Mental Disorders Cost Society Billions in Unearned Income

Wednesday, May 7, 2008

Major mental disorders cost the nation at least $193 billion annually in lost earnings alone, according to a new study funded by the National Institutes of Health’s National Institute of Mental Health (NIMH). The study was published in the May 2008 issue of the American Journal of Psychiatry.

"Lost earning potential, costs associated with treating coexisting conditions, Social Security payments, homelessness and incarceration are just some of the indirect costs associated with mental illnesses that have been difficult to quantify," said NIMH Director Thomas R. Insel, M.D. "This study shows us that just one source of these indirect costs is staggeringly high."

Direct costs associated with mental disorders like medication, clinic visits, and hospitalization, are relatively easy to quantify, but they reveal only a small portion of the economic burden these illnesses place on society. Indirect costs like lost earnings likely account for enormous expenses, but they are very difficult to define and estimate.

In the new study, Ronald C. Kessler, Ph.D., of Harvard University, and colleagues analyzed data from the 2002 National Comorbidity Survey Replication (NCS-R) a nationally representative study of Americans age 18 to 64.

Using data from 4,982 respondents, the researchers calculated the amount of earnings lost in the year prior to the survey among people with serious mental illness (SMI). SMI is a broad category of illnesses that includes mood and anxiety disorders that have seriously impaired a person’s ability to function for at least 30 days in the year prior to the survey. It also includes cases of any mental disorder associated with life-threatening suicidal behaviors or repeated acts of violence.

Eighty-six percent of respondents reported earning income in the previous year. But those with SMI reported earning significantly less — around $22,545 — than respondents without SMI, who averaged $38,852. Although men with SMI took a greater hit in earnings than women with SMI, men still earned more overall than women with and without SMI.

By extrapolating these results to the general population, the researchers calculated that SMI costs society $193.2 billion annually in lost earnings. The researchers attributed about 75 percent of this total to the reduced income that people with SMI likely earn, while 25 percent is attributed to the increased likelihood that people with SMI would have no earnings.

"The results of this study confirm the belief that mental disorders contribute to enormous losses of human productivity," said Kessler. "Yet this estimate is probably conservative because the NCS-R did not assess people in hospitals or prisons, and included very few participants with autism, schizophrenia or other chronic illnesses that are known to greatly affect a person’s ability to work. The actual costs are probably higher that what we have estimated."

The researchers concluded by recommending that future studies on the effectiveness of treatments should consider measuring employment status and earnings over the long term to document the effects of mental disorders on a person’s functioning and ability to remain productive.

The National Institute of Mental Health (NIMH) mission is to reduce the burden of mental and behavioral disorders through research on mind, brain, and behavior.

Source: NIMH

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Time Stamp: 5/7/2008 at 2:27:23 PM UTC

Researchers Find that a Small Molecule Can Activate an Important Cancer Suppressor Gene

Thursday, May 1, 2008

By activating a cancer suppressor gene, a small molecule called nutlin-3a can block cancer cell division, according to researchers at the National Cancer Institute (NCI), part of the National Institutes of Health. This activation of the p53 gene leads to cellular senescence, a process by which cells lose their ability to grow and divide. An opportunity for new genetic mutations occurs each time a cell divides, so limiting the number of cell divisions in a cancer cell inhibits tumor progression. This study is published in the May 1, 2008, issue of Cancer Research.

Activation of p53 can suppress tumor growth through more than one mechanism. It can interfere with the cell cycle, prompting a cell with unrepaired DNA damage to commit suicide through a complex signaling pathway called apoptosis. Alternatively, p53 may trigger cellular senescence in response to DNA damage or cellular stress.

The expression of p53 is regulated by Mdm2, a protein that is overexpressed in several human cancers. Nutlins are small-molecule inhibitors that prevent the p53 protein from forming a complex with Mdm2, resulting in activation of p53. Previous studies have shown that nutlin can induce apoptosis in human cancer cells.

"Although p53 is mutated or deleted in about half of all cancers, it is still potentially functional in the other 50 percent," said Curtis C. Harris, M.D., chief of the Laboratory of Human Carcinogenesis at NCI's Center for Cancer Research and an author of the study. "A better understanding of molecules, such as nutlin-3a, that can activate p53 may lead to the development of new treatment options for certain cancers."

