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Synovium-Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis

Wed, 05/03/2017 - 9:51am

Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high-throughput qPCR-based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p < 0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR-221-3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR-221-3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation.

Harms of cervical cancer screening in the United States and the Netherlands

Wed, 05/03/2017 - 9:51am

We studied harms related to cervical cancer screening and management of screen-positive women in the United States (US) and the Netherlands. We utilized data from four US integrated health care systems (SEARCH), the US National Health Interview Survey, New Mexico state, the Netherlands national histopathology registry, and included studies on adverse health effects of cervical screening. We compared the number of Papanicolaou (Pap) smear tests, abnormal test results, punch biopsies, treatments, health problems (anxiety, pain, bleeding and discharge) and preterm births associated with excisional treatments. Results were age-standardized to the 2007 US population. Based on SEARCH, an estimated 36 million Pap tests were performed in 2007 for 91 million US women aged 21-65 years, leading to 2.3 million abnormal Pap tests, 1.5 million punch biopsies, 0.3 million treatments for precancerous lesions, 5 thousand preterm births and over 8 million health problems. Under the Netherlands screening practice, fewer Pap tests (58%), abnormal test results (64%), punch biopsies (75%), treatment procedures (40%), preterm births (60%) and health problems (63%) would have occurred. The SEARCH data did not differ much from other US data for 2007 or from more recent data up to 2013. Thus compared to the less intensive screening practice in the Netherlands, US practice of cervical cancer screening may have resulted in two- to threefold higher harms, while the effects on cervical cancer incidence and mortality are similar. The results are also of high relevance in making recommendations for HPV screening. Systematic collection of harms data is needed for monitoring and for better incorporation of harms in making screening recommendations.

The safety of emerging biosimilar drugs for the treatment of rheumatoid arthritis

Wed, 05/03/2017 - 9:51am

INTRODUCTION: Biological disease-modifying anti-rheumatic drugs (bDMARDs), often administered in combination with methotrexate, target specific inflammatory mediators and have transformed the treatment of rheumatic diseases, especially rheumatoid arthritis (RA) but also the spondyloarthritides. However, the high cost of these drugs in many countries restricts patient access. As many bDMARDs have reached or are near to patent expiration, numerous biosimilar drugs are in development and some have already been approved. Biosimilars are generally priced lower than their reference products (RPs), or bio-originators, and as prices come down it is hoped that patient access to these drugs will increase, making the safety of these drugs an area of major interest. Areas covered: This article reviews publicly available safety data on biosimilars in RA. Expert opinion: Most available data for biosimilars in RA relate to tumor necrosis factor inhibitors (TNFi) and rituximab (an anti-CD20 monoclonal antibody). As biosimilar use around the world increases, evidence supporting the clinical safety of the biosimilars compared with their RPs also grows. To date, no new safety concerns have been raised in studies with TNFi or rituximab biosimilars for the treatment of RA; safety profiles have been consistent with those of their RPs. However, careful post-marketing pharmacovigilance remains necessary.

Introduction to Graphic Medicine

Tue, 05/02/2017 - 4:10pm

This webinar, taught by Matthew Noe from the Lamar Soutter Library at UMass Medical School, will introduce the emerging field of graphic medicine, or, the use of comics in healthcare. We will begin with a brief overview of the field’s emergence, and then switch directions to highlight the role that comics can play in two key areas of librarianship: health literacy and medical education. The webinar will conclude with suggestions for collection development and programming to kickstart graphic medicine in your library.

Educational Games & Health Sciences

Tue, 05/02/2017 - 4:09pm

This webinar will begin with an overview of educational games and their benefits. Rina Wehbe, University of Waterloo, will speak about her research and recent game “Above Water” which informs people about strategies for coping with anxiety. Zeb Mathews, University of Tennessee, will speak about his game, “PubWizard” which quizzes graduate level informatics students' knowledge of primary and secondary sources. This will be followed by an interactive exercise of exploring some of the National Institutes of Health (NIH) & National Library of Medicine (NLM) endorsed games. A Q&A session will follow. Are you interested in creating a game? We’ll have an exit survey to discuss hosting a game creation course.

