Turning on Dormant Gene May Hold Key for Correcting a Neurodevelopmental Defect

Finding Shows Therapeutic Potential of Small-Molecule Targeting Strategy

Scientists working in cell culture and in mice have been able to correct the loss of gene activity underlying a rare but severe developmental disorder by turning on a gene that is normally silenced in brain cells. Further testing of the identified compound that activates the gene will determine whether it has potential as a genetically-based treatment for the disorder, Angelman syndrome.

Background

Infants with Angelman syndrome appear normal at birth, but show developmental delays by 6 to 12 months. Features of the disorder include impaired speech, seizures, hyperactivity, and motor difficulties. No effective treatment exists CADC I & II Continuing Education

In the late 1990s, researchers found that the disorder results from changes or deletions in the maternal gene for the enzyme ubiquitin protein ligase E3A (Ube3a). Most genes are inherited in sets of two, one from the mother and one from the father. In some cases, either the maternal or paternal gene is silenced, or prevented from being translated into protein. This normal silencing based on inheritance from a mother or father is called imprinting. The Ube3a gene is an example of genetic imprinting, as the paternal gene is normally silenced in neurons. With the maternal gene out of action, infants with Angelman syndrome lack the enzyme, leading to changes in the brain that underlie the symptoms of the disorder.

This Study

This research is reported online in the journal Nature, and was carried out by scientists at the University of North Carolina School of Medicine at Chapel Hill, led by the labs of Ben Philpot, Bryan Roth, and Mark Zylka. In an effort to restore the absent Ube3a enzyme in neurons, the research team screened thousands of compounds for their ability to “wake up” the paternal Ube3a gene. The investigators used neurons from genetically engineered mice to test whether compounds could activate the gene; the neurons fluoresce if the paternal Ube3a gene is expressed, or translated into protein. The team screened 2,306 candidate small molecules from multiple molecular libraries. If fluorescence was detected, that meant that the test compound activated the Ube3a gene. The screening and access to the molecular libraries was made possible through NIMH’s Psychoactive Drug Screening Program, funded by contract to perform pharmacological and functional screening of novel compounds. Bryan Roth at UNC Chapel Hill is the project director and a coauthor of the Nature paper.

The investigators found that a class of compounds—topoisomerase inhibitors—could unsilence the paternal gene. They chose one, topotecan, and tested it to see whether it could do the same thing in vivo in a mouse. They administered topotecan directly into the brain and later into spinal fluid; in both cases it was able to activate paternal Ube3a. Activation persisted for 12 weeks after delivery of the compound had stopped.

Significance

"This is the first time anyone has used a small molecule to successfully target activation of a disease-relevant gene," said senior author Benjamin Philpot. "The work demonstrates that turning on a dormant gene could represent a therapeutic intervention for Angelman syndrome."

NIMH helped to fund this project and has issued a grant to the UNC team to continue studies of topotecan, initially in mice. Although topotecan is already in use in both children and adults as a cancer chemotherapeutic agent, further testing is essential to determine the dosage of the agent that would be needed to be effective, the best means of administering the medication, and whether side-effects at the necessary dosage level are within a range that make it feasible to use. The authors emphasize that much work remains before this or related agents can or should be used for treatment of this condition.

Reference

Huang, H.-S., Allen, J., Mabb, A., King, I., Miriyala, J., Taylor-Blake, B., Sciaky, N., Dutton, J. Jr., Lee, H.M., Chen, X., Jin, J. Bridges, A., Zylka, M., Roth, B., Philpot, B. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature. Published online ahead of print December 21, 2011, doi: 10.1038/nature10726.


This image shows Ube3a staining in a neurotypical mouse brain and its absence in the Angelman syndrome model mouse brain.

Source: Ben Philpot, Ph.D., University of North Carolina School of Medicine

Atypical antipsychotic more effective than older drugs in treating childhood mania, but side effects can be serious

The antipsychotic medication risperidone is more effective for initial treatment of mania in children diagnosed with bipolar disorder compared to other mood stabilizing medications, but it carries the potential for serious metabolic side effects, according to an NIMH-funded study published online ahead of print January 2, 2012, in the Archives of General Psychiatry social worker continuing education

Background

Childhood bipolar disorder is a relatively rare but seriously impairing condition. It is also associated with an increased risk of substance use disorders and suicide. To treat symptoms of mania, a key symptom of the disorder, medications such as mood stabilizers or antipsychotics are often prescribed. However, no prior study has addressed the question of which medication to try first.