To examine the effects of nutlin-3a on cellular senescence, the Harris team exposed human skin cells and cancer cells to two different forms of nutlin-3: forms a and b. (Nutlin-3a has a 150-fold greater affinity for Mdm2 than nutlin-3b.) After a seven-day exposure period, the scientists found that almost 100 percent of the cells treated with nutlin-3a had stopped proliferating. These cells did not regain the ability to proliferate even after being removed from nutlin-3a, indicating that they had undergone permanent senescence. By contrast, nutlin-3b had little effect on the cells.

Next, the researchers investigated whether the senescence induced by nutlin-3a is dependent on the presence of p53 protein. After exposure to nutlin-3a for seven or 14 days, more than 80 percent of the human cells containing a functional p53 gene exhibited signs of senescence. The researchers also found that nutlin-3 treatment increased the expression of p53. However, the researchers did not observe any changes in p53-deficient cells.

Previous research by this team showed that the genes affected by p53 activation differed depending on the type of activator. To gain a better understanding of nutlin-3a-induced senescence, the researchers used microarray analysis to determine the effect of p53 activation on gene expression after cancer cells were treated with nutlin-3a. Microarray analysis is a technique that allows researchers to examine the expression of thousand of genes simultaneously. Almost 3,000 genes were differentially expressed when cells with normal p53, cells with mutant p53, and p53-deficient cells were compared. Among the genes with increased expression after nutlin-3a-activation of p53 were several genes that play a role in cellular senescence and cell death.

The researchers also found that the inhibitor of growth 2 gene (ING2) was among those with decreased expression in response to nutlin-3a treatment. ING2 regulates gene activation or expression, and it may play a role in tumor development, cell proliferation, and senescence. The researchers found that p53 seemed to suppress ING2 expression by binding directly to two sites on the ING2 promoter.

"This study further characterizes the actions of nutlin-3a on genes that can play a role in the development of cancer," said Harris. "Our study reinforces the idea that using Mdm2 inhibitors, such as nutlin-3a, to promote the growth suppressive and cell-killing activity of p53 is a potentially valuable strategy to pursue in cancer treatment."

For more information on Harris's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5761.

Source: NIH

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Time Stamp: 5/1/2008 at 1:49:25 PM UTC

Research Findings Open New Front in Fight against AIDS Virus

Tuesday, April 29, 2008

Human Protein May Offer Novel Target for Blocking HIV Infection

A research group supported by the National Institutes of Health (NIH) has uncovered a new route for attacking the human immunodeficiency virus (HIV) that may offer a way to circumvent problems with drug resistance. In findings published today in the online edition of the Proceedings of the National Academy of Sciences, the researchers report that they have blocked HIV infection in the test tube by inactivating a human protein expressed in key immune cells.

Most of the drugs now used to fight HIV, which is the retrovirus that causes acquired immune deficiency syndrome (AIDS), target the virus’s own proteins. However, because HIV has a high rate of genetic mutation, those viral targets change quickly and lead to the emergence of drug-resistant viral strains. Doctors have tried to outmaneuver the rapidly mutating virus by prescribing multi-drug regimens or switching drugs. But such strategies can increase the risk of toxic side effects, be difficult for patients to follow and are not always successful. Recently, interest has grown in attacking HIV on a new front by developing drugs that target proteins of human cells, which are far less prone to mutations than are viral proteins.

In the new study, Pamela Schwartzberg, M.D., Ph.D., a senior investigator at the National Human Genome Research Institute (NHGRI), part of NIH; Andrew J. Henderson, Ph.D., of Boston University; and their colleagues found that when they interfered with a human protein called interleukin-2-inducible T cell kinase (ITK) they inhibited HIV infection of key human immune cells, called T cells. ITK is a signaling protein that activates T cells as part of the body’s healthy immune response.

"This new insight represents an important contribution to HIV research," said NHGRI Scientific Director Eric D. Green, M.D., Ph.D. "Finding a cellular target that can be inhibited so as to block HIV validates a novel concept and is an exciting model for deriving potential new HIV therapies."

When HIV enters the body, it infects T cells and takes over the activities of these white blood cells so that the virus can replicate. Eventually, HIV infection compromises the entire immune system and causes AIDS. The new work shows that without active ITK protein, HIV cannot effectively take advantage of many signaling pathways within T cells, which in turn slows or blocks the spread of the virus.

"We were pleased and excited to realize the outcome of our approach," Dr. Schwartzberg said. "Suppression of the ITK protein caused many of the pathways that HIV uses to be less active, thereby inhibiting or slowing HIV replication."

