell Cycle 2010; 9: 638–639. | Article | PubMed | ISI |
  156. Balog Z, Kiss I, Keri S. CACNA1C risk allele for psychotic disorders is related to the activation of the AKT-pathway. Am J Psychiatry 2010; 167: 1276–1277. | Article | PubMed | ISI |
  157. Li XQ, Cao W, Li T, Zeng AG, Hao LL, Zhang XN et al. Amlodipine inhibits TNF-alpha production and attenuates cardiac dysfunction induced by lipopolysaccharide involving PI3K/Akt pathway. Int Immunopharmacol 2009; 9: 1032–1041. | Article | PubMed | ISI |
  158. Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119: 19–31. | Article | PubMed | ISI | CAS |
  159. Okazaki R, Iwasaki YK, Miyauchi Y, Hirayama Y, Kobayashi Y, Katoh T et al. Lipopolysaccharide induces atrial arrhythmogenesis via down-regulation of L-type Ca2+ channel genes in rats. Int Heart J 2009; 50: 353–363. | Article | PubMed | ISI |
  160. Azenabor AA, Chaudhry AU. Effective macrophage redox defense against Chlamydia pneumoniae depends on L-type Ca2+ channel activation. Med Microbiol Immunol 2003; 192: 99–106. | PubMed | ISI |
  161. Wieland H, Hechtel N, Faigle M, Neumeister B. Efficient intracellular multiplication of Legionella pneumophila in human monocytes requires functional host cell L-type calcium channels. FEMS Immunol Med Microbiol 2006; 47: 296–301. | Article | PubMed | ISI |
  162. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452. | Article | PubMed | ISI | CAS |
  163. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56. | Article | PubMed | ISI | CAS |
  164. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. New Engl J Med 2001; 344: 961–966. | Article | PubMed |
  165. Raison CL, Borisov AS, Broadwell SD, Capuron L, Woolwine BJ, Jacobson IM et al. Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction. J Clin Psychiatry 2005; 66: 41–48. | Article | PubMed | ISI | CAS |
  166. Kraus MR, Schafer A, Csef H, Scheurlen M. Psychiatric side effects of pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients with chronic hepatitis C. World J Gastroenterol 2005; 11: 1769–1774. | PubMed | ISI |
  167. Reichenberg A, Gorman JM, Dieterich DT. Interferon-induced depression and cognitive impairment in hepatitis C virus patients: a 72 week prospective study. AIDS 2005; 19(Suppl 3): S174–S178. | Article | PubMed | ISI | CAS |
  168. Andreasson A, Arborelius L, Erlanson-Albertsson C, Lekander M. A putative role for cytokines in the impaired appetite in depression. Brain Behav Immun 2007; 21: 147–152. | Article | PubMed | ISI |
  169. Maier SF, Watkins LR. Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 1998; 105: 83–107. | Article | PubMed | ISI | CAS |
  170. Yirmiya R, Weidenfeld J, Pollak Y, Morag M, Morag A, Avitsur R et al. Cytokines, “depression due to a general medical condition,” and antidepressant drugs. Adv Exper Med Biol 1999; 461: 283–316.
  171. Hayley S, Merali Z, Anisman H. Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: implications for depressive illness. Stress 2003; 6: 19–32. | Article | PubMed | ISI |
  172. Gibb J, Audet MC, Hayley S, Anisman H. Neurochemical and behavioral responses to inflammatory immune stressors. Front Biosci (Schol Ed) 2009; 1: 275–295. | PubMed |
  173. Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G et al. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis 2009; 24: 27–53. | Article | PubMed | ISI | CAS |
  174. Simon GE, Ludman EJ, Linde JA, Operskalski BH, Ichikawa L, Rohde P et al. Association between obesity and depression in middle-aged women. Gen Hosp Psychiatry 2008; 30: 32–39. | Article | PubMed | ISI |
  175. Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry 2006; 63: 824–830. | Article | PubMed | ISI |
  176. Miller GE, Freedland KE, Carney RM, Stetler CA, Banks WA. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun 2003; 17: 276–285. | Article | PubMed | ISI |
  177. Lampert R, Bremner JD, Su S, Miller A, Lee F, Cheema F et al. Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men. Am Heart J 2008; 156: 759 e751–757. | Article | PubMed |
  178. Ranjit N, Diez-Roux AV, Shea S, Cushman M, Seeman T, Jackson SA et al. Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Arch Int Med 2007; 167: 174–181. | Article |
  179. Kloiber S, Ising M, Reppermund S, Horstmann S, Dose T, Majer M et al. Overweight and obesity affect treatment response in major depression. Biol Psychiatry 2007; 62: 321–326. | Article | PubMed | ISI |
  180. Himmerich H, Fulda S, Linseisen J, Seiler H, Wolfram G, Himmerich S et al. TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population. Eur Cytokine Network 2006; 17: 196–201. | ISI |
  181. Suarez EC. C-reactive protein is associated with psychological risk factors of cardiovascular disease in apparently healthy adults. Psychosom Med 2004; 66: 684–691. | Article | PubMed | ISI |
  182. Douglas KM, Taylor AJ, O’Malley PG. Relationship between depression and C-reactive protein in a screening population. Psychosom Med 2004; 66: 679–683. | Article | PubMed | ISI | CAS |
  183. Roberts RE, Deleger S, Strawbridge WJ, Kaplan GA. Prospective association between obesity and depression: evidence from the Alameda County Study. Int J Obes Relat Metab Disord 2003; 27: 514–521. | Article | PubMed | CAS |
  184. Pine DS, Goldstein RB, Wolk S, Weissman MM. The association between childhood depression and adulthood body mass index. Pediatrics 2001; 107: 1049–1056. | Article | PubMed | ISI | CAS |
  185. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280: E745–E751. | PubMed | ISI | CAS |
  186. Katz JR, Taylor NF, Goodrick S, Perry L, Yudkin JS, Coppack SW. Central obesity, depression and the hypothalamo-pituitary-adrenal axis in men and postmenopausal women. Int J Obesity Related Metab Disord 2000; 24: 246–251. | Article |
  187. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 1999; 33: 407–418. | Article | PubMed | ISI | CAS |
  188. Vieira VJ, Valentine RJ, McAuley E, Evans E, Woods JA. Independent relationship between heart rate recovery and C-reactive protein in older adults. J Am Geriat Soc 2007; 55: 747–751. | Article | PubMed |
  189. Moyna NM, Bodnar JD, Goldberg HR, Shurin MS, Robertson RJ, Rabin BS. Relation between aerobic fitness level and stress induced alterations in neuroendocrine and immune function. Int J Sports Med 1999; 20: 136–141. | PubMed | ISI |
  190. Kohut ML, McCann DA, Russell DW, Konopka DN, Cunnick JE, Franke WD et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun 2006; 20: 201–209. | Article | PubMed | ISI | CAS |
  191. Balducci S, Zanuso S, Nicolucci A, Fernando F, Cavallo S, Cardelli P et al. Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss. Nutr Metab Cardiovasc Dis 2010; 20: 608–617. | Article | PubMed |
  192. Ghosh S, Khazaei M, Moien-Afshari F, Ang LS, Granville DJ, Verchere CB et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol 2009; 296: F700–F708. | Article | PubMed | ISI |
  193. Anton SD, Newton Jr RL, Sothern M, Martin CK, Stewart TM, Williamson DA. Association of depression with body mass index, sedentary behavior, and maladaptive eating attitudes and behaviors in 11 to 13-year old children. Eat Weight Disord 2006; 11: e102–e108. | PubMed |
  194. Colditz GA. Economic costs of obesity and inactivity. Med Sci Sports Exerc 1999; 31: S663–S667. | Article | PubMed | ISI | CAS |
  195. Rajala U, Uusimaki A, Keinanen-Kiukaanniemi S, Kivela SL. Prevalence of depression in a 55-year-old Finnish population. Soc Psychiatry Psychiatr Epidemiol 1994; 29: 126–130. | PubMed |
  196. Tanskanen A, Hibbeln JR, Tuomilehto J, Uutela A, Haukkala A, Viinamaki H et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv 2001; 52: 529–531. | Article | PubMed | ISI | CAS |
