segunda-feira, 7 de julho de 2014

New treatment for borderline personality disorder


A group of Swiss investigators reports on a new type of psychotherapy for borderline personality disorder in the current issue of Psychotherapy and Psychosomatics.

Motive-oriented therapeutic relationship (MOTR) was postulated to be a particularly helpful therapeutic ingredient in the early treatment phase of patients with personality disorders, in particular with borderline personality disorder (BPD).

This randomized controlled study using an add-on design is the first study to test this assumption in a 10-session general psychiatric treatment with patients presenting with BPD on symptom reduction and therapeutic alliance. A total of 85 patients were randomized. They were either allocated to a manual-based short variant of the general psychiatric management (GPM) treatment (in 10 sessions) or to the same treatment where MOTR was deliberately added to the treatment. Treatment attrition and integrity analyses yielded satisfactory results.

After performing the inter-to-treat analysis, results suggested a global efficacy of MOTR, in the sense of an additional reduction of general problems, i.e. symptoms, interpersonal and social problems. However, they also showed that MOTR did not yield an additional reduction of specific borderline symptoms. It was also shown that a stronger therapeutic alliance, as assessed by the therapist, developed in MOTR treatments compared to GPM.

These findings suggest that adding MOTR to psychiatric and psychotherapeutic treatments of BPD is promising. Moreover, the findings shed additional light on the perspective of shortening treatments for patients presenting with BPD.

Temperament may contribute to cardiac complications in high blood pressure


Temperament has been traditionally associated with high blood pressure. A new study that has appeared in the current issue of Psychotherapy and Psychosomatics has substantiated this issue.

Major depression and coronary heart disease have a strong, bidirectional relationship. A type A behavioral pattern, as well as cyclothymic disorder, is a subclinical manifestation of bipolar illness, and in cardiovascular patients may result in extreme behavioral changes detrimental to cardiac prognosis.

To further characterize this most vulnerable group, Authors examined the affective temperamental traits (Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire, TEMPS-A) on depressive, cyclothymic, hyperthymic, irritable and anxious subscales, ICD-10-diagnosed depression and depressive symptoms (Beck Depression Inventory, BDI) in relation to cardiac complications (CC) requiring acute hospitalization (acute coronary syndrome, acute myocardial infarction) in a primary hypertensive outpatient population.

Results showed that patients with CC scored markedly higher on the cyclothymic temperament scale (p = 0.027) than those without CC. Also, cyclothymic temperament significantly predicted CC independently of depression (either ICD-10-diagnosed or depressive symptoms), age, gender and smoking in hypertensive outpatients.

Even though, the study presents some limitations (cross-sectional nature hinders drawing a causal relationship, the relatively small sample size and low proportion of CC restrict generalizability), the findings shed light on the possible role of affective temperaments in cardiovascular morbidity and carry the advantage of exploring trait-like characteristics which precede and also determine the type of depression affecting the clinical outcome. Further research in the field would enrich the preventative options in clinical medicine in the future.


Story Source:

The above story is based on materials provided by Journal of Psychotherapy and Psychosomatics. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ajandek Eory, Sandor Rozsa, Peter Torzsa, Laszlo Kalabay, Xenia Gonda, Zoltan Rihmer. Affective Temperaments Contribute to Cardiac Complications in Hypertension Independently of Depression. Psychotherapy and Psychosomatics, 2014; 83 (3): 187 DOI: 10.1159/000357364

Participant Index Seeks to Determine Why One Film Spurs Activism, While Others Falter

 

By MICHAEL CIEPLYJULY 6, 2014

 

The documentary film "The Square," about the Egyptian uprising in Tahrir Square, Cairo. On an impact scale of 100, the film scored an average of 92. Credit Noujaim Films

LOS ANGELES — You watched the wrenching documentary. You posted your outrage on Twitter. But are you good for more than a few easy keystrokes of hashtag activism?

Participant Media and some powerful partners need to know.

For the last year Participant, an activist entertainment company that delivers movies with a message, has been quietly working with the Bill & Melinda Gates Foundation, the Knight Foundation and the University of Southern California’s Annenberg School for Communication and Journalism to answer a question vexing those who would use media to change the world.