In the Treatment of Early Age Mania (TEAM) study, Barbara Geller, M.D., of Washington University in St. Louis, and colleagues randomized 290 children ages 6-15 years diagnosed with bipolar I disorder (having mixed or manic symptoms) to treatment with lithium, divalproex sodium or risperidone for an 8-week trial. None of the children had taken an anti-manic medication before. Lithium has been used to treat bipolar disorder for many years. Divalproex sodium is an anticonvulsant mood stabilizer commonly prescribed to treat bipolar disorder as well. Risperidone is an atypical antipsychotic that has been approved by the U.S. Food and Drug Administration for the treatment of mania in youth age 10 and older.

Results of the Study

After eight weeks, 68.5 percent of the children taking risperidone showed improvement in manic symptoms, compared to 35.6 percent of those taking lithium and 24 percent of those taking divalproex sodium. Overall, 24.7 percent discontinued the trial, but more children taking lithium—32.2 percent—discontinued the trial compared to those taking risperidone (15.7 percent discontinued) or divalproex sodium (26 percent discontinued.)

However, those taking risperidone also gained more weight than those on the other medications—an average of more than 7 lbs compared to around 3 lbs for those taking lithium and 3.7 lbs for those taking divalproex sodium. Those taking risperidone were also more likely to experience other metabolic side effects, such as an increase in cholesterol levels, compared to those on the other medications.

Significance

The researchers concluded that risperidone was significantly more effective than lithium or divalproex sodium for initial treatment of childhood mania. In addition, the children were less likely to discontinue the drug compared to those taking lithium or divalproex sodium, indicating a higher tolerance for it. This finding is consistent with other studies that have compared second-generation antipsychotics like risperidone to placebo in treating childhood mania.

However, the researchers caution that risperidone is associated with adverse metabolic effects that can increase the risk for diabetes and cardiovascular problems. They note that many children responded to low doses of the medication, suggesting that clinicians should be conservative when determining how to dose the medication. A lower dose may minimize the potential for serious side effects. The researchers also caution that because diagnostic measures for childhood bipolar disorder are not always consistent across studies, and because the validity of such a diagnosis in younger children is under debate, TEAM findings may not generalize to patients diagnosed using other measures.

What’s Next

More research is needed to develop safer, more effective interventions for children with early onset bipolar disorder for both initial and longer term treatment.

Reference

Geller B, Luby J, Josh P, Wagner KD, Emslie G, Walkup JT, Axelson DA, Bolhofner K, Robb A, Wolf DV, Riddle MA, Birmaher B, Ryan ND, Severe J, Vitiello B, Tillman R, Lavori P. A randomized controlled trial of risperidone, lithium and divalproex sodium for initial treatment of bipolar I disorder, manic or mixed phase, in children and adolescents. Archives of General Psychiatry. Online ahead of print January 2, 2012.

School absenteeism, mental health problems linked

School absenteeism is a significant problem, and students who are frequently absent from school more often have symptoms of psychiatric disorders. A new longitudinal study of more than 17,000 youths has found that frequently missing school is associated with a higher prevalence of mental health problems later on in adolescence, and that mental health problems during one year also predict missing additional school days in the following year for students in middle and high school social worker continuing education

The study, published in the journal Child Development, was conducted by researchers at the University of California, Los Angeles (UCLA), the University of Florida, Boston University, the Child and Adolescent Services Research Center, the Oregon Social Learning Center, and Johns Hopkins University.

"We've long known that students who are frequently absent from school are more likely to have symptoms of psychiatric disorders, but less clear is the reason why," says Jeffrey Wood, associate professor of educational psychology and psychiatry at UCLA, who led the study. "These two aspects of youths' adjustment may at times exacerbate one another, leading over the course of time to more of each."

The study found that between grades 2 and 8, students who already had mental health symptoms (such as antisocial behavior or depression) missed more school days over the course of a year than they had in the previous year and than students with few or no mental health symptoms. Conversely, middle and high school students who were chronically absent in an earlier year of the study tended to have more depression and antisocial problems in subsequent years. For example, 8th graders who were absent more than 20 days were more likely to have higher levels of anxiety and depression in 10th grade than were 8th graders who were absent fewer than 20 days.