  197. Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer HY. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 1999; 85: 275–291. | Article | PubMed | ISI | CAS |
  198. Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H. Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J Affect Disord 1996; 38: 35–46. | Article | PubMed | ISI | CAS |
  199. Williams LL, Kiecolt-Glaser JK, Horrocks LA, Hillhouse JT, Glaser R. Quantitative association between altered plasma esterified omega-6 fatty acid proportions and psychological stress. Prostaglandins Leukot Essent Fatty Acids 1992; 47: 165–170. | Article | PubMed | ISI |
  200. Dai J, Miller AH, Bremner JD, Goldberg J, Jones L, Shallenberger L et al. Adherence to the mediterranean diet is inversely associated with circulating interleukin-6 among middle-aged men: a twin study. Circulation 2008; 117: 169–175. | Article | PubMed | ISI |
  201. Zampelas A, Panagiotakos DB, Pitsavos C, Das UN, Chrysohoou C, Skoumas Y et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiol 2005; 46: 120–124. | Article | PubMed | ISI |
  202. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol 2004; 44: 152–158. | Article | PubMed | ISI |
  203. Westover AN, Marangell LB. A cross-national relationship between sugar consumption and major depression? Depress Anxiety 2002; 16: 118–120. | Article | PubMed | ISI |
  204. O’Keefe JH, Gheewala NM, O’Keefe JO. Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health. J Am Coll Cardiol 2008; 51: 249–255. | Article | PubMed | ISI | CAS |
  205. Schulze MB, Hoffmann K, Manson JE, Willett WC, Meigs JB, Weikert C et al. Dietary pattern, inflammation, and incidence of type 2 diabetes in women. Am J Clin Nutr 2005; 82: 675–684; quiz 714–715. | PubMed | ISI | CAS |
  206. Lee O, Bruce WR, Dong Q, Bruce J, Mehta R, O’Brien PJ. Fructose and carbonyl metabolites as endogenous toxins. Chem Biol Interact 2009; 178: 332–339. | Article | PubMed | CAS |
  207. O’Connor MF, Bower JE, Cho HJ, Creswell JD, Dimitrov S, Hamby ME et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009; 23: 887–897. | Article | PubMed | ISI |
  208. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989; 262: 1479–1484. | Article | PubMed | CAS |
  209. Livingston G, Blizard B, Mann A. Does sleep disturbance predict depression in elderly people? A study in inner London. Brit J Gen Pract 1993; 43: 445–448.
  210. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996; 39: 411–418. | Article | PubMed | ISI | CAS |
  211. Gillin JC. Are sleep disturbances risk factors for anxiety, depressive and addictive disorders? Acta Psychiatr Scand Suppl 1998; 393: 39–43. | Article | PubMed |
  212. Irwin MR, Wang M, Ribeiro D, Cho HJ, Olmstead R, Breen EC et al. Sleep loss activates cellular inflammatory signaling. Biol Psychiatry 2008; 64: 538–540. | Article | PubMed | ISI |
  213. McDade TW, Hawkley LC, Cacioppo JT. Psychosocial and behavioral predictors of inflammation in middle-aged and older adults: the Chicago health, aging, and social relations study. Psychosom Med 2006; 68: 376–381. | Article | PubMed | ISI |
  214. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Int Med 2006; 166: 1756–1762. | Article |
  215. Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004; 43: 678–683. | Article | PubMed | ISI | CAS |
  216. Friedman EM, Hayney MS, Love GD, Urry HL, Rosenkranz MA, Davidson RJ et al. Social relationships, sleep quality, and interleukin-6 in aging women. Proc Natl Acad Sci USA 2005; 102: 18757–18762. | Article | PubMed | CAS |
  217. Irwin M, Rinetti G, Redwine L, Motivala S, Dang J, Ehlers C. Nocturnal proinflammatory cytokine-associated sleep disturbances in abstinent African American alcoholics. Brain Behav Immun 2004; 18: 349–360. | Article | PubMed | ISI |
  218. Vgontzas AN, Zoumakis M, Papanicolaou DA, Bixler EO, Prolo P, Lin HM et al. Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime. Metab Clin Exper 2002; 51: 887–892. | Article |
  219. Redwine L, Hauger RL, Gillin JC, Irwin M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 2000; 85: 3597–3603. | Article | PubMed | ISI | CAS |
  220. Saules KK, Pomerleau CS, Snedecor SM, Mehringer AM, Shadle MB, Kurth C et al. Relationship of onset of cigarette smoking during college to alcohol use, dieting concerns, and depressed mood: results from the Young Women’s Health Survey. Addict Behav 2004; 29: 893–899. | Article | PubMed |
  221. Lenz BK. Tobacco, depression, and lifestyle choices in the pivotal early college years. J Am Coll Health 2004; 52: 213–219. | Article | PubMed |
  222. Handwerker WP. Cultural diversity, stress, and depression: working women in the Americas. J Women Health Gend Based Med 1999; 8: 1303–1311. | Article |
  223. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 2007; 370: 851–858. | Article | PubMed | ISI |
  224. Brown GW, Harris TO, Hepworth C. Life events and endogenous depression. A puzzle reexamined. Arch Gen Psychiat 1994; 51: 525–534. | Article | PubMed |
  225. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry 2000; 157: 1243–1251. | Article | PubMed | ISI | CAS |
  226. DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock 1995; 4: 233–240. | Article | PubMed | ISI | CAS |
  227. Ross SR, Bloomsmith MA, Bettinger TL, Wagner KE. The influence of captive adolescent male chimpanzees on wounding: management and welfare implications. Zoo Biol 2009; 28: 623–634. | Article | PubMed | ISI |
  228. Eshed V, Gopher A, Pinhasi R, Hershkovitz I. Paleopathology and the origin of agriculture in the Levant. Am J Phys Anthropol 2010; 143: 121–133. | Article | PubMed | ISI |
  229. Pinker S. The Better Angels of Our Nature: Why Violence Has Declined. Viking Adult: New York, NY, 2011.
  230. Dhabhar FS. Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology. Neuroimmunomodulation 2009; 16: 300–317. | Article | PubMed | ISI |
  231. Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med 1993; 55: 364–379. | PubMed | ISI | CAS |
  232. Bailey MT, Kinsey SG, Padgett DA, Sheridan JF, Leblebicioglu B. Social stress enhances IL-1beta and TNF-alpha production by Porphyromonas gingivalis lipopolysaccharide-stimulated CD11b+ cells. Physiol Behav 2009; 98: 351–358. | Article | PubMed | ISI |
  233. Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, Miller AH et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry 2006; 163: 1630–1633. | Article | PubMed | ISI |
  234. Powell ND, Mays JW, Bailey MT, Hanke ML, Sheridan JF. Immunogenic dendritic cells primed by social defeat enhance adaptive immunity to influenza A virus. Brain Behav Immun 2011; 25: 46–52. | Article | PubMed | ISI |
  235. Mays JW, Bailey MT, Hunzeker JT, Powell ND, Papenfuss T, Karlsson EA et al. Influenza virus-specific immunological memory is enhanced by repeated social defeat. J Immunol 2010; 184: 2014–2025. | Article | PubMed | ISI |
  236. Steptoe A, Hamer M, Chida Y. The effect of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 2007; 7: 901–912. | Article |
  237. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA 2003; 100: 1920–1925. | Article | PubMed | CAS |
  238. Avitsur R, Kavelaars A, Heijnen C, Sheridan JF. Social stress and the regulation of tumor necrosis factor-alpha secretion. Brain Behav Immun 2005; 19: 311–317. | Article | PubMed | ISI |
  239. Quan N, Avitsur R, Stark JL, He L, Shah M, Caligiuri M et al. Social stress increases the susceptibility to endotoxic shock. J Neuroimmunol 2001; 115: 36–45. | Article | PubMed | ISI | CAS |