The learning objectives currently include the following:

- Understand how educational games and gamification are unique - Learn about the possible benefits and advantages of learning with games - Better general understanding of the process of creating an educational game - Become acquainted with 2 educational games that intersect with the health sciences - Understand how basic game design elements are significant in educational games - Become familiar with some NIH & NLM endorsed games

Outline:
Introduction/Overview: 5-10 min.
Rina Wehbe (Above Water): 20 min.
Zeb Mathews (PubWizard): 20 min.
Game Exercise: 15-20 min.
Q&A & Survey: 5–10 min.

RNA-Sequencing Reveals Direct Targets of Tumor Suppressor miR-203 in Human Mammary Epithelial Cells

Tue, 05/02/2017 - 3:41pm

Background: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Since a significant portion of cases present with or progress to metastatic disease, furthering our understanding of metastasis is critical to develop better treatments. Epithelial cells maintain contact with the extracellular matrix (ECM) predominantly via integrin engagement, a process required for tissue integrity and barrier function. In non-transformed cells, loss of ECM adhesion promotes a specialized form of programmed cell death, anoikis. In order for efficient metastasis to occur, breast tumor cells must evade anoikis. miR-203, known to be down-regulated in several cancers, was found by our lab to be induced ten-fold 24 hours following detachment in breast epithelial cells, but not invasive triple negative breast cancer (TNBC) cells, suggesting that miR-203 may participate in promoting anoikis. Interestingly, more invasive breast cancer cell lines have been shown to express miR-203 at significantly lower levels than those of less invasive lines.

Objectives: Since restoration of miR-203 expression ectopically is not feasible in a clinical setting, we sought to identify and characterize miR-203 target genes in order to provide a pharmaceutical platform for restoration of anoikis sensitivity in metastatic breast cancer.

Methods: We performed traditional RNA-sequencing (RNA-Seq) coupled with immunoprecipitation of the RNA-induced silencing complex (RISC; Ago2 RIP-Seq) in MCF-10A, an immortalized, but non-transformed breast epithelial cell line, overexpressing precursor miR-203 or an empty vector control. MDA-MB-231, triple negative ductal carcinoma cells, were used as our invasive comparison cell line.

Results: Here we show that miR-203 induction in detached MCF-10A cells is due to loss of integrin signaling. Our coupled RNA-Seq and Ago2 RIP-Seq approach revealed 72 potential candidates, 42 of which were predicted miR-203 targets based on the TargetScan algorithm. We subjected the candidates to stringent characterization and found 9 bona-fide miR-203 targets that promote cell death when inhibited. Among these, WDR69, PRKAB1, PRPS2, and HBEGF were significantly elevated in TNBC tumor samples, as determined by RNA-Seq analysis in The Cancer Genome Atlas (TCGA).

Conclusion: Understanding the mechanisms by which cells evade anoikis during tumor dissemination is crucial to developing more effective therapies in breast cancer. miR-203, which is expressed at very low levels in more invasive breast cancers, is a positive regulator of anoikis that is upregulated in response to loss of contact with the ECM. Our combined RNA-sequencing screen revealed 42 direct miR-203 targets. Inhibition of 9 bona-fide targets promoted cell death, suggesting that they are negative regulators of anoikis. WDR69, PRKAB1, PRPS2, and HBEGF were all significantly elevated in TNBC tumor samples relative to less invasive samples, likely a consequence of low miR-203 expression. The identified genes represent potential pharmaceutical targets for novel breast cancer therapies.

Interventional Radiology Readiness Assessment Tool for Global Health

Mon, 05/01/2017 - 4:40pm

The Interventional Radiology Readiness Assessment Tool for Global Health is a new tool to methodically evaluate the environment of a medical institution for interventional radiology services given the existing infrastructure. Global health provides an exciting opportunity for interventional radiology to impact health outcomes in developing countries. A systematic and thoughtful approach to integrating interventional radiology services in the health care institutions of resource poor countries is needed in order to maximize global health efforts and outcomes.

The IR Readiness Assessment Tool is available as on online form and in PDF format under "Additional Files" below.

Collecting Histories of Education and Employment During Recovery (CHEER) Project

Mon, 05/01/2017 - 2:02pm

The Collecting Histories and Employment during Recovery (CHEER) study aims to provide a long-term picture of career development activities of young adults living with serious mental health conditions. From this study, we will better understand the work and education experiences, and the supports and barriers encountered by young adults with serious mental health conditions when trying to achieve their work and/or education goals, as well as how becoming a parent has impacted their work and education experiences.