"The findings can help inform the development of programs to reduce school absenteeism," according to Wood. "School personnel in middle schools and high schools could benefit from knowing that mental health issues and school absenteeism each influence the other over time. Helping students address mental health issues may in turn help prevent the emergence of chronic absenteeism. At the same time, working to help students who are developing a pattern of chronic absenteeism come to school more consistently may help prevent psychiatric problems."

The researchers looked at more than 17,000 children in 1st through 12th grades using three datasets: the National Longitudinal Study of Adolescent Health, a longitudinal study of a nationally representative sample of adolescents in grades 7 to 12; the Johns Hopkins Prevention Intervention Research Center Study, a longitudinal study of classroom-based interventions involving children in grades 1 to 8; and the Linking the Interests of Families and Teachers trial, a longitudinal study of children in grades 1 through 12.

Researchers interviewed students and parents annually or biennially, and they gathered information from school attendance records. In addition, students, parents, and teachers filled out questionnaires.


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The study was funded by the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with cooperative funding from 17 other agencies.

NDAR Federation Creates Largest Source of Autism Research Data to Date

NIH-funded Database Sets Standard for Collaboration and Data Sharing

Source: NDAR

A data partnership between the National Database for Autism Research (NDAR), and the Autism Genetic Resource Exchange (AGRE) positions NDAR as possibly the largest repository to date of genetic, phenotypic, clinical, and medical imaging data related to research on autism spectrum disorders (ASD)LPC Continuing Education

“The collaboration between AGRE and NDAR exemplifies the efforts of government and stakeholders to work together for a common cause,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health, part of NIH. “NDAR continues to be a leader in the effort to standardize and share ASD data with the research community, and serves as a model to all research communities.”

NDAR is supported by the National Institutes of Health; AGRE is an Autism Speaks program.

NDAR’s mission is to facilitate data sharing and scientific collaboration on a broad scale, providing a shared common platform for autism researchers to accelerate scientific discovery. Built around the concept of federated repositories, NDAR integrates and standardizes data, tools, and computational techniques across multiple public and private autism databases. Through NDAR, researchers can access results from these different sources at the same time, using the rich data set to conduct independent analyses, supplement their own research data, or evaluate the data supporting published journal articles, among many other uses.

Databases previously federated with NDAR include Autism Speaks’ Autism Tissue Program, the Kennedy Krieger Institute’s Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. AGRE currently houses a clinical dataset with detailed medical, developmental, morphological, demographic, and behavioral information from people with ASD and their families.

Approved NDAR users will have access to data from the 25,000 research participants represented in NDAR, as well as 2,500 AGRE families and more than 7,500 participants who reported their own information to IAN.

NDAR is supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, and the NIH Center for Information Technology.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Suspect Gene Variants Boost PTSD Risk after Mass Shooting

Profile of Risk Emerging for Trauma-triggered Molecular Scars

College students exposed to a mass shooting were 20-30 percent more likely to later develop post traumatic stress disorder (PTSD) symptoms if they harbored a risk version of a gene, NIMH-funded researchers have discovered. This boost in risk, traced to common variants of the gene that controls recycling of serotonin, was comparable to the risk conferred by close proximity to the shooting – for example, being in the room with the shooter versus just being on campus.

The discovery is the latest of several recently reported that collectively profile heightened biological vulnerability to developing PTSD following trauma – and the molecular scars it leaves in the brain.

For example, early this year, researchers linked high levels of a stress-triggered, estrogen-related hormone to PTSD symptoms in women, with certain versions of the hormone receptor’s gene conferring higher risk. A PET scan study in September traced increased PTSD symptoms to heightened levels of a serotonin receptor. Both studies suggest potential new drug targets for treating the disorder. Evidence is also mounting that trauma – particularly if experienced very early in life – can adversely alter the set-points of gene expression in brain stress circuits and compromise immune and inflammatory system function continuing education for counselors

Gene-by-environment – caught in the act

By chance, researchers at Northern Illinois University (NIU) had already collected data on students’ PTSD symptoms prior to the 2008 murder-suicide that killed six on the Dekalb, Illinois campus.*

“This provided a rare opportunity to pinpoint not just a correlation but a cause – to document that such a tragedy can conspire with a risk gene to produce the disorder,” explained Kerry Ressler, M.D., Ph.D., of Emory University.