  240. Rosenberger PH, Ickovics JR, Epel E, Nadler E, Jokl P, Fulkerson JP et al. Surgical stress-induced immune cell redistribution profiles predict short-term and long-term postsurgical recovery. A prospective study. J Bone Joint Surg Am 2009; 91: 2783–2794. | Article | PubMed |
  241. Joachim RA, Handjiski B, Blois SM, Hagen E, Paus R, Arck PC. Stress-induced neurogenic inflammation in murine skin skews dendritic cells towards maturation and migration: key role of intercellular adhesion molecule-1/leukocyte function-associated antigen interactions. Am J Pathol 2008; 173: 1379–1388. | Article | PubMed | ISI |
  242. Viswanathan K, Daugherty C, Dhabhar FS. Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity. Int Immunol 2005; 17: 1059–1069. | Article | PubMed | ISI | CAS |
  243. Miller GE, Chen E. Harsh family climate in early life presages the emergence of a proinflammatory phenotype in adolescence. Psychol Sci 2010; 21: 848–856. | Article | PubMed |
  244. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 2008; 65: 409–415. | Article | PubMed | ISI |
  245. Miller GE, Rohleder N, Cole SW. Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later. Psychosom Med 2009; 71: 57–62. | Article | PubMed | ISI |
  246. Miller GE, Chen E, Sze J, Marin T, Arevalo JM, Doll R et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry 2008; 64: 266–272. | Article | PubMed | ISI | CAS |
  247. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011; 137: 959–997. | Article | PubMed | ISI |
  248. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA 2003; 100: 9090–9095. | Article | PubMed | CAS |
  249. Nesse RM. The smoke detector principle. Natural selection and the regulation of defensive responses. Ann NY Acad Sci 2001; 935: 75–85. | Article | PubMed |
  250. Kiecolt-Glaser JK. Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge. Psychosom Med 2010; 72: 365–369. | Article | PubMed | ISI |
  251. Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacol: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137–162. | Article | PubMed | ISI |
  252. Irwin MR, Cole SW. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol 2011; 11: 625–632. | Article | PubMed | ISI | CAS |
  253. Leutscher PD, Lagging M, Buhl MR, Pedersen C, Norkrans G, Langeland N et al. Evaluation of depression as a risk factor for treatment failure in chronic hepatitis C. Hepatology 2010; 52: 430–435. | Article | PubMed | ISI |
  254. Raison CL, Broadwell SD, Borisov AS, Manatunga AK, Woolwine BJ, Jacobson IM et al. Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C. Brain Behav Immun 2005; 19: 23–27. | Article | PubMed | ISI | CAS |
  255. Doering LV, Martinez-Maza O, Vredevoe DL, Cowan MJ. Relation of depression, natural killer cell function, and infections after coronary artery bypass in women. Eur J Cardiovasc Nurs 2008; 7: 52–58. | Article | PubMed | ISI |
  256. Faulkner S, Smith A. A longitudinal study of the relationship between psychological distress and recurrence of upper respiratory tract infections in chronic fatigue syndrome. Br J Health Psychol 2008; 13: 177–186. | Article | PubMed |
  257. Cruess DG, Petitto JM, Leserman J, Douglas SD, Gettes DR, Ten Have TR et al. Depression and HIV infection: impact on immune function and disease progression. CNS Spectr 2003; 8: 52–58. | PubMed | ISI |
  258. Leserman J. Role of depression, stress, and trauma in HIV disease progression. Psychosom Med 2008; 70: 539–545. | Article | PubMed | ISI |
  259. Evans DL, Ten Have TR, Douglas SD, Gettes DR, Morrison M, Chiappini MS et al. Association of depression with viral load, CD8T lymphocytes, and natural killer cells in women with HIV infection. Am J Psychiatry 2002; 159: 1752–1759. | Article | PubMed | ISI |
  260. Zorrilla EP, McKay JR, Luborsky L, Schmidt K. Relation of stressors and depressive symptoms to clinical progression of viral illness. Am J Psychiatry 1996; 153: 626–635. | PubMed | ISI |
  261. Herbert TB, Cohen S. Depression and immunity: a meta-analytic review. Psychol Bull 1993; 113: 472–486. | Article | PubMed | ISI | CAS |
  262. Castilla-Cortazar I, Castilla A, Gurpegui M. Opioid peptides and immunodysfunction in patients with major depression and anxiety disorders. J Physiol Biochem 1998; 54: 203–215. | PubMed | ISI |
  263. Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in depression. Brain Behav Immun 2011; 25: 221–229. | Article | PubMed | ISI |
  264. Vaknin I, Blinder L, Wang L, Gazit R, Shapira E, Genina O et al. A common pathway mediated through Toll-like receptors leads to T- and natural killer-cell immunosuppression. Blood 2008; 111: 1437–1447. | Article | PubMed | ISI |
  265. Moraska A, Campisi J, Nguyen KT, Maier SF, Watkins LR, Fleshner M. Elevated IL-1beta contributes to antibody suppression produced by stress. J Appl Physiol 2002; 93: 207–215. | PubMed | ISI |
  266. Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997; 185: 1573–1584. | Article | PubMed | ISI | CAS |
  267. Cope AP. Exploring the reciprocal relationship between immunity and inflammation in chronic inflammatory arthritis. Rheumatology (Oxford) 2003; 42: 716–731. | Article | PubMed | ISI | CAS |
  268. Eleftheriadis T, Kartsios C, Yiannaki E, Antoniadi G, Kazila P, Pliakos K et al. Decreased CD3+CD16+ natural killer-like T-cell percentage and zeta-chain expression accompany chronic inflammation in haemodialysis patients. Nephrology (Carlton) 2009; 14: 471–475. | Article | PubMed |
  269. Muller AJ, Sharma MD, Chandler PR, Duhadaway JB, Everhart ME, Johnson III BA et al. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc Natl Acad Sci USA 2008; 105: 17073–17078. | Article | PubMed |
  270. Clark J, Vagenas P, Panesar M, Cope AP. What does tumour necrosis factor excess do to the immune system long term? Ann Rheum Dis 2005; 64(Suppl 4): iv70–iv76. | Article | PubMed |
  271. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002; 46: 2287–2293. | Article | PubMed | ISI |
  272. Armelagos GJ, Brown PJ, Turner B. Evolutionary, historical and political economic perspectives on health and disease. Soc Sci Med 2005; 61: 755–765. | Article | PubMed |
  273. May L, van den Biggelaar AH, van Bodegom D, Meij HJ, de Craen AJ, Amankwa J et al. Adverse environmental conditions influence age-related innate immune responsiveness. Immun Ageing 2009; 6: 7. | Article | PubMed |
  274. Drenos F, Westendorp RG, Kirkwood TB. Trade-off mediated effects on the genetics of human survival caused by increasingly benign living conditions. Biogerontology 2006; 7: 287–295. | Article | PubMed | ISI |
  275. Raison CL, Lowry CA, Rook GA. Inflammation, sanitation, and consternation: loss of contact with coevolved, tolerogenic microorganisms and the pathophysiology and treatment of major depression. Arch Gen Psychiatry 2010; 67: 1211–1224. | Article | PubMed | ISI |
  276. Joosten KF, de Kleijn ED, Westerterp M, de Hoog M, Eijck FC, Hop WCJ et al. Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000; 85: 3746–3753. | Article | PubMed | ISI | CAS |
  277. Pinto RA, Arredondo SM, Bono MR, Gaggero AA, Diaz PV. T helper 1/T helper 2 cytokine imbalance in respiratory syncytial virus infection is associated with increased endogenous plasma cortisol. Pediatrics 2006; 117: e878–e886. | Article | PubMed | ISI |
  278. Gallagher PM, Lowe G, Fitzgerald T, Bella A, Greene CM, McElvaney NG et al. Association of IL-10 polymorphism with severity of illness in community acquired pneumonia. Thorax 2003; 58: 154–156. | Article | PubMed | ISI |
  279. Li J, Cowden LG, King JD, Briles DA, Schroeder Jr HW, Stevens AB et al. Effects of chronic stress and interleukin-10 gene polymorphisms on antibody response to tetanus vaccine in family caregivers of patients with Alzheimer’s disease. Psychosom Med 2007; 69: 551–559. | Article | PubMed | ISI |