That is, what actually gets people moving? Do grant-supported media projects incite change, or are they simply an expensive way of preaching to the choir?

Ultimately, the answers may help determine which projects get financed, which formats are favored and how stories are structured. That could be true for so-called double bottom line companies like Participant, which seek to profit (or at least break even) while creating social change, and also for nonprofits like the Gates Foundation, which increasingly rely on entertainment-style media (like the education documentary “Waiting for ‘Superman’ ”) to drive an agenda.

 

"The Square" scored extremely high for emotional involvement at 97 out of 100, but dropped to 87 in terms of provoking action. Credit Netflix/Noujaim Films

More immediate, those behind the effort say, new measures of social impact will enable sharper focus and rapid course corrections in what have often been guesswork campaigns to convert films into effective motivational weaponry. That approach would apply to a hit like the movie “Lincoln,” which counseled civic engagement, or to a box-office miss like the antifracking film “Promised Land.” Both were Participant-backed films.

To get the answers it wants, Participant is developing a measuring tool that it calls the Participant Index, assisted in the effort by the Annenberg school’s Media Impact Project. In rough parallel to the Nielsen television ratings, the still-evolving index compiles raw audience numbers for issue-driven narrative films, documentaries, television programs and online short videos, along with measures of conventional and social media activity, including Twitter and Facebook presence.

The two measures are then matched with the results of an online survey, about 25 minutes long, that asks as many as 350 viewers of each project an escalating set of questions about their emotional response and level of engagement.

Did it affect you emotionally? Did you share information about it? Did you boycott a product or company? Did it change your life?

“If this existed, we would not be doing it,” said James G. Berk, chief executive of Participant. “We desperately need more and more information, to figure out if what we were doing is actually working.”

The answers result in a score that combines separate emotional and behavioral measures. On a scale of 100, for instance, “The Square,” a documentary about Egyptian political upheaval that was included in Participant’s first echelon of 35 indexed titles this year, scored extremely high for emotional involvement, with a 97, but lower in terms of provoking action, with an 87, for a combined average of 92.

By contrast, “Farmed and Dangerous,” a comic web series about industrial agriculture, hit 99 on the action scale, as respondents said, for instance, that they had bought or shunned a product, and 94 for emotion, for an average of 97. That marked it as having potentially higher impact than “The Square” among those who saw it.

 

The documentary "The Cove," which looks closely at dolphin killing in Japan, had worldwide ticket sales of just $1.2 million after its release in 2009. Yet it has repeatedly led to campaigns to protect the Japanese dolphins. Credit Oceanic Preservation Society/Roadside Attractions

Daniel Green, the deputy director for strategic media partnerships at the Gates Foundation, traces the new drive for impact measurement to a Seattle meeting in December 2011 among about two dozen representatives of nonprofits with an interest in social change.

“Grantors didn’t have a lot of sophistication around their analytics,” said Michael Maness of the Knight Journalism and Media Innovation program, a group that attended. He joined Mr. Green last month in describing frustration among nonprofits at their inability to gauge how much change their projects are prompting.

The Seattle gathering led to an association with the Annenberg school’s Norman Lear Center, which early last year established its Media Impact Project. That project then served as a consultant to Participant in creating its index, which received $4.2 million in combined financing from the Knight and Gates foundations and from George Soros’s Open Society Foundations.

The methodologies being used for the index will be provided on an open-source basis to those who are interested — whether on the left or right or in the center of the ideological spectrum.

“We’re developing a set of tools and measures that will be available for any researcher, no matter what their viewpoint,” said Martin Kaplan, director of the Lear Center.

Participant, created in 2004 by the eBay co-founder Jeffrey S. Skoll, is using that methodology to build a proprietary database. It will feature three echelons with 35 projects each, or about 100 distinct bits of media, annually.

The company will lean heavily toward films and television shows of its own, especially those carried on its activism-driven online and pay-television network, Pivot. But it will also index properties for partners, like the Gates and Kaiser Family foundations, and for companies or others who will pay a fee.

Photo

Participant was created in 2004 by the eBay co-founder Jeffrey S. Skoll, left, pictured here with James G. Berk, chief executive. Credit Emily Berl for The New York Times

(Prices have not been set, Mr. Berk said, but he expects to serve nonprofits at cost. He declined to say how much Participant has invested in the index.)