NIMH grantees Ressler, NIU’s Holly Orcutt, Ph.D., and colleagues, report on discovery of this gene-by-environment interaction online September 5th 2011 in the Archives of General Psychiatry.

Previous efforts to confirm such an interaction in PTSD had been confounded by lack of data on individuals’ pre-trauma symptoms. Any pre-existing symptoms must be taken into account to establish a common baseline – so that new symptoms that develop can confidently be pegged to the traumatic event.

By chance, before the tragedy, Orcutt’s team had prospectively surveyed PTSD symptoms in more than a thousand NIU undergraduate women, as part of a longitudinal study on predictors of sexual victimization, which can trigger the disorder. Within a few weeks after the tragedy, they seized the opportunity and – with help from a NIMH RAPID grant – conducted follow-up surveys, using the same measures, in subsets of the original sample – and then again after several months – to track symptom changes. Ressler’s team ultimately analyzed saliva samples from 235 women for gene type.

Previous studies had linked PTSD to a version of the gene that codes for the serotonin transporter (SERT), the protein on neurons that recycles the chemical messenger serotonin back into the cell after it is secreted into the synapse. So the researchers focused their genetic analysis on this variation, noting that it is “the most commonly described polymorphism in the psychiatric genetics literature.”

For example, this same site of genetic variation has also been linked to increased risk for anxiety - and, in some studies, increased risk for depression following stressful life events, although the latter findings remain controversial. Some hypothesize that these implicated variants may have less to do with conferring disease risk, per se, than with increased sensitivity to environmental influences more generally.**

Antidepressant medications, serotonin selective reuptake inhibitors (SSRIs), work by blocking SERT, thereby enhancing serotonin activity. SSRIs are the main medication treatment for PTSD.

Everyone inherits two copies of the SERT gene, one from each parent. So people can inherit one or two copies of risk-associated versions that are common in the population. Carrying any combination of these risk versions had been associated with increased risk for PTSD in 8 out of 9 previous studies.

The new study more definitively connects the dots between the environmental trigger and these risk gene types. Among 204 women without prior symptoms, 20 percent of those who showed acute symptoms within a few weeks after the shooting had developed PTSD symptoms when surveyed several months later. Proximity to the shooting and the risk gene types were about equally predictive of increased risk among this group.

These results come at a time of ferment in the field over confidence in gene-by-environment findings. A recent analysis by NIMH grantees of more than 100 such studies over the past decade uncovered what they call “publication bias.” They found that positive new findings were more likely to get published, while direct replications – which tend be less likely to confirm positive new findings – were under-reported. The net effect: an unintentional bias toward false positive reports. Notably, the researchers singled out as a prime example of this bias the scientific literature on serotonin transporter gene-by-environment interactions.

“How we measure environment may be at least as important as how we measure genetics, but to date, little effort has been focused on that,” noted Ressler. “We think that performing prospective studies in populations with shared trauma may be one way to 'hold constant' the environment variable, thus allowing for more clarity in the role of genetics.”

PTSD symptoms of NIU undergraduate women with a risk-associated serotonin transporter gene type (s/s, lG/lG, s/lG) increased 20-30 percent more than in classmates with a protective gene type after the 2008 campus shootings (Time 2). The increased risk was comparable to that conferred by close proximity to the shooting.
Source: Kerry Ressler, M.D., Ph.D., Emory University

Why Women are More Vulnerable

Earlier this year, Ressler and colleagues reported findings that may help to explain why women are twice as likely as men to develop PTSD. They linked PTSD symptoms in women to higher blood levels of what has been dubbed the “master regulator” of the stress response, a hormone called PACAP (pituitary adenyl cyclase-activating peptide).

PTSD symptoms were 5-fold higher in women with above average PACAP levels, compared to women with below average levels. Also in women only, a certain version of the gene that codes for PACAP’s receptor, PAC-1, conferred increased vulnerability. Experiments in rodents confirmed that this variable part of the PAC-1 gene is regulated, in part, by the female hormone estrogen.

This suggests that heightened vulnerability to PTSD in females may be traceable to this brain system critical to proper stress circuit function. Genetic variation in a different pathway may similarly be linked to increased risk for PTSD in men, say the researchers.