  280. Hohler T, Reuss E, Freitag CM, Schneider PM. A functional polymorphism in the IL-10 promoter influences the response after vaccination with HBsAg and hepatitis A. Hepatology 2005; 42: 72–76. | Article | PubMed | ISI | CAS |
  281. Corsini E, Vismara L, Lucchi L, Viviani B, Govoni S, Galli CL et al. High interleukin-10 production is associated with low antibody response to influenza vaccination in the elderly. J Leukoc Biol 2006; 80: 376–382. | Article | PubMed | ISI |
  282. Forte GI, Scola L, Misiano G, Milano S, Mansueto P, Vitale G et al. Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever. Clin Vaccine Immunol 2009; 16: 811–815. | Article | PubMed | ISI |
  283. Pravica V, Asderakis A, Perrey C, Hajeer A, Sinnott PJ, Hutchinson IV. In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene. Eur J Immunogenet 1999; 26: 1–3. | Article | PubMed | ISI | CAS |
  284. Pravica V, Perrey C, Stevens A, Lee JH, Hutchinson IV. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 2000; 61: 863–866. | Article | PubMed | ISI | CAS |
  285. Pacheco AG, Cardoso CC, Moraes MO. IFNG +874T/A, IL10 −1082G/A and TNF −308G/A polymorphisms in association with tuberculosis susceptibility: a meta-analysis study. Hum Genet 2008; 123: 477–484. | Article | PubMed | ISI | CAS |
  286. Ansari A, Talat N, Jamil B, Hasan Z, Razzaki T, Dawood G et al. Cytokine gene polymorphisms across tuberculosis clinical spectrum in Pakistani patients. PLoS One 2009; 4: e4778. | Article | PubMed |
  287. Cardoso CC, Pereira AC, Brito-de-Souza VN, Dias-Baptista IM, Maniero VC, Venturini J et al. IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians. Hum Genet 2010; 128: 481–490. | Article | PubMed | ISI |
  288. Chong WP, Ip WK, Tso GH, Ng MW, Wong WH, Law HK et al. The interferon gamma gene polymorphism +874 A/T is associated with severe acute respiratory syndrome. BMC Infect Dis 2006; 6: 82. | Article | PubMed |
  289. Torres OA, Calzada JE, Beraun Y, Morillo CA, Gonzalez A, Gonzalez CI et al. Role of the IFNG +874T/A polymorphism in Chagas disease in a Colombian population. Infect Genet Evol 2010; 10: 682–685. | Article | PubMed | ISI |
  290. Gao QJ, Liu DW, Zhang SY, Jia M, Wang LM, Wu LH et al. Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 2009; 15: 5610–5619. | Article | PubMed | ISI |
  291. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M et al. Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology 2001; 24: 531–544. | Article | PubMed | ISI | CAS |
  292. Merali Z, Brennan K, Brau P, Anisman H. Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for “free chow” and “earned” sucrose intake. Psychopharmacology (Berl) 2003; 165: 413–418. | PubMed | CAS |
  293. Dunn AJ, Swiergiel AH. The reductions in sweetened milk intake induced by interleukin-1 and endotoxin are not prevented by chronic antidepressant treatment. Neuroimmunomodulation 2001; 9: 163–169. | Article | PubMed | ISI | CAS |
  294. Castanon N, Bluthe RM, Dantzer R. Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat. Psychopharmacology 2001; 154: 50–60. | Article | PubMed | ISI |
  295. Shen Y, Connor TJ, Nolan Y, Kelly JP, Leonard BE. Differential effect of chronic antidepressant treatments on lipopolysaccharide-induced depressive-like behavioural symptoms in the rat. Life Sci 1999; 65: 1773–1786. | Article | PubMed | ISI |
  296. Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs 2005; 19: 105–123. | Article | PubMed | ISI | CAS |
  297. Capuron L, Fornwalt FB, Knight BT, Harvey PD, Ninan PT, Miller AH. Does cytokine-induced depression differ from idiopathic major depression in medically healthy individuals? J Affect Disord 2009; 119: 181–185. | Article | PubMed | ISI |
  298. Raison CL, Woolwine BJ, Demetrashvili MF, Borisov AS, Weinreib R, Staab JP et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharm Ther 2007; 25: 1163–1174. | Article |
  299. Kraus MR, Schafer A, Al-Taie O, Scheurlen M. Prophylactic SSRI during interferon alpha re-therapy in patients with chronic hepatitis C and a history of interferon-induced depression. J Viral Hepatitis 2005; 12: 96–100. | Article | ISI |
  300. Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment Pharm Ther 2002; 16: 1091–1099. | Article |
  301. Hauser P, Khosla J, Aurora H, Laurin J, Kling MA, Hill J et al. A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7: 942–947. | Article | PubMed | ISI | CAS |
  302. Wichers MC, Koek GH, Robaeys G, Praamstra AJ, Maes M. Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med 2005; 35: 433–441. | Article | PubMed | ISI | CAS |
  303. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 2010; 68: 748–754. | Article | PubMed | ISI |
  304. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009; 66: 407–414. | Article | PubMed | ISI |
  305. Raison CL, Rye DB, Woolwine BJ, Vogt GJ, Bautista BM, Spivey JR et al. Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with Hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry 2010; 68: 942–949. | Article | PubMed | ISI |
  306. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 2010; 15: 393–403. | Article | PubMed | ISI |
  307. Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Mol Psychiatry 2010; 15: 535–547. | Article | PubMed | ISI |
  308. Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ et al. Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression. Biol Psychiatry 2009; 65: 296–303. | Article | PubMed | ISI | CAS |
  309. Capuron L, Pagnoni G, Demetrashvili MF, Lawson DH, Fornwalt FB, Woolwine BJ et al. Basal ganglia hypermetabolism and symptoms of fatigue during interferon-alpha therapy. Neuropsychopharmacology 2007; 32: 2384–2392. | Article | PubMed | ISI |
  310. Capuron L, Pagnoni G, Demetrashvili M, Woolwine BJ, Nemeroff CB, Berns GS et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry 2005; 58: 190–196. | Article | PubMed | ISI | CAS |
  311. Hanff TC, Furst SJ, Minor TR. Biochemical and anatomical substrates of depression and sickness behavior. Isr J Psychiatry Relat Sci 2010; 47: 64–71. | PubMed |
  312. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988; 12: 123–137. | Article | PubMed | ISI | CAS |
  313. Hart BL. Behavioral adaptations to pathogens and parasites: five strategies. Neurosci Biobehav Rev 1990; 14: 273–294. | Article | PubMed | ISI |
  314. Kluger MJ. Phylogeny of fever. Fed Proc 1979; 38: 30–34. | PubMed |
  315. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D. Role of fever in disease. Ann NY Acad Sci 1998; 856: 224–233. | Article | PubMed |
  316. Sweet C, Cavanagh D, Collie MH, Smith H. Sensitivity to pyrexial temperatures: a factor contributing to virulence differences between two clones of influenza virus. Br J Exp Pathol 1978; 59: 373–380. | PubMed |
  317. Dixon G, Booth C, Price E, Westran R, Turner M, Klein N. Fever as nature’s engine. Part of beneficial host response? BMJ 2010; 340: c450. | Article | PubMed |
  318. Tyrrell D, Barrow I, Arthur J. Local hyperthermia benefits natural and experimental common colds. BMJ 1989; 298: 1280–1283. | Article | PubMed | ISI |
  319. Ostberg JR, Taylor SL, Baumann H, Repasky EA. Regulatory effects of fever-range whole-body hyperthermia on the LPS-induced acute inflammatory response. J Leukoc Biol 2000; 68: 815–820. | PubMed | ISI |
  320. Jiang Q, Detolla L, Singh IS, Gatdula L, Fitzgerald B, van Rooijen N et al. Exposure to febrile temperature upregulates expression of pyrogenic cytokines in endotoxin-challenged mice. Am J Physiol 1999; 276: R1653–R1660. | PubMed | CAS |