In an inaugural general survey, which polled 1,055 of its viewers in March and April of this year, Chad Boettcher, Participant’s executive vice president for social action, and Caty Borum Chattoo, a researcher and communications professor at American University, found some perhaps surprising results.

Even among the presumably progressive Participant audience, crime ranked near the top of the list of 40 primary concerns. It was cited by 73 percent of respondents as an important social issue, placing it just behind human rights, health care and education.

Gay rights, female empowerment and prison sentencing reform, by contrast, ranked near the bottom of the list, while climate change was stuck in the middle, a concern among 59 percent of respondents. Digital intellectual property issues, at 38 percent, brought up the rear.

Stories about animal rights and food production, it turned out, were the most likely to provoke individual action. But tales about economic inequality — not so much.

Over all, said Marc Karzen, a social media entrepreneur whose company, RelishMix, advises film and television marketers, Participant will most likely affirm what is becoming clear to conventional film studios: Impact can be less about persuasion than nudging an audience to go where it is already pointed.

“You have to embrace your fans, not shout at them,” Mr. Karzen said. “They need to be inspired to spread the word.”

One of the weirdest problems in measuring social impact, and one still unresolved, Mr. Boettcher said, is the paradox of “The Cove.”

That documentary, which looks closely at dolphin killing in Japan, had worldwide ticket sales of just $1.2 million after its release in 2009. Yet it has repeatedly led to campaigns to protect the Japanese dolphins, Mr. Boettcher notes, particularly among activists who are aware of the film but will not watch (and hence, would not be counted under the current methodology of the index) because of its gory content.

“They don’t want to see it,” Mr. Boettcher said, “but they will sign up.”

A version of this article appears in print on July 7, 2014, on page B1 of the New York edition with the headline: Divining Why One Film Spurs Activism, While Others Falter. Order ReprintsToday's PaperSubscribe

Personality and heart attacks: A new look

 

A new study published in the current issue of Psychotherapy and Psychosomatics has addressed the relationship between personality and heart attacks. Distressed (type D) personality (TDP), characterized by high negative affectivity (NA) and social inhibition (SI), along with depression, anxiety and other negative affects (such as demoralization, hopelessness, pessimism and rumination) have been implicated as potential risk factors for coronary artery disease. While some evidence suggests that the NA dimension of TDP overlaps at least partially with depression, other studies underline how 'TDP refers to a chronic, more covert form of distress that is distinct from depression'.

In this study, authors aimed to clarify whether, among never depressed patients at their first acute coronary syndrome (ACS), there is an overlap between the constructs of TDP and depression, evaluating the stability of NA and SI 6 months after the ACS, and their relationship with depressive symptoms. Patients consecutively admitted to the Coronary Intensive Care Unit of the University Hospital of Parma between January 2009 and March 2012 who had their first ACS and no history of major depression (MD) or other psychiatric disorders, were included.

During the follow-up period 30 patients developed depressive symptoms (MD: n = 12; minor depression (md): n = 18), whereas 220 subjects maintained a nondepressive condition throughout the study period. At baseline the NA and SI levels were higher in subjects who developed depression than in patients who did not. However, at the baseline evaluation 19 patients without previous depressive episodes already satisfied the criteria for md. Interestingly, at baseline these subjects showed higher levels of NA and SI than subjects without md. Among patients who developed depression (n = 30) HADS scores significantly changed during the 6-month follow-up: both anxiety and depression scores increased from baseline to the second month of follow-up and then decreased. The same pattern of change was observed for the NA score, whereas the SI score did not vary during follow-up. In nondepressed patients, both HADS depression and anxiety scores and NA score significantly decreased throughout the follow-period, whereas the SI did not change.

In this study, the overlap between depressive psychopathology and NA features is suggested by the course of these two dimensions over time. Indeed, in both depressed and nondepressed patients, NA levels were not stable during the 6-month follow-up, but they changed along with the variation of HADS scores. This finding suggests that the NA dimension is sensitive to mood-state, because its levels increase and decrease according to the fluctuation of severity of depressive and anxious symptoms. This result supports the view that the disposition to experience and report negative emotions (NA) can be sensitive to mood-state. Therefore, the presence of depressive state is crucial when assessing TDP, since NA and anhedonic depression are partially overlapping and co-varying constructs.