Females with higher-than-average levels of the stress-managing hormone PACAP had 5 times more PTSD symptoms than females with lower-than-average levels. By contrast, PACAP levels were unrelated to PTSD symptoms in males. Since the PACAP system is shaped, in part, by the female hormone estrogen, these differences could help to explain why women are twice as likely as men to develop the disorder.
Source: Kerry Ressler, M.D., Ph.D., Emory University

PACAP, “master regulator” of the stress response.
Source: Lee Eiden, Ph.D., NIMH Section on Molecular Neuroscience

Molecular scars

The Emory researchers also found increased methylation – epigenetic regulation of gene expression in response to the environment – in the part of Pac1 associated with PTSD in both women and men. Adverse experiences can induce molecules called methyl groups to attach to DNA and block genes from turning on. This results in enduring changes in the proteins the genes express. These molecular scars can weaken the brain’s defenses against PTSD.

Indeed, methylation increases pervasively in PTSD, according to Ressler and colleagues. Notably, they pinpointed such increases in several genes implicated in inflammatory and immune system abnormalities that go along with PTSD. They also saw abnormalities in immune system chemical messengers, called cytokines. Increased blood levels of one such cytokine TNF-alpha, known to trigger stress response symptoms, correlated with a history of child abuse and cumulative life stresses.

Early trauma may deplete resilience molecule

In September, a NIMH-funded brain imaging study reported that levels of a type of serotonin receptor (1B) were markedly lower in stress circuits of PTSD patients than in others exposed to trauma. This protein on neurons, to which the neurotransmitter binds, plays a pivotal role in stress resilience and antidepressant effect. By contrast, PET scans revealed that people who had experienced trauma but didn’t develop PTSD had only slightly fewer receptors than healthy controls.

NIMH grantee Alexander Neumeister, M.D., of Mount Sinai School of Medicine, and colleagues, traced both the severity of symptoms and the depleted receptors largely to the age at which trauma was first experienced. The earlier the age and the more subsequent trauma exposures, the fewer receptors expressed and the more severe the PTSD symptoms and overlap with depression. The dearth of receptors likely reflects such features of patients’ trauma histories, with those who develop PTSD also having other genetic or environmental vulnerabilities, say the researchers.

Patients with PTSD (right) had significantly fewer serotonin 1B receptors (yellow & red areas) in their brain stress circuits than healthy controls (left). PET scan images show destinations of a radioactive tracer that binds to serotonin 1B receptors. Front of brain is at bottom.
Source: Alexander Neumeister, M.D., Mount Sinai School of Medicine

Possible Uses: Risk profile and treatment targets?

Such epigenetic and genetic signatures of PTSD proneness in blood and brain, together with behavioral measures, may collectively prove useful in profiling a patient’s risk for developing the disorder. Molecules such as PACAP and the serotonin 1B receptor may also hold promise as potential targets of new drugs aimed at correcting specific abnormalities in the affected brain pathways, suggest the researchers.


NIMH RAPID grant helps salvage science from tragedy
2/14/08 Mass shooting on NIU campus
2/19/08 NIU researcher Holly Orcutt, Ph.D., contacts NIMH to discuss how to make the most of her prospectively collected data on PTSD and other parameters to learn from the tragedy.
3/26/08 Orcutt submits a concept for a follow-up study under the NIMH Rapid Assessment Post Impact of Disaster (RAPID) research program announcement – a unique time sensitive mechanism for expediting funding of research grants in response to emergency situations.
5/17/08 Grant application submitted.
6/18/08 Application undergoes peer review.
9/18/08 Grant awarded to NIU and Orcutt.