  321. Ostberg JR, Dayanc BE, Yuan M, Oflazoglu E, Repasky EA. Enhancement of natural killer (NK) cell cytotoxicity by fever-range thermal stress is dependent on NKG2D function and is associated with plasma membrane NKG2D clustering and increased expression of MICA on target cells. J Leukoc Biol 2007; 82: 1322–1331. | Article | PubMed | ISI |
  322. Ostberg JR, Repasky EA. Emerging evidence indicates that physiologically relevant thermal stress regulates dendritic cell function. Cancer Immunol Immunother 2006; 55: 292–298. | Article | PubMed | ISI |
  323. Evans SS, Wang WC, Bain MD, Burd R, Ostberg JR, Repasky EA. Fever-range hyperthermia dynamically regulates lymphocyte delivery to high endothelial venules. Blood 2001; 97: 2727–2733. | Article | PubMed | ISI | CAS |
  324. Swenson BR, Hedrick TL, Popovsky K, Pruett TL, Sawyer RG. Is fever protective in surgical patients with bloodstream infection? J Am Coll Surg 2007; 204: 815–821; discussion 822–823. | Article | PubMed | ISI |
  325. Mizushima Y, Ueno M, Idoguchi K, Ishikawa K, Matsuoka T. Fever in trauma patients: friend or foe? J Trauma 2009; 67: 1062–1065. | Article | PubMed |
  326. Ohsugi Y. Recent advances in immunopathophysiology of interleukin-6: an innovative therapeutic drug, tocilizumab (recombinant humanized anti-human interleukin-6 receptor antibody), unveils the mysterious etiology of immune-mediated inflammatory diseases. Biol Pharm Bull 2007; 30: 2001–2006. | Article | PubMed | ISI |
  327. Kung’u JK, Wright VJ, Haji HJ, Ramsan M, Goodman D, Tielsch JM et al. Adjusting for the acute phase response is essential to interpret iron status indicators among young Zanzibari children prone to chronic malaria and helminth infections. J Nutr 2009; 139: 2124–2131. | Article | PubMed | ISI |
  328. Cartwright GE, Lauritsen MA et al. The anemia of infection; hypoferremia, hypercupremia, and alterations in porphyrin metabolism in patients. J Clin Invest 1946; 25: 65–80. | Article | PubMed | CAS |
  329. Kochan I, Wagner SK, Wasynczuk J. Effect of iron on antibacterial immunity in vaccinated mice. Infect Immun 1984; 43: 543–548. | PubMed | ISI |
  330. Weinberg ED. Survival advantage of the hemochromatosis C282Y mutation. Perspect Biol Med 2008; 51: 98–102. | Article | PubMed | ISI |
  331. Foster SL, Richardson SH, Failla ML. Elevated iron status increases bacterial invasion and survival and alters cytokine/chemokine mRNA expression in Caco-2 human intestinal cells. J Nutr 2001; 131: 1452–1458. | PubMed | ISI |
  332. Wander K, Shell-Duncan B, McDade TW. Evaluation of iron deficiency as a nutritional adaptation to infectious disease: an evolutionary medicine perspective. Am J Hum Biol 2009; 21: 172–179. | Article | PubMed | ISI |
  333. Mitra AK, Akramuzzaman SM, Fuchs GJ, Rahman MM, Mahalanabis D. Long-term oral supplementation with iron is not harmful for young children in a poor community of Bangladesh. J Nutr 1997; 127: 1451–1455. | PubMed | ISI |
  334. Smith AW, Hendrickse RG, Harrison C, Hayes RJ, Greenwood BM. The effects on malaria of treatment of iron-deficiency anaemia with oral iron in Gambian children. Ann Trop Paediatr 1989; 9: 17–23. | PubMed | ISI |
  335. van den Hombergh J, Dalderop E, Smit Y. Does iron therapy benefit children with severe malaria-associated anaemia? A clinical trial with 12 weeks supplementation of oral iron in young children from the Turiani Division, Tanzania. J Trop Pediatr 1996; 42: 220–227. | Article | PubMed |
  336. Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R et al. Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial. Lancet 2006; 367: 144–152. | Article | PubMed | ISI | CAS |
  337. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006; 367: 133–143. | Article | PubMed | ISI | CAS |
  338. McEnany GW, Lee KA. Effects of light therapy on sleep, mood, and temperature in women with nonseasonal major depression. Issues Ment Health Nurs 2005; 26: 781–794. | Article | PubMed |
  339. Rausch JL, Johnson ME, Corley KM, Hobby HM, Shendarkar N, Fei Y et al. Depressed patients have higher body temperature: 5-HT transporter long promoter region effects. Neuropsychobiology 2003; 47: 120–127. | Article | PubMed | ISI | CAS |
  340. Szuba MP, Guze BH, Baxter Jr LR. Electroconvulsive therapy increases circadian amplitude and lowers core body temperature in depressed subjects. Biol Psychiatry 1997; 42: 1130–1137. | Article | PubMed | ISI |
  341. Daimon K, Yamada N, Tsujimoto T, Takahashi S. Circadian rhythm abnormalities of deep body temperature in depressive disorders. J Affect Disord 1992; 26: 191–198. | Article | PubMed | ISI | CAS |
  342. Avery DH, Shah SH, Eder DN, Wildschiodtz G. Nocturnal sweating and temperature in depression. Acta Psychiatr Scand 1999; 100: 295–301. | Article | PubMed | ISI | CAS |
  343. Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafaelsen OJ. REM latency and core temperature relationships in primary depression. Acta Psychiatr Scand 1986; 74: 269–280. | Article | PubMed | ISI |
  344. Avery DH, Wildschiodtz G, Rafaelsen OJ. Nocturnal temperature in affective disorder. J Affect Disord 1982; 4: 61–71. | Article | PubMed | ISI |
  345. Sugahara H, Akamine M, Kondo T, Fujisawa K, Yoshimasu K, Tokunaga S et al. Somatic symptoms most often associated with depression in an urban hospital medical setting in Japan. Psychiatry Res 2004; 128: 305–311. | Article | PubMed |
  346. Rangan AM, Blight GD, Binns CW. Iron status and non-specific symptoms of female students. J Am Coll Nutr 1998; 17: 351–355. | PubMed | ISI |
  347. Maes M, Van de Vyvere J, Vandoolaeghe E, Bril T, Demedts P, Wauters A et al. Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process. J Affect Disord 1996; 40: 23–33. | Article | PubMed | ISI |
  348. Maes M, Vandewoude M, Scharpe S, De Clercq L, Stevens W, Lepoutre L et al. Anthropometric and biochemical assessment of the nutritional state in depression: evidence for lower visceral protein plasma levels in depression. J Affect Disord 1991; 23: 25–33. | Article | PubMed | ISI |
  349. Maes M, Scharpe S, Bosmans E, Vandewoude M, Suy E, Uyttenbroeck W et al. Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness. Prog Neuropsychopharmacol Biol Psychiatry 1992; 16: 501–515. | Article | PubMed |
  350. Albacar G, Sans T, Martin-Santos R, Garcia-Esteve L, Guillamat R, Sanjuan J et al. An association between plasma ferritin concentrations measured 48h after delivery and postpartum depression. J Affect Disord 2011; 131: 136–142. | Article | PubMed | ISI |
  351. Engel GL, Schmale AH. Conservation-withdrawal: a primary regulatory process for organismic homeostasis. Ciba Found Symp 1972; 8: 57–75. | PubMed |
  352. Majer M, Wellberg LAM, Capuron L, Pagnoni G, Raison CL, Miller AH. IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C. Brain Behav Immun 2008; 25: 870–880. | Article |
  353. Capuron L, Gumnick JF, Musselman DL, Lawson DH, Reemsnyder A, Nemeroff CB et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 2002; 26: 643–652. | Article | PubMed | ISI | CAS |
  354. Schaller M, Murray DR. Pathogens, personality, and culture: disease prevalence predicts worldwide variability in sociosexuality, extraversion, and openness to experience. J Pers Soc Psychol 2008; 95: 212–221. | Article | PubMed |
  355. Cole SW. The complexity of dynamic host networks. In: Deisboeck TS, Kresh JY (eds). Complex Systems Science in Biomedicine. Springer: New York, NY, 2006, pp 605–629.
  356. Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun 2010; 24: 558–563. | Article | PubMed | ISI |
  357. Slavich GM, Way BM, Eisenberger NI, Taylor SE. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci USA 2010; 107: 14817–14822. | Article | PubMed |