Story Source:

The above story is based on materials provided by Journal of Psychotherapy and Psychosomatics. Note: Materials may be edited for content and length.


Journal Reference:

  1. Carlo Marchesi, Paolo Ossola, Francesca Scagnelli, Francesca Paglia, Sonja Aprile, Alberto Monici, Matteo Tonna, Giulio Conte, Franco Masini, Chiara De Panfilis, Diego Ardissino. Type D Personality in Never Depressed Patients at Their First Acute Coronary Syndrome. Psychotherapy and Psychosomatics, 2014; 83 (3): 190 DOI: 10.1159/000358525

domingo, 6 de julho de 2014

How you cope with stress may increase your risk for insomnia


A new study is the first to identify specific coping behaviors through which stress exposure leads to the development of insomnia.

Results show that coping with a stressful event through behavioral disengagement -- giving up on dealing with the stress -- or by using alcohol or drugs each significantly mediated the relationship between stress exposure and insomnia development. Surprisingly, the coping technique of self-distraction -- such as going to the movies or watching TV -- also was a significant mediator between stress and incident insomnia. Furthermore, the study found that cognitive intrusion -- recurrent thoughts about the stressor -- was a significant and key mediator, accounting for 69 percent of the total effect of stress exposure on insomnia.

"Our study is among the first to show that it's not the number of stressors, but your reaction to them that determines the likelihood of experiencing insomnia," said lead author Vivek Pillai, PhD, research fellow at the Sleep Disorders & Research Center at Henry Ford Hospital in Detroit, Michigan. "While a stressful event can lead to a bad night of sleep, it's what you do in response to stress that can be the difference between a few bad nights and chronic insomnia."

Study results are published in the July 1 issue of the journal Sleep.

The study involved a community-based sample of 2,892 good sleepers with no lifetime history of insomnia. At baseline the participants reported the number of stressful life events that they had experienced in the past year, such as a divorce, serious illness, major financial problem, or the death of a spouse. They also reported the perceived severity and duration of each stressful event. Questionnaires also measured levels of cognitive intrusion and identified coping strategies in which participants engaged in the seven days following the stressful event. A follow-up assessment after one year identified participants with insomnia disorder, which was defined as having symptoms of insomnia occurring at least three nights per week for a duration of one month or longer with associated daytime impairment or distress. "This study is an important reminder that stressful events and other major life changes often cause insomnia," said American Academy of Sleep Medicine President Dr. Timothy Morgenthaler. "If you are feeling overwhelmed by events in your life, talk to you doctor about strategies to reduce your stress level and improve your sleep."

According to the authors, the study identified potential targets for therapeutic interventions to improve coping responses to stress and reduce the risk of insomnia. In particular, they noted that mindfulness-based therapies have shown considerable promise in suppressing cognitive intrusion and improving sleep.

"Though we may not be able to control external events, we can reduce their burden by staying away from certain maladaptive behaviors," said Pillai.

The American Academy of Sleep Medicine reports that short-term insomnia disorder lasting less than three months occurs in 15 to 20 percent of adults and is more prevalent in women than in men.

The research was performed under the supervision of Thomas Roth, PhD, and Christopher Drake, PhD, in the Sleep & Research Center at Henry Ford Hospital in Detroit. The study was supported by funding from the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH).


Story Source:

The above story is based on materials provided by American Academy of Sleep Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. Vivek Pillai, Thomas Roth, Heather M. Mullins, Christopher L. Drake. Moderators and Mediators of the Relationship Between Stress and Insomnia: Stressor Chronicity, Cognitive Intrusion, and Coping. SLEEP, 2014; DOI: 10.5665/sleep.3838

New insights on conditions for new blood vessel formation


A new capillary sprouting off a blood vessel.

Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is essential to the body's development. As organs grow, vascular networks must grow with them to feed new cells and remove their waste. The same process, however, also plays a critical role in the onset and progression of many cancers, as it allows the rapid growth of tumors.