Recent Trends in Sepsis Mortality, Associations between Initial Source of Sepsis and Hospital Mortality, and Predictors of Sepsis Readmission in Sepsis Survivors

Thu, 04/27/2017 - 3:10pm

Background: Sepsis, a leading cause of US deaths, is associated with high mortality, although advances in early recognition and treatment have increased survivorship. Many aspects of sepsis pathophysiology and epidemiology have not been fully elucidated; the heterogeneous nature of infections that lead to sepsis has made fully characterizing the underlying epidemiology challenging.

Methods: The University HealthSystem Consortium (UHC) from 2011-2014 and the Cerner HealthFacts® database from 2008-2014 were used. We examined associations between infection source and in-hospital mortality in the UHC dataset, stratified by age and presenting sepsis stage. We examined recent temporal trends in present-on-admission (POA) sepsis diagnoses and mortality and predictors of 30-day sepsis readmissions following sepsis hospitalizations using the HealthFacts® dataset.

Results: Patients with sepsis due to genitourinary or skin, soft tissue, or bone sources had lower mortality than patients with sepsis due to respiratory sources regardless of age or presenting sepsis stage. Overall diagnoses of sepsis increased from 2008-2014; however, POA diagnoses and case fatality rates decreased. Factors that predicted re-hospitalization for sepsis included discharge to hospice, admission from or discharge to a skilled nursing facility, and abdominal infection.

Conclusion: Further investigation will reveal more detail to explain the impact of infection source on in-hospital sepsis mortality for all age groups and sepsis stages. Decreasing mortality rates for all POA sepsis stages and all age groups suggest current approaches to sepsis management are having broad impact. Sepsis survivors are at significant risk for re-hospitalization; further studies are needed to understand the post discharge risks and needs of survivors.

A Synthetic Genetic System to Investigate Brain Connectivity and Genetically Manipulate Interacting Cells

Thu, 04/27/2017 - 3:10pm

The underlying goal of neuroscience research is to understand how the nervous system functions to bring about behavior. A detailed map of neural circuits is required for scientists to tackle this question. To this purpose, we developed a synthetic and genetically-encoded system, TRanscellular ACtivation of Transcription (TRACT) to monitor cell-cell contact. Upon ligand-receptor interaction at sites of cell-cell contact, the transmembrane domain of an engineered Notch receptor is cleaved by intramembrane proteolysis and releases a fragment that regulates transcription in the receptor-expressing cell. We demonstrate that in cultured cells, the synthetic receptor can be activated to drive reporter gene expression by co-incubation with ligand-expressing cell or by growth on ligand-coated surfaces. We further show that TRACT can detect interactions between neurons and glia in the Drosophila brain; expressing the ligand in spatially-restricted subsets of neurons leads to transcription of a reporter in the glial cells that interact with those neurons. To optimize TRACT for neural tracing, we attempted to target the synthetic receptor to post-synaptic sites by fusion with the intracellular domain of Drosophila neuroligin2. However, this modification only facilitate the receptor to be localized homogeneously throughout the neurites. The induction data of the modified receptor shows that the new receptor has better sensitivity compared to the original receptor, but the ligand-receptor interaction still happened at non-synaptic sites of membrane contact. To further target the ligand to pre-synaptic sites, we fused the ligand to different pre-synaptic markers. We found the one fused with synaptobrevin is likely located at axon terminals, but only able to trigger moderate induction. Therefore, more examinations are required to further characterize the capability of this ligand. In summary, TRACT is useful for monitoring cell-cell interactions in animals and could also be used to genetically manipulate cells based on contact. Moreover, we believe that proper targeting of the ligand to synaptic sites will improve the specificity of TRACT for synaptic connections in the future.

Intensity of Offending Following State Prison Release Among Persons Treated for Mental Health Problems While Incarcerated

Tue, 04/25/2017 - 10:28pm

OBJECTIVE: This study examined a range of demographic, clinical, and criminal history factors as they relate to the intensity of offending for up to two years postrelease.