  358. Nguyen KB, Biron CA. Synergism for cytokine-mediated disease during concurrent endotoxin and viral challenges: roles for NK and T cell IFN-gamma production. J Immunol 1999; 162: 5238–5246. | PubMed | ISI | CAS |
  359. Jakab GJ, Dick EC. Synergistic effect in viral-bacterial infection: combined infection of the murine respiratory tract with Sendai virus and Pasteurella pneumotropica. Infect Immun 1973; 8: 762–768. | PubMed |
  360. Degre M, Glasgow LA. Synergistic effect in viral-bacterial infection. I. Combined infection of the respiratory tract in mice with parainfluenza virus and Hemophilus influenza. J Infect Dis 1968; 118: 449–462. | Article | PubMed |
  361. Jones WT, Menna JH, Wennerstrom DE. Lethal synergism induced in mice by influenza type A virus and type Ia group B streptococci. Infect Immun 1983; 41: 618–623. | PubMed | ISI |
  362. Beadling C, Slifka MK. How do viral infections predispose patients to bacterial infections? Curr Opin Infect Dis 2004; 17: 185–191. | Article | PubMed | ISI |
  363. Molyneux EM, Tembo M, Kayira K, Bwanaisa L, Mweneychanya J, Njobvu A et al. The effect of HIV infection on paediatric bacterial meningitis in Blantyre, Malawi. Arch Dis Child 2003; 88: 1112–1118. | Article | PubMed | ISI |
  364. McCullers JA, McAuley JL, Browall S, Iverson AR, Boyd KL, Henriques Normark B. Influenza enhances susceptibility to natural acquisition of and disease due to Streptococcus pneumoniae in ferrets. J Infect Dis 2010; 202: 1287–1295. | Article | PubMed | ISI |
  365. Thornhill R, Fincher CL, Aran D. Parasites, democratization, and the liberalization of values across contemporary countries. Biol Rev Camb Philos Soc 2009; 84: 113–131. | Article | PubMed |
  366. Diagnostic and Statistical Manual of Mental Disorders, 4th edn Text Revision: DSM-IV–4–TR. American Psychiatric Association: Washington, DC, 2000.
  367. Schmidt WD, O’Connor PJ, Cochrane JB, Cantwell M. Resting metabolic rate is influenced by anxiety in college men. J Appl Physiol 1996; 80: 638–642. | PubMed | ISI |
  368. Blaza SE, Garrow JS. The effect of anxiety on metabolic rate. Proc Nutr Soc 1980; 39: 13A. | Article | PubMed |
  369. Bonnet MH, Arand DL. Insomnia, metabolic rate and sleep restoration. J Intern Med 2003; 254: 23–31. | Article | PubMed | ISI |
  370. Bonnet MH, Arand DL. 24-h metabolic rate in insomniacs and matched normal sleepers. Sleep 1995; 18: 581–588. | PubMed | ISI |
  371. Miller GE, Cohen S. Infectious disease and psychoneuroimmunology. In: Vedhara K, Irwin MR (eds). Human Psychoneuroimmunology. Oxford University Press: Oxford, UK, 2005, pp 219–242.
  372. Constant A, Castera L, Dantzer R, Couzigou P, de Ledinghen V, Demotes-Mainard J et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry 2005; 66: 1050–1057. | Article | PubMed | ISI | CAS |
  373. Critchley HD, Mathias CJ, Josephs O, O’Doherty J, Zanini S, Dewar BK et al. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 2003; 126: 2139–2152. | Article | PubMed | ISI |
  374. Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? An FMRI study of social exclusion. Science 2003; 302: 290–292. | Article | PubMed | ISI | CAS |
  375. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 2008; 63: 1022–1029. | Article | PubMed | CAS |
  376. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry 2009; 66: 415–422. | Article | PubMed | ISI |
  377. Wing EJ, Barczynski LK, Boehmer SM. Effect of acute nutritional deprivation on immune function in mice. I. Macrophages. Immunol 1983; 48: 543–550.
  378. Murray MJ, Murray AB. Anorexia of infection as a mechanism of host defense. Am J Clin Nutr 1979; 32: 593–596. | PubMed |
  379. Heuer JG, Bailey DL, Sharma GR, Zhang T, Ding C, Ford A et al. Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness. J Surg Res 2004; 121: 178–186. | Article | PubMed | ISI | CAS |
  380. Sena MJ, Utter GH, Cuschieri J, Maier RV, Tompkins RG, Harbrecht BG et al. Early supplemental parenteral nutrition is associated with increased infectious complications in critically ill trauma patients. J Am Coll Surg 2008; 207: 459–467. | Article | PubMed | ISI |
  381. Heyland DK. Parenteral nutrition in the critically-ill patient: more harm than good? Proc Nutr Soc 2000; 59: 457–466. | Article | PubMed | ISI |
  382. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365: 506–517. | Article | PubMed | ISI | CAS |
  383. Carter JD, Joyce PR, Mulder RT, Luty SE, McKenzie J. Gender differences in the presentation of depressed outpatients: a comparison of descriptive variables. J Affect Disord 2000; 61: 59–67. | Article | PubMed | ISI | CAS |
  384. Adamo SA, Fidler TL, Forestell CA. Illness-induced anorexia and its possible function in the caterpillar, Manduca sexta. Brain Behav Immun 2007; 21: 292–300. | Article | PubMed | ISI |
  385. Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 1998; 280: 2013–2019. | Article | PubMed | CAS |
  386. Amprey JL, Spath GF, Porcelli SA. Inhibition of CD1 expression in human dendritic cells during intracellular infection with Leishmania donovani. Infect Immun 2004; 72: 589–592. | Article | PubMed | ISI | CAS |
  387. Roura-Mir C, Wang L, Cheng TY, Matsunaga I, Dascher CC, Peng SL et al. Mycobacterium tuberculosis regulates CD1 antigen presentation pathways through TLR-2. J Immunol 2005; 175: 1758–1766. | PubMed | ISI | CAS |
  388. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep 2011; 13: 467–475. | Article | PubMed |
  389. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry 2000; 57: 14–20. | Article | PubMed | ISI | CAS |
  390. Sloman L, Gilbert P, Hasey G. Evolved mechanisms in depression: the role and interaction of attachment and social rank in depression. J Affect Disord 2003; 74: 107–121. | Article | PubMed | ISI |
  391. Andrews PW, Thomson Jr JA. The bright side of being blue: depression as an adaptation for analyzing complex problems. Psychol Rev 2009; 116: 620–654. | Article | PubMed | ISI |
  392. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003; 160: 1554–1565. | Article | PubMed | ISI |
  393. Norbiato G, Bevilacqua M, Vago T, Taddei A, Clerici M. Glucocorticoids and the immune function in the human immunodeficiency virus infection: a study in hypercortisolemic and cortisol-resistant patients. J Clin Endocrinol Metab 1997; 82: 3260–3263. | Article | PubMed | ISI |
  394. Huff GR, Huff WE, Balog JM, Rath NC. The effects of behavior and environmental enrichment on disease resistance of turkeys. Brain Behav Immun 2003; 17: 339–349. | Article | PubMed | ISI |
  395. Schaller M. The behavioural immune system and the psychology of human sociality. Philos Trans R Soc London B Biol Sci 2011; 366: 3418–3426. | Article | PubMed |
  396. Fincher CL, Thornhill R, Murray DR, Schaller M. Pathogen prevalence predicts human cross-cultural variability in individualism/collectivism. Proc Biol Sci 2008; 275: 1279–1285. | Article | PubMed |
  397. Kim YK, Suh IB, Kim H, Han CS, Lim CS, Choi SH et al. The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 2002; 7: 1107–1114. | Article | PubMed | ISI |
  398. Foster R, Kandanearatchi A, Beasley C, Williams B, Khan N, Fagerhol MK et al. Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? Eur J Neurosci 2006; 24: 3561–3566. | Article | PubMed | ISI |
  399. Weigelt K, Carvalho LA, Drexhage RC, Wijkhuijs A, de Wit H, van Beveren NJ et al. TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors. Brain Behav Immun 2011; 25: 1162–1169. | Article | PubMed | ISI |
  400. Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 1997; 66: 1–11. | Article | PubMed | ISI | CAS |