References

Acute and Posttraumatic Stress Symptoms in a Prospective Gene x Environment Study of a University Campus Shooting. Mercer KB, Orcutt HK, Quinn JF, Fitzgerald CA, Conneely KN, Barfield RT, Gillespie CF, Ressler KJ. Arch Gen Psychiatry. 2011 Sep 5. [Epub ahead of print]
PMID:21893641

A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry. Duncan LE, Keller MC. Am J Psychiatry. 2011 Sep 2. [Epub ahead of print]
PMID: 21890791

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V.Nature. 2011 Feb 24;470(7335):492-7. Erratum in: Nature. 2011 Sep 1;477(7362):120.
PMID:21350482

PACAP: a master regulator of neuroendocrine stress circuits and the cellular stress response.
Stroth N, Holighaus Y, Ait-Ali D, Eiden LE. Ann N Y Acad Sci. 2011 Mar;1220:49-59. doi: 10.1111/j.1749-6632.2011.05904.x. Review. PMID:21388403

The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding. Murrough JW, Czermak C, Henry S, Nabulsi N, Gallezot JD, Gueorguieva R, Planeta-Wilson B, Krystal JH, Neumaier JF, Huang Y, Ding YS, Carson RE, Neumeister A. Arch Gen Psychiatry. 2011 Sep;68(9):892-900. PMID:21893657

Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, Tang Y, Gillespie CF, Cubells JF, Ressler KJ. Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156(6):700-8. doi: 10.1002/ajmg.b.31212. Epub 2011 Jun 28. PMID:21714072

Psychiatry: A molecular shield from trauma. Stein MB. Nature. 2011 Feb 24;470(7335):468-9. No abstract available. PMID:21350472

*http://en.wikipedia.org/wiki/Northern_Illinois_University_shooting

** http://www.theatlantic.com/magazine/archive/2009/12/the-science-of-success/7761/

HIV Variants in Spinal Fluid May Hold Clues in Development of HIV-related Dementia

NIMH-funded researchers found two variants of HIV in the cerebrospinal fluid (CSF) of infected study participants that were genetically distinct from the viral variants found in the participants’ blood. The study, published October 6, 2011, in the journal PLoS Pathogens, suggests these CSF variants may help to inform research on the development and treatment of cognitive problems related to HIV infection.

Background

The advent of antiretroviral medications has helped many with HIV to manage the illness effectively. But even with proper treatment, a significant percentage of HIV-infected people develop HIV-associated dementia (HAD) or more mild neurological disorders. Research suggests that some people with HAD harbor variants of HIV in their cerebrospinal fluid (CSF) that may be less responsive to current treatments and thus contribute to cognitive decline. Understanding the role of HIV in HAD may also inform efforts to treat or prevent mild neurocognitive disorders associated with HIV.

To explore this issue, Ronald Swanstrom, Ph.D., of the University of North Carolina at Chapel Hill, and colleagues collected samples of blood and CSF from 11 people with HIV. All samples were collected just before and shortly after the person started antiretroviral therapy. The researchers also had access to additional samples from two of the 11 participants, collected several years prior to their starting treatment ceus for counselors

Results of the Study

The researchers found two variants of HIV in participants’ CSF that were genetically distinct from HIV found in their blood. Among participants diagnosed with HAD, the HIV variants in CSF showed greater genetic differences from the type of HIV in their blood, compared with participants with no HAD symptoms.

HIV typically targets a type of immune cell called T-cells. However, researchers found that one CSF variant replicated in macrophages, a different type of immune cell that typically lives longer than T-cells. In one of the participants with longer-term data, the researchers found evidence of this variant before the participant was diagnosed with HAD. During that time, the participant’s neurological assessments reported only mild impairment. The proportion of macrophage-targeting variants in the CSF increased over time, particularly in the first month after the participant was diagnosed with HAD.

In the other participant with longer-term data, the researchers noted the presence of the second CSF variant, which targeted T-cells, after the participant was diagnosed with HAD. Before the participant was diagnosed with HAD, the T-cell-targeting variant was not present in CSF samples.

Significance

The findings indicate that the genetically distinct variants of HIV in the CSF may each play a role in the development of HAD and related neurological disorders.

According to the researchers, the variant that targets macrophages provides clues to how HIV may evolve in order to replicate in a new cell type. The presence of the T-cell-targeting variant suggests that HIV infection may cause T-cells to migrate into the CSF. If confirmed, this migration would provide an alternative mechanism for maintaining viral replication in the central nervous system, which is associated with neurocognitive impairment.

What’s Next

Examining samples of blood, CSF, and brain tissue from a larger number of HIV- infected people with more mild symptoms of neurocognitive impairment may reveal physiological features that distinguish the two CSF variants identified in the current study. According to the researchers, identifying such features may help predict either current or future neurocognitive impairment and would emphasize the benefits of starting treatment early.