METHODS: This study drew on data from 1,438 individuals released from Massachusetts state prisons between 2007 and 2009 who, while incarcerated, received treatment from the prisons' mental health services and were followed for 24 months postrelease. These data were used to explore predictive factors related to the intensity of criminal justice involvement, defined as number of arrests in the two-year follow-up period.

RESULTS: Predictors of subsequent arrests included number of previous incarcerations and black race. Protective factors included older age, supervision by parole, and a drug-related or person-related governing offense on previous arrest. Clinical symptoms were not related to incidence of postrelease arrests.

CONCLUSIONS: This study identified factors related to criminal history, such as type of charge, that were associated with the intensity of subsequent criminal justice involvement. These findings have not been reported in previous studies, perhaps because intensity of offending as opposed to a different dependent variable was used to measure criminal justice involvement. Further investigation should focus on whether the type of previous offense is related to postrelease risk factors for recidivism.

The NITRC image repository

Tue, 04/25/2017 - 10:28pm

The Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC - www.nitrc.org) suite of services include a resources registry, image repository and a cloud computational environment to meet the needs of the neuroimaging researcher. NITRC provides image-sharing functionality through both the NITRC Resource Registry (NITRC-R), where bulk data files can be released through the file release system (FRS), and the NITRC Image Repository (NITRC-IR), a XNAT-based image data management system. Currently hosting 14 projects, 6845 subjects, and 8285 MRI imaging sessions, NITRC-IR provides a large array of structural, diffusion and resting state MRI data. Designed to be flexible about management of data access policy, NITRC provides a simple, free, NIH-funded service to support resource sharing in general, and image sharing in particular.

Is Helplessness Still Helpful in Diagnosing Posttraumatic Stress Disorder

Tue, 04/25/2017 - 10:28pm

Criteria A2, experience of helplessness, fear, or horror at the time of the traumatic event, was removed from the posttraumatic stress disorder diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. We argue that there is empirical support for retention of A2, a criterion that has clinical value and may improve diagnostic accuracy. Specifically, we demonstrate that A2 has high negative predictive power, aids in the prediction of symptom severity, and can be indispensible to detecting the disorder in children. We examine how augmenting A2 with other peritramautic emotions could improve clinical and diagnostic utility. In our opinion, rather than being eliminated, A2 needs to be reconstructed and included as one criterion of PTSD.

What is the experience of psychiatry residents learning to prescribe? A qualitative research inquiry

Tue, 04/25/2017 - 10:28pm

BACKGROUND: Understanding how psychiatry residents learn to prescribe is important for the future of psychiatry. Prescribing is a complicated act that involves much more than signing a prescription. During residency, psychiatrists develop seminal attitudes and habits about prescribing. There have been no published studies focusing on psychiatry residents' experience when learning to prescribe.

AIMS: Qualitative methodology lends itself to a deep exploration of the process of learning how to prescribe. We undertook a qualitative study questioning psychiatry residents about their prescribing.

METHODS: Psychiatry residents were recruited from three residency programs and focus groups were conducted at each program. The focus groups were audiotaped and transcribed by a professional service. Thematic analysis was used to analyze the data and triangulation to increase the rigor of the study.

RESULTS: A total of 12 residents participated. Three themes were identified concerning identity development as a psychiatrist, uncertainty and fear about prescribing, and the centrality of collaborating with the patient during the prescribing process.

CONCLUSION: Psychiatry residents struggle with significant anxiety and frustration in their experience of learning to prescribe, suggesting a place for mentors and supervisors to focus.

Games for Health for Children-Current Status and Needed Research

Tue, 04/25/2017 - 10:28pm

Videogames for health (G4H) offer exciting, innovative, potentially highly effective methods for increasing knowledge, delivering persuasive messages, changing behaviors, and influencing health outcomes. Although early outcome results are promising, additional research is needed to determine the game design and behavior change procedures that best promote G4H effectiveness and to identify and minimize possible adverse effects. Guidelines for ideal use of different types of G4H by children and adolescents should be elucidated to enhance effectiveness and minimize adverse effects. G4H stakeholders include organizational implementers, policy makers, players and their families, researchers, designers, retailers, and publishers. All stakeholders should be involved in G4H development and have a voice in setting goals to capitalize on their insights to enhance effectiveness and use of the game. In the future, multiple targeted G4H should be available to meet a population's diverse health needs in developmentally appropriate ways. Substantial, consistent, and sophisticated research with appropriate levels of funding is needed to realize the benefits of G4H.