In their laboratory experiments, the researchers used a chemical inhibitor and a type of genetic inhibitor, called RNA interference, to inactivate ITK in human T cells. Then, the T cells were exposed to HIV, and the researchers studied the effects of ITK inactivation upon various stages of HIV’s infection and replication cycle. Suppression of ITK reduced HIV’s ability to enter T cells and have its genetic material transcribed into new virus particles. However, ITK suppression did not interfere significantly with T cells’ normal ability to survive, and mice deficient in ITK were able to ward off other types of viral infection, although antiviral responses were delayed.

"ITK turns out to be a great target to examine," said Dr. Schwartzberg, noting that researchers had been concerned that blocking other human proteins involved in HIV replication might kill or otherwise impair the normal functions of T cells.

According to Dr. Schwartzberg, ITK already is being investigated as a therapeutic target for asthma and other diseases that affect immune response. In people with asthma, ITK is required to activate T cells, triggering lung inflammation and production of excess mucus.

"There are several companies who have published research about ITK inhibitors as part of their target program," Schwartzberg said. "We hope that others will extend our findings and that ITK inhibitors will be pursued as HIV therapies."

NHGRI researchers received support for this work from the NIH Intramural AIDS Targeted Antiviral Program. Chemical compounds used in the research were synthesized at the NIH Chemical Genomics Center, which was established through the NIH Roadmap for Medical Research and is administered by NHGRI. The Boston University group originally participated in the research while at Pennsylvania State University, where they received support from Penn State Tobacco Formula Funds, and where Dr. Henderson received support from the National Institute of Allergy and Infectious Diseases (NIAID).

Image Caption: HIV ( human immunodeficiency virus )

Source: NIH

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Time Stamp: 4/29/2008 at 3:49:23 PM UTC

Human Brain Appears "Hard-Wired" for Hierarchy

Apr. 23, 2008

Scans Hint at Why It Can be Unhealthy Even at the Top

Human imaging studies have for the first time identified brain circuitry associated with social status, according to researchers at the National Institute of Mental Health (NIMH) of the National Institutes of Health. They found that different brain areas are activated when a person moves up or down in a pecking order -- or simply views perceived social superiors or inferiors. Circuitry activated by important events responded to a potential change in hierarchical status as much as it did to winning money.

"Our position in social hierarchies strongly influences motivation as well as physical and mental health," said NIMH Director Thomas R Insel, M.D. "This first glimpse into how the brain processes that information advances our understanding of an important factor that can impact public health."

Caroline Zink, Ph.D., Andreas Meyer-Lindenberg, M.D., Ph.D., and colleagues of the NIMH Genes Cognition and Psychosis Program, report on their functional magnetic resonance imaging (fMRI) study in the April 24, 2008, issue of the journal Neuron. Meyer-Lindenberg is now director of Germany's Central Institute of Mental Health.

Prior studies have shown that social status strongly predicts health. Animals chronically stressed by their hierarchical position have high rates of cardiovascular and depression/anxiety-like syndromes. A classic study of British civil servants found that the lower one ranked, the higher the odds for developing cardiovascular disease and dying early. Lower social rank likely compromises health through psychological effects, such as by limiting control over one's life and interactions with others. However, in hierarchies that allow for more upward mobility, those at the top who stand to lose their positions can have higher risk for stress-related illness. Yet little is known about how the human brain translates such factors into health risk.

To find out, the NIMH researchers created an artificial social hierarchy in which 72 participants played an interactive computer game for money. They were assigned a status that they were told was based on their playing skill. In fact, the game outcomes were predetermined and the other "players" simulated by computer. While their brain activity was monitored by fMRI, participants intermittently saw pictures and scores of an inferior and a superior "player" they thought were simultaneously playing in other rooms.

Although they knew the perceived players' scores would not affect their own outcomes or reward -- and were instructed to ignore them -- participants' brain activity and behavior were highly influenced by their position in the implied hierarchy.

"The processing of hierarchical information seems to be hard-wired, occurring even outside of an explicitly competitive environment, underscoring how important it is for us," said Zink.

Key study findings included:

• The area that signals an event's importance, called the ventral striatum, responded to the prospect of a rise or fall in rank as much as it did to the monetary reward, confirming the high value accorded social status.