Reference

Schnell G, Joseph S, Spudich S, Price RW, Swanstrom. HIV-1 Replication in the Central nervous System Occurs in Two Distinct Cell Types. PLoS Pathog. 2011 Oct;7(10):e1002286

Training Peers Improves Social Outcomes for Some Kids with ASD

NIH-funded Study Finds Engaging Peers in Social Skills Intervention May Be More Helpful than Training Children with ASD Directly

Children with autism spectrum disorder (ASD) who attend regular education classes may be more likely to improve their social skills if their typically developing peers are taught how to interact with them than if only the children with ASD are taught such skills. According to a study funded by the National Institutes of Health, a shift away from more commonly used interventions that focus on training children with ASD directly may provide greater social benefits for children with ASD. The study was published online ahead of print on November 28, 2011, in the Journal of Child Psychology and Psychiatry.

"Real life doesn't happen in a lab, but few research studies reflect that," said Thomas R. Insel, director of the National Institute of Mental Health (NIMH), a part of NIH. "As this study shows, taking into account a person’s typical environment may improve treatment outcomes." CEUs for Counselors

The most common type of social skills intervention for children with ASD is direct training of a group of children with social challenges, who may have different disorders and may be from different classes or schools. The intervention is usually delivered at a clinic, but may also be school-based and offered in a one-on-one format. Other types of intervention focus on training peers how to interact with classmates who have difficulty with social skills. Both types of intervention have shown positive results in studies, but neither has been shown to be as effective in community settings.

Connie Kasari, Ph.D., of the University of California, Los Angeles, and colleagues compared different interventions among 60 children, ages 6-11, with ASD. All of the children were mainstreamed in regular education classrooms for at least 80 percent of the school day.

These children were randomly assigned to either receive one-on-one training with an intervention provider or to receive no one-on-one intervention. The children were also randomized to receive a peer-mediated intervention or no peer-mediated intervention. The two-step randomization resulted in four intervention categories, each with 15 children who had ASD:
Child-focused: direct, one-on-one training between the child with ASD and intervention provider to practice specific social skills, such as how to enter a playground game or conversation
Peer-mediated: group training with the intervention provider for three typically developing children from the same classroom as the student with ASD; the affected student did not receive any social skills training. The participating children were selected by study staff and teachers and were taught strategies for engaging students with social difficulties.
Both child-focused and peer-mediated interventions
Neither intervention.

All interventions were given for 20 minutes two times a week for six weeks. A follow-up was conducted 12 weeks after the end of the study. After the follow up phase, all children with ASD who had received neither intervention were re-randomized to one of the other treatment categories.

Children with ASD whose peers received training—including those who may also have received the child-focused intervention—spent less time alone on playgrounds and had more classmates naming them as a friend, compared to participants who received the child-focused interventions. Teachers also reported that students with ASD in the peer-mediated groups showed significantly better social skills following the intervention. However, among all intervention groups, children with ASD showed no changes in the number of peers they indicated as their friends.

At follow-up, children with ASD from the peer-mediated groups continued to show increased social connections despite some of the children having changed classrooms due to a new school year and having new, different peers.

According to the researchers, the findings suggest that peer-mediated interventions can provide better and more persistent outcomes than child-focused strategies, and that child-focused interventions may only be effective when paired with peer-mediated intervention.

In addition to the benefits of peer-mediated interventions, the researchers noted several areas for improvement. For example, peer engagement especially helped children with ASD to be less isolated on the playground, but it did not result in improvement across all areas of playground behavior, such as taking turns in games or engaging in conversations and other joint activities. Also, despite greater inclusion in social circles and more frequent engagement by their peers, children with ASD continued to cite few friendships. Further studies are needed to explore these factors as well as other possible mediators of treatment effects.

The study was supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute on Deafness and Other Communication Disorders through the Studies to Advance Autism Research and Treatment (STAART) network program and received additional funding from the Health Resources and Services Administration (HRSA).

Reference

Kasari C, Rotheram-Fuller E, Locke J, Gulsrud A. Making the Connection Randomized Controlled Trial of Social Skills at School for Children with Autism Spectrum Disorders. J Ch Psychol Psychiatry. 2011 Nov 28. [epub ahead of print]

Clinical Trials Number: NCT00095420

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.