With lifesaving applications possible in both inhibiting and accelerating the creation of new blood vessels, a more fundamental understanding of what regulates angiogenesis is needed. Now, researchers at the University of Pennsylvania, Boston University and Harvard University have uncovered the existence of a threshold above which fluid flowing through blood vessel walls causes new capillaries to sprout.

This discovery could help pave the way for cancer-fighting drugs, treatments for the hardened blood vessels found in the cardiovascular disease arthrosclerosis or even growing synthetic organs in the lab.

The research was led by postdoctoral fellow Peter Galie of the Department of Bioengineering in Penn's School of Engineering and Applied Science and Christopher Chen, then a professor of bioengineering at Penn who is now at Boston University and an associate faculty member of the Wyss Institute for Biologically Inspired Engineering at Harvard University. They collaborated with Duc-Huy Nguyen, Colin Choi and Daniel Cohen, all members of Chen's lab, and professor Paul Janmey, also of the Department of Bioengineering, as well as the Department of Physiology in Penn's Perelman School of Medicine.

Their study was published in the Proceedings of the National Academy of Sciences.

The team's experiments incorporated "blood-vessel-on-a-chip" devices, which use microfluidic technology to simulate processes that normally occur deep within tissues. They found that cells lining each artificial vessel sprouted to form new vessels once the force exerted by fluid flow through the vessel exceeded a certain threshold.

"These findings suggest that our blood vessels can sense when blood flow exceeds their carrying capacity and respond by producing additional vessels on demand," Chen explained. "Perhaps we could one day take advantage of this response to enhance vessel regrowth where the need is critical, such as after a heart attack."

During their experiments, the researchers controlled the fluid flow within the artificial vessel, and ultimately where new vessels would sprout, by changing the shape and orientation of thin needles deployed within a collagen gel containing each vessel. Using a mathematical model, they predicted the exact spots along the vessel where force exceeded the sprouting threshold, thereby pinpointing the location where new vessels would form.

Now the researchers aim to advance new experiments designed to figure out how cells sense this mechanical threshold.

"The logical next step is to determine the molecular mechanism behind this phenomenon," said Galie, "what proteins are involved and how might they be targeted in new drug therapies."

Their work was funded by the National Institutes of Health and the University of Pennsylvania's Center for Engineering Cells and Regeneration, where Chen was the founding director.


Story Source:

The above story is based on materials provided by University of Pennsylvania. Note: Materials may be edited for content and length.


Journal Reference:

  1. P. A. Galie, D.-H. T. Nguyen, C. K. Choi, D. M. Cohen, P. A. Janmey, C. S. Chen. Fluid shear stress threshold regulates angiogenic sprouting. Proceedings of the National Academy of Sciences, 2014; 111 (22): 7968 DOI: 10.1073/pnas.1310842111

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Biological signal processing: Body cells -- instrumentalists in a symphony orchestra


Like an isolated note in a symphony orchestra, an isolated signal in the cell is of subordinate importance.

Every organism has one aim: to survive. Its body cells all work in concert to keep it alive. They do so through finely tuned means of communication. Together with cooperation partners from Berlin and Cambridge, scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have now successfully revealed for the first time the laws by which cells translate signals from their surroundings into internal signals. Like an isolated note in a symphony orchestra, an isolated signal in the cell is of subordinate importance. "What is important is the relative variation of intensity and frequency at which the signals are transmitted from the cell membrane into the cell," says Dr. Alexander Skupin, who led the studies at LCSB. The research group published their results now in the scientific journal Science Signaling.

The instruments in an orchestra produce signals -- musical notes -- by causing the air to vibrate. Inside a cell, calcium ions carry signals. When a piece of information from the environment -- say a biological messenger -- meets the outer envelope of the cell, calcium ions are released inside the cell. There, they control various adaptation processes. "At first sight, there is no simple pattern to the ion impulses," Skupin explains; "yet they still culminate in a meaningful response inside the cell, like the activation of a specific gene, for instance."