Receipt of pharmacotherapy for opioid use disorder by justice-involved U.S. Veterans Health Administration patients

Tue, 04/25/2017 - 10:28pm

BACKGROUND: Pharmacotherapy - methadone, buprenorphine, or naltrexone - is an evidence-based treatment for opioid use disorder, but little is known about receipt of these medications among veterans involved in the justice system. The current study examines receipt of pharmacotherapy for opioid use disorder among veterans with a history of justice involvement at U.S. Veterans Health Administration (VHA) facilities compared to veterans with no justice involvement.

METHODS: Using national VHA clinical and pharmacy records, we conducted a retrospective cohort study of veterans with an opioid use disorder diagnosis in fiscal year 2012. Using a mixed-effects logistic regression model, we examined receipt of pharmacotherapy in the 1-year period following diagnosis as a function of justice involvement, adjusting for patient and facility characteristics.

RESULTS: The 1-year rate of receipt for pharmacotherapy for opioid use disorder was 27% for prison-involved veterans, 34% for jail/court-involved veterans, and 33% for veterans not justice-involved. Compared to veterans not justice-involved, those prison-involved had 0.75 lower adjusted odds (95% confidence interval [CI]: 0.65-0.87) of receiving pharmacotherapy whereas jail/court-involved veterans did not have significantly different adjusted odds.

CONCLUSIONS: Targeted efforts to improve receipt of pharmacotherapy for opioid use disorder among veterans exiting prison is needed as they have lower odds of receiving these medications.

microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration

Tue, 04/25/2017 - 10:27pm

The aggregation of Abeta42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Abeta42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Abeta42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-small ka, CyrillicB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Abeta42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFalpha-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Abeta42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Abeta42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.

Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment

Tue, 04/25/2017 - 10:27pm

BACKGROUND: Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent.

METHOD: Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons.

RESULTS: At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018).

CONCLUSIONS: White matter deficits were validated in the present study by a relatively large sample of medication naive and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.

5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking

Tue, 04/25/2017 - 10:27pm

Cocaine addiction and depression are comorbid disorders. Although it is well recognized that 5-hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. This study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine-seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. In addition, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes antidepressive-like behaviors. Finally, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 h access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNshort right arrowNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction.

Pharmacogenetics of Ketamine-Induced Emergence Phenomena: A Pilot Study

Tue, 04/25/2017 - 9:51pm

BACKGROUND: Up to 55% of patients who are administered ketamine experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury; however, to date, no studies have investigated genetic association of ketamine-induced EP in healthy patients.

OBJECTIVES: The aim of the study was to investigate the feasibility and sample sizes required to explore the relationship between CYP2B6*6 and GRIN2B single-nucleotide polymorphisms and ketamine-induced EP.

METHODS: This cross-sectional, pharmacogenetic candidate, gene pilot study recruited 75 patients having minor elective outpatient surgeries. EP was measured with the Clinician Administered Dissociative State Scale. Genetic association of CYP2B6*6 and GRIN2B (rs1019385 and rs1806191) single-nucleotide polymorphisms and ketamine-induced EP occurrence and severity were tested using logistic and linear regression.

RESULTS: Forty-seven patients (63%) received ketamine and were genotyped, and 40% of them experienced EP. Occurrence and severity of EP were not associated with CYP2B6*6 or GRIN2B (p > .10). Exploratory analysis of nongenotype models containing age, ketamine dose, duration of anesthesia, and time from ketamine administration to assessment for EP significantly predicted EP occurrence (p = .001) and severity (p = .007). This pilot study demonstrates feasibility for implementing a pharmacogenetic study in a clinical setting, and we estimate that between 380 and 570 cases will be needed to adequately power future genetic association studies.

DISCUSSION: Younger age, higher dose, and longer duration of anesthesia significantly predicted EP occurrence and severity among our pilot sample. Although the small sample size limited our ability to demonstrate significant genotype differences, we generated effect sizes, sample size estimates, and nongenetic covariates information in order to support future pharmacogenetic study design for evaluating this adverse event.