 

 

 

 

 

Related:

Pathogen Host Defense (PATHOS-D)

PATHOS-D and the Evolution, Symptoms and Treatment

Scholarly articles for genome-wide association study (GWAS)

Is Depression an Evolutionary Survival Mechanism?

Genome-wide association study

Evolutionary approaches to depression

Cultural diversity, stress, and depression: working women in …

Experiences of Depression: A study in phenomenology (2015)

Max Planck Principal Investigators in the Area of Collective Behavior of Biological Systems

 

MTHFR Mutation: A Missing Piece in the Chronic Disease Puzzle

Tags

, , , , , ,

MTHFRMethylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes in human physiology, having influence on at least as many biochemical processes as it has syllables in its nearly unpronounceable name.

Deficiencies in production or function of this enzyme have been associated with increased risk of myocardial infarction, stroke, venous thrombosis, several types of cancer, congenital defects, inflammatory bowel disease, and several neuropsychiatric conditions. In practice, MTHFR function is an important predictor of predispositions to chronic disease states, and interventions aimed at optimizing MTHFR function can often be preventive or therapeutic

Put most simply, MTHFR converts 5,10-methylenetetrahydrofolate into the activated form, 5-MTHF or 5-methyltetrahydrofolate. Though this reaction plays a part in many biochemical pathways, it is probably best-known in the context of  breaking down the amino acid homocysteine. This process produces methionine and eventually S-Adenosylmethionine (SAMe), crucial DNA Methylation.

Other significant roles of a properly functioning MTHFR enzyme include Nucleic Acid Metabolism, Neurotransmitter Synthesis, and production of signaling molecules important for regulating embryonic development, all of which will be discussed in more detail in later sections.

MTHFR enzymeThe role of MTHFR in health and disease has been the subject of intense research in recent years, and this work is beginning to influence clinical practice. In many ways, MTHFR function provides important clues to the risk of developing particular diseases, and to the etiology of seemingly unexplained or unexpected symptom patterns.

Fortunately, it is now possible and practical to test for the presence of mutations in the gene coding for this important enzyme.

MTHFR Mutations

The normal wild type (C/C) MTHFR gene gives instruction for production of the methylenetetrahydrofolate reductase enzyme. Currently, over 40 point mutations of this gene have been identified. Of these, mutations on the points at C677T and A1298C seem to have the most clinical significance.

In particular, the C677T polymorphism shows a wide regional and ethnic variation. MTHFRHomozygosity (TT) among Whites is 6-14%. In African populations and in Blacks living outside of Africa such as in Brazil and in the United States, the frequency falls to less than 2% for the TT variant. The prevalence rises in Mediterranean and Hispanic population. For example, among Hispanics in prevalence ranges as high as 21%.  Northern China and Japan show an 18 and 12% prevalence respectively (R. Castro, et al. J Med Genet. 2004;41:454-458).

The A1298C mutation, on the other hand, does not show as much population variance; its prevalence is more uniform within the currently studied groups. The table below notes the variant frequencies lumping the heterozygous and homozygous genotypes together.
For the most part, the other MTHFR gene mutations are still under study and their effects are not completely understood.

Geneticists and evolutionary biologists hypothesize that, in the past, mutations in MTHFR may have conferred benefits for people living in areas with higher incidence of malaria and tuberculosis. Some mutations may also play a role in protection from colon cancer and acute lymphocytic leukemia. It is interesting to note, however, that geneticists have not been able to identify any clear evolutionary advantage for C677T nor A1298C, the two most relevant mutations for our current discussion.

A more in-depth look at the regional and ethnic variations, with subgroupings by wild type, heterozygotes and homozygotes, can be found in the Journal of Medical Genetics in an article authored by Wilcken and colleagues.

MTHFR Mutations & Disease Risk

The level of MTHFR enzyme activity in a given individual depends on the genotype variant he or she carries. For example, Atherosclerosis for C677T have approximately a 70% reduction of normal MTHFR enzyme activity and Heterozygote have approximately a 40% reduction of normal enzyme activity, according to ARUP Laboratories/National Reference Laboratory.
Impaired MTHFR function has multiple negative impacts on DNA synthesis and repair, embryonic development, neurotransmitter synthesis, and cardiovascular risk factors.

Cardiovascular Disease:  The normal recycling of homocysteine to methionine relies on 5-MTHF.  If there is a defect in the MTHFR enzyme, the result is lower levels of 5-MTHF and consequently, elevated levels of homocysteine.  Hyperhomocysteinemia is an independent risk factor for cardiovascular disease including Atherosclerosis, heart attack, stroke and venous thrombosis from increased blood clots (Varga, E. et al.  Circulation; 2005; 111: e289-e293).

Currently, only the C677T mutation is thought to be associated with elevated homocysteine levels and thus a majority of the research has been done on this variant.