In order to determine the laws underlying this phenomenon, the researchers studied human kidney cells and rat liver cells using a combination of imaging technologies and mathematical methods. They discovered that the intensity and frequency of calcium impulses undergo extreme variation -- both cell-internally and cell-to-cell. Accordingly, the information they convey cannot be interpreted by analyzing isolated signals alone. "It's like in an orchestra, where studying an isolated note on its own allows no inference of the melody," Skupin continues the musical analogy. "You have to hear how the frequency and volume of all instruments vary and produce the melody. Then you gain an impression of the musical piece."

Now, for the first time, the researchers have managed to gain such an impression of the whole by listening in on the cells' communications. They discovered that the plethora of calcium impulses vary relatively to one another in a specific relationship: A stimulus from outside does not lead to an absolute increase in calcium impulses, but instead to a change in the frequency at which they occur -- in the concert hall, the notes of the instruments rise and fall in symphony. "This pattern is the actual signal that leads to a response in the cells," Skupin says. "With our analyses, we have rendered it interpretable."

"The results are of great importance for analyzing diseases," says Director of LCSB Prof. Dr. Rudi Balling. "We know that, in Parkinson's disease, the calcium balance in the nerve cells is disrupted, and suspect that errant communications between the cells could play a role in the onset of neurodegenerative diseases. With the discovery of the fundamental laws of these communications, as Alexander Skupin, his team and our cooperation partners have now achieved, we are set to take a major step forward in the analysis of Parkinson's disease."


Story Source:

The above story is based on materials provided by University of Luxembourg. Note: Materials may be edited for content and length.


Journal Reference:

  1. K. Thurley, S. C. Tovey, G. Moenke, V. L. Prince, A. Meena, A. P. Thomas, A. Skupin, C. W. Taylor, M. Falcke. Reliable Encoding of Stimulus Intensities Within Random Sequences of Intracellular Ca2 Spikes. Science Signaling, 2014; 7 (331): ra59 DOI: 10.1126/scisignal.2005237

Explaining 'healthy' obesity

 

July 3, 2014

Cell Press

Up to one-quarter of individuals currently labeled as obese are actually metabolically healthy. Though obesity is a major risk factor for diabetes, the two conditions aren't always linked. A new study sheds light on a possible explanation, revealing that high levels of a molecule HO-1 are linked to poor metabolic health and an increased risk of type 2 diabetes in obese humans. HO-1 blockers could represent a promising new strategy for the treatment of metabolic disease.


Up to one-quarter of individuals currently labeled as obese are actually metabolically healthy and do not have a high risk of developing type 2 diabetes. Though obesity is a major risk factor for diabetes, the two conditions aren't always linked. A study published by Cell Press July 3rd in the journal Cell sheds light on a possible explanation, revealing that high levels of a molecule called heme oxygenase-1 (HO-1) are linked to poor metabolic health and an increased risk of type 2 diabetes in obese humans. Moreover, HO-1 inhibition improves metabolic health in obese mice, suggesting that HO-1 blockers could represent a promising new strategy for the treatment of metabolic disease.

"The results indicate that HO-1 is in fact necessary for the development of metabolic disease and call for a re-evaluation of numerous findings in the field," says senior study author Harald Esterbauer of the Medical University of Vienna. "The study also reveals HO-1 as a candidate biomarker for the stratification of metabolically healthy and unhealthy obesity and provides a framework for selective, personalized therapy."

The factors that determine whether obesity leads to poor metabolic health have been unclear, but the evidence suggests that a maladaptive immune response called metabolic inflammation plays an important role. However, studies examining the relationship between a supposedly anti-inflammatory molecule called HO-1 and metabolic disease have produced conflicting results.

To address this question, Esterbauer teamed up with senior study author J. Andrew Pospisilik of the Max Planck Institute of Immunobiology and Epigenetics. In contrast to past findings, they found higher levels of HO-1 in liver and fat biopsies from obese, insulin-resistant humans compared with obese, metabolically healthy individuals. When the researchers deleted the HO-1 gene in immune cells called macrophages, molecular signs of inflammation decreased in mice, suggesting that HO-1 actually promotes inflammation, contrary to widespread belief. Moreover, deletion of the HO-1 gene specifically in the liver or macrophages of mice fed a high-fat diet led to better liver function and an increase in insulin sensitivity -- a clear sign of improved metabolic health.