• Just viewing a superior human "player," as opposed to a perceived inferior one or a computer, activated an area near the front of the brain that appears to size people up -- making interpersonal judgments and assessing social status. A circuit involving the mid-front part of the brain that processes the intentions and motives of others and emotion processing areas deep in the brain activated when the hierarchy became unstable, allowing for upward and downward mobility.

• Performing better than the superior "player" activated areas higher and toward the front of the brain controlling action planning, while performing worse than an inferior "player" activated areas lower in the brain associated with emotional pain and frustration.

• The more positive the mood experienced by participants while at the top of an unstable hierarchy, the stronger was activity in this emotional pain circuitry when they viewed an outcome that threatened to move them down in status. In other words, people who felt more joy when they won also felt more pain when they lost.

"Such activation of emotional pain circuitry may underlie a heightened risk for stress-related health problems among competitive individuals," suggested Meyer-Lindenberg.

In collaboration with other NIMH researchers, Zink and colleagues are planning follow-up studies to explore brain activity in response to the experimental social hierarchy in patients with mental illnesses like schizophrenia or autism, which are marked by social and thinking deficits. The researchers will also be exploring whether particular gene variants might differentially affect brain responses in similar experiments.

Also participating in the study were Yunxia Tong, Qiang Chen, Danielle Bassett, and Jason Stein, NIMH.

Source: NIMH

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Time Stamp: 4/23/2008 at 4:32:58 PM CST

Mouse Studies Identify Gene that May Influence Metastasis Risk in Breast Cancer

Tuesday, April 22, 2008

Researchers have identified a pattern of gene activity in mice that may help to predict individual risk for breast cancer metastasis and survival in humans. A single gene, called bromodomain 4 (Brd4), regulates the expression of this pattern, also called a signature. The researchers found that one result of this Brd4 regulation is the suppression of tumor growth and metastasis in a mouse model of cancer. These findings, published by researchers at the National Cancer Institute (NCI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), parts of the National Institutes of Health, appear in the April 29, 2008, issue of the Proceedings of the National Academy of Sciences.

"Theses findings are exciting," said Kent W. Hunter, Ph.D., of NCI's Center for Cancer Research. "For the first time in mice, we have a candidate gene for what drives an entire gene signature. This should allow a better understanding of the mechanisms underlying cancer progression in humans."

Normal Brd4 activity is involved in important cell processes, including cell proliferation, cell cycle progression, and DNA replication. Defects in the processes related to Brd4 activity are well documented in breast cancer in humans. It is known that the Brd4 protein physically interacts with and regulates the activity of another important gene, called Sipa1, which reduces tumor invasiveness in mice.

The researchers began their search for the Brd4-induced gene signature by engineering highly metastatic mouse mammary tumor cells that expressed Brd4. They found that Brd4-expressing cells were less invasive and less mobile in laboratory experiments than non-Brd4-expressing cells, yet showed no change in their rate of growth.

Next, they implanted their metastatic Brd4-expressing cells into mice. For comparison, they engineered and implanted some of the same metastatic cells so that an unrelated control gene was expressed. After 4 weeks, the researchers found that Brd4-expressing metastatic cells seemed to suppress both tumor growth and metastasis. This group of mice had dramatically smaller tumors and had fewer metastatic tumors in their lungs compared to the mice in the control group. Overall, these findings appear to indicate that activation of Brd4 reduces tumor growth by influencing the response of tumor cells to signals from the microenvironment — the area immediately surrounding the tumor — that promote both tumor growth and metastasis.

Taking the knowledge gained from their mouse models of metastasis, the researchers' turned to examine human gene signatures identified from microarray data from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus and Rosetta Informatics. Microarray techniques allow researchers to examine the activity of thousands of genes simultaneously.

Hunter's team identified a set of 379 genes in humans that are similar to the genes affected by Brd4 expression in the mouse model. They found that the level of activation of Brd4 or Brd4-associated pathways within a tumor were an important determinant of relapse and survival. Brd4 seemed to drive the expression of many of the genes present in the signature.

Using the Brd4 gene signature, the researchers were able to predict survival and relapse of breast cancer patients in five separate datasets. They were also able to predict the survival of subsets of patients whose breast cancer had not spread to their lymph nodes and patients with estrogen-receptor positive tumors. Estrogen is known to play an important role in the development of breast cancer and about 70 percent of all breast cancers are estrogen-receptor positive. Further research is needed to determine the exact role of Brd4 in the progression of breast cancer, noted Hunter.