Cancer Risk:  Appropriate DNA methylation is important for proper DNA replication.  A disruption in methylation may occur due to a reduction 5-MTHF, which leads to a buildup of Homocysteine. This eventually results in a drop in production of S-adenosylhomocysteine (SAMe) – an inhibitor of several methyltransferases.

MTHFR enzymeIndividuals with MTHFR mutations have altered DNA Methylation, which is associated with changes in gene expression and could potentially influence oncogenic processes. One example is the 2.8-fold increased risk for endometrial cancer in women with the C677T homozygous genotype (Crott, J. et al.  Carcinogenesis. 2004; 22(7): 1019-1025).

Defects in Developing Embryos:

The mechanism for this concern actually comes from multiple consequences of a mutated MTHFR enzyme.  Developing embryos may be adversely affected by toxic levels of homocysteine that result from MTHFR mutations. Altered DNA methylation may also have direct negative effects on gene expression and DNA synthesis. The main concerns here are neural tube defects and other midline defects such as cleft palate, although they are not the only ones.  Noteworthy research includes a study from Ireland showing that 26% of all neural tube defects were related to either the homozygous or heterozygous MTHFR mutations (Kirke, P. et al.  BMJ. 2004;328:1535-1536)

Additionally, a 2.6-fold increase in the frequency of the MTHFR C677T polymorphism has been observed in the mothers of Down Syndrome patients in South India (Cyril, C. et al. Indian J Hum Genet. 2009; 15(2): 60-64).

A very recent meta-analysis supports the association between recurrent pregnancy loss (RPL) and the C677T genotype in Asians, although this association was not found in Caucasians (Wu, X. Genet Test Mol Biomarkers. 2012 Feb 7).

Congenital heart disease (CHD) in children has also been linked to MTHFR gene mutations in either the mother or the child, although a complete analysis and conclusion is still unclear.  One of the more recent studies however, did find a clear relationship between CHD and MTHFR mutations (Garcia-Fragoso, L. et al.  Int J Genet Mol Biol.  2010; 2(3): 43–47).

mthfr-mutations-pregnancyThe prevalence of the TT polymorphism was higher in mothers (22%) than in controls (10%). Compound heterozygosity for both polymorphisms was 3.7 times more common in children with CHD than in the newborn controls. Mothers of children with CHD were more likely to be compound heterozygotes.

An interesting question in relation to embryonic development is whether it is the MTHFR mutation in the mother or in the developing child that is the critical determinant in the development of congenital defects. It is certainly possible that both mutations play a role. Further research is certainly needed to shed light on this very important area of prenatal and pregnancy health.

Neuropsychiatric & Neurological Conditions:

MTHFR mutations have been linked to neuropsychiatric conditions due to the indirect effects of MTHFR activity on the production of serotonin, dopamine and norepinephrine, as well as the potentially toxic effect of hyperhomocysteinemia. Schizophrenia-like syndromes, bipolar disorder, Parkinson’s disease, Alzheimer’s disease and vascular dementia have all been associated with one or more mutations of the MTHFR gene (Lewis, X.  Molecular Psychiatry. 2006;11, 352–360).

Insomnia, irritability, forgetfulness, endogenous depression, organic psychosis, peripheral neuropathy, myelopathy and restless leg syndrome are all also mentioned in the literature as potentially being influenced by this enzyme deficiency. The MTHFR C677T homozygous genotype has also been associated with an increased risk for migraine with aura in most ethnic groups except for Caucasian populations (Schurks M., et al. Headache. 2010; 50(4):588-99).
In a recent metanalysis, there was a relationship between the C677T mutation and increased susceptibility for depression (Lewis, X.  Molecular Psychiatry. 2006;11, 352–360).

Understanding the indirect connection between MTHFR mutation and neurotransmitter production opens up the possibility of using folate supplementation alone or as an adjunct to medications as a treatment for depression.

Some studies indicate a connection between the C677T MTHFR mutation and increased risk of autism and ADHD. Case-control comparisons revealed significantly higher frequency of homozygosity as well as heterozygosity for both the C677T and A1298T genotypes among autistic versus non-autistic children (Liu X. et al. J. Autism Dev Disord. 2011;41(7):938-44). Interestingly, it is the A1298C genotype which may be associated with increased rates of ADD/ADHD, and not the C677T genotype (Gokcen, C. et al.  Int J Med Sci. 2011; 8(7): 523–528).

Other Chronic Health Concerns: Other areas of recent study include the association between MTHFR mutation and epilepsy, Turner’s syndrome, infertility and inflammatory bowel disease. With regard to the latter, researchers have reported a 2.7 and 2.8-fold higher risk for Crohn’s disease and ulcerative colitis, respectively, in people who are homozygous for the C677T variant (Crott, J. et al.  Carcinogenesis. 2004; 22(7): 1019-1025).

Therapeutic Implications

No number of medications or surgeries can “fix” a deficient enzyme. This is not to say the situation is hopeless, and patients must simply live with the risks and predispositions inherent in their genes.

Corrective treatment must move in the direction of optimizing each individual’s genotype expression. In the context of MTHFR mutations, the goal is to optimize as far as possible the production and function of this enzyme, to counterbalance the individual’s natural tendency for under-expression. This can be done through a nutrigenomics approach.

Some clinicians treat patients with MTHFR mutations by supplementation with 5-MTHF , the end product of MTHFR’s main catalytic reaction. Other vitamins and minerals that affect Methylation Cycle can also be helpful.

methylation-cycleBefore effective protocols can be designed, however, one must know what one is treating (do your homework). MTHFR genetic tests are now readily available, but to date, there are no firm guidelines on who should be tested for MTHFR mutations.

It is wise to be vigilant when working with people who fall into any of the above-mentioned chronic disease categories, or who have family members with known MTHFR Mutation, or histories suggestive of this possibility.

You can learn a lot from a simple blood screening for MTHFR mutation at the C677T and A1298C points. Any patient who is positive for any form of MTHF genotype mutation should be counseled on the importance of repleting 5-MTHF. It’s usually a good idea to give information about MTHFR testing to other family members who may also carry mutations ( link for test: 23andMe – Genetic kit for ancestry | DNA Service )

There is no advantage to waiting until a patient shows signs or symptoms of one of the MTHFR mutation-associated chronic diseases states; if there is a suspected family history or if a patient is not responding as would be expected to your usual therapeutic approaches – test and treat appropriately. What you discover could have big impact on someone’s future health.

 

Related:

MTHFR nomenclature:
MTHFR 677 = Ala222Val = rs1801133
MTHFR 677CC or GG is a normal or ‘wild type’ gene.
MTHFR 677CT is a heterozygous polymorphism.
MTHFR 677TT or AA is a homozygous polymorphism.
MTHFR 1298 = Glu429Ala = rs1801131
MTHFR 1298AA or TT is a normal or ‘wild type’ gene.
MTHFR 1298AC or GT is a heterozygous polymorphism.
MTHFR 1298CC or GG is a homozygous polymorphism.

Prevalence of MTHFR 677 and 1298:

Homozygous 677 or 1298: about 10% generally, but up to 20% in Hispanics.
Heterozygous 677 or 1298: about 43-44%
Normal 677 or 1298: about 46-48%
The frequency of 677/1298 compound heterozygosity is highest in Turkey (21.6 %), as compared to Canada (15 %), the United States (17 %) and The Netherlands (20 %)
“Genotype and allele frequencies of the polymorphic methylenetetrahydrofolate reductase gene in Turkey” Sazci et al.

MTHFR enzyme activity reductions:
MTHFR 677 heterozygotes (one copy) have about 40% reduced activity, while homozygotes (two copies) can have about 70% reduced activity.

Follow

Get every new post delivered to your Inbox.

Join 3,311 other followers