"Our findings show that HO-1 is among the strongest predictors of metabolically unhealthy obesity in humans, and it could have a high prognostic value for detecting disease onset," Pospisilik says. "This could allow clinicians to use targeted interventions to prevent disease progression specifically in obese individuals who show early signs of type 2 diabetes."

New strategy could uncover genes at the root of psychiatric illnesses

 

July 3, 2014

Cell Press

Understanding the basis of psychiatric disorders has been extremely challenging because there are many genetic variants that may increase risk but are insufficient to cause disease. Now investigators describe a strategy that may help reveal how such 'subthreshold' genetic risks interact with other risk factors or environmental exposures to affect the development of the nervous system. Their research pinpoints a genetic variant that may predispose individuals to schizophrenia.


Yoon et al. use modeling in iPSCs and mice to examine the functional effects of 15q11.2 CNVs, a known risk factor for several neuropsychiatric disorders including schizophrenia. Their analysis highlights defects in adherens junctions and polarity in neural stem cells associated with haploinsufficiency of the cytoskeletal regulator CYFIP1. The cover image was created using images of neural rosettes derived from human iPSCs with and without a 15q11.2 microdeletion (round circles) and images of radial glial cells in the developing mouse cortex (thin filaments), and it is inspired by July 4th fireworks.

 

Understanding the basis of psychiatric disorders has been extremely challenging because there are many genetic variants that may increase risk but are insufficient to cause disease. Now investigators reporting in the July 3rd issue of the Cell Press journal Cell Stem Cell describe a strategy that may help reveal how such "subthreshold" genetic risks interact with other risk factors or environmental exposures to affect the development of the nervous system. Their research pinpoints a genetic variant that may predispose individuals to schizophrenia.

The work takes advantage of a recently developed technology that allows skin cells from patients to be reprogrammed into induced pluripotent stem cells (iPSCs) that can then generate any cell type in the body. Through this technology, scientists obtained stem cells from individuals with a genetic abnormality that confers increased susceptibility to schizophrenia, and they observed deficits during nerve development that could be traced to a specific gene called CYFIP1, which helps maintain a nerve cell's structure. The team then blocked the expression of this gene in developing mouse embryos and noticed defects in the formation of the cerebral cortex, a brain region that plays an important role in consciousness.

Next, the scientists turned to human genetic studies to see how CYFIP might interact with other factors. They found that mutations in two genes within a cellular pathway linked to CYFIP1 led to a significantly increased risk of schizophrenia. The findings support the theory that multiple factors within the same pathway may interact to affect one's risk for psychiatric disorders.

"We were able to use a set of cutting-edge tools to gain insight into a critical cellular process for normal brain development, the dysregulation of which may be a manifestation of a genetic predisposition for schizophrenia," says senior author Dr. Guo-li Ming, of Johns Hopkins University School of Medicine. The researchers' strategy -- generating disease-specific nerve cells, identifying a causative gene for developmental defects, validating the gene-specific defect in animal models, and then investigating interactions with other genes both in animal models and in humans -- represents a promising new approach for understanding the mechanisms underlying some of the most intractable psychiatric illnesses.

The work also highlights the promise of iPSC technology as a discovery tool in understanding and treating human disorders. "Despite an enormous amount of time and resources devoted to producing solid, reproducible results in animal models, far too often, results from preclinical trials deviate from our expectations," says co-author Dr. Hongjun Song. "The lack of access to disease-relevant human cell types has been a missing link in our current drug discovery process, which has now been resolved through advances in cellular reprogramming."


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ki-Jun Yoon, Ha Nam Nguyen, Gianluca Ursini, Fengyu Zhang, Nam-Shik Kim, Zhexing Wen, Georgia Makri, David Nauen, Joo Heon Shin, Youngbin Park, Raeeun Chung, Eva Pekle, Ce Zhang, Maxwell Towe, Syed Mohammed Qasim Hussaini, Yohan Lee, Dan Rujescu, David St. Clair, Joel E. Kleinman, Thomas M. Hyde, Gregory Krauss, Kimberly M. Christian, Judith L. Rapoport, Daniel R. Weinberger, Hongjun Song, Guo-li Ming. Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity. Cell Stem Cell, 2014; 15 (1): 79 DOI: 10.1016/j.stem.2014.05.003