"The results of this study and other work in our laboratory suggests that people with inherited differences in Brd4 and the proteins that it induces have a genetic predisposition for developing cancer metastasis," he added. "A better understanding of this gene may lead to improved methods of diagnosing and treating cancer."

For more information on Hunter's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=13660.

Source: NIH

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Time Stamp: 4/22/2008 at 9:14:14 AM CST

Mouse Studies Show Tumors Suppress Cells Responsible for Regulating the Immune System

Friday, April 18, 2008

New research has shown that the function of a type of cell that helps modulate immune responses is impaired inside tumors in mice. Researchers also identified several factors that may contribute to an accumulation of these cells, called T regulatory cells (Tregs), within and around the tumor, which may be how they respond to their loss of functionality. The study, by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, appeared online April 18, 2008, in The Journal of Immunology.

"These findings provide insight into the impact of a growing tumor on the immune system," said Helen Sabzevari, Ph.D., of NCI's Center for Cancer Research, an author of the study. "Understanding the tumor's effects on Tregs and how these cells maintain themselves inside tumors, and in the environment immediately surrounding tumors, will be important for designing new immunotherapies."

Tregs are a specialized subset of T cells that help manage the immune system by suppressing the response of immune cells once a foreign invader has been defeated. They also prevent autoimmune diseases by keeping the body from attacking its own cells and tissues or reacting to its own antigens, called self-antigens. Since tumor-associated antigens are primarily derived from self-antigens, Treg cells also play an important role in suppressing immune responses directed against tumors, yet Tregs are thought to somehow escape the immunosuppressive effects of the tumor microenvironment.

Previous studies have shown that the suppressive actions of Tregs require other immune cells to first become activated through the T cell receptor (TCR), a surface landing site where these cells recognize and bind to begin an immune response. This triggers the eventual suppressive activity of Tregs through a step-wise series of biochemical events called signaling pathways.

In laboratory experiments, Sabzevari's team demonstrated that Tregs taken from the spleens of mice bearing tumors exhibited a less suppressive influence on the rate of proliferation of immune cells than did Tregs from spleens of the same strain of mice without tumors. In addition, they found that suppression of overall immune responses decreased about 2.4-fold in tumor-associated Tregs when compared to normal Tregs in the spleen.

To explore possible mechanisms for a tumor's effects on Treg cell function, the researchers implanted cancer cells under the skin of mice. Then they compared gene expression patterns in Tregs collected from spleen tumors that formed in mice implanted with Treg cells vs. expression patterns of spleens of implant-free control mice. Microarray analysis — which allows researchers to examine the activity of thousands of genes simultaneously — revealed differences in the gene expression of several types of genes, including those involved in immune responses, signal transduction, T cell activation, and the TCR signaling pathway. Comparing individual genes, they found reduced expression of several molecules that are involved in TCR signaling in the tumor-associated Tregs when compared to normal Treg cells.

Further analysis indicated that Treg cells in tumors lose some of their functionality because they do not become effectively activated. "Our studies demonstrate that Treg cells from tumors are less capable of responding to activation through the TCR than are Treg cells from normal spleens, indicating that the tumor microenvironment inhibits functionality of Treg cells," said Sabzevari.

In some human cancers, the number of Tregs increases in the peripheral blood, and these cells accumulate at the site of tumors. Increases in Treg cell numbers also have been observed in the spleen of animal tumor models.

Similarly, in this new research, as tumors grew larger in implanted mice, the number of Treg cells increased in both the spleen and in the tumors, but, in tumors, the percent of Treg cells actively copying themselves was 23 to 43 percent of the population of Tregs compared to 11 to 16 percent in the spleen. Additionally, cell death in the tumor-associated Tregs was two percent compared to 11 percent for spleen-associated Tregs in the same animals, likely because of the increased expression of other molecules that interfere with factors that signal cell death.

Despite their reduced functionality, the accumulation of larger numbers of Tregs in tumors may still allow the suppression of antitumor immune responses. Targeting Treg cells may be one way of improving cancer immunotherapy.

"Our findings indicate that treatments, such as chemotherapy or radiation therapy, can directly affect Treg cells," said Sabzevari. "By decreasing the number of Treg cells at the site of tumors, treatments, such as immunotherapies, may be more effective."

For more information on Sabzevari's research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5674.

Source: National Institutes of Health

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Time Stamp: 4/18/2008 at 10:53:46 AM CST