Language Intervention Isn't Just Spoken: Assessment and Treatment of a Deaf Signing Child With Specific Language Impairment.

Purpose This case study describes the language evaluation and treatment of a 5-year-old boy, Lucas, who is Deaf, uses American Sign Language (ASL), and presented with a language disorder despite native access to ASL and no additional diagnosis that would explain the language difficulties. Method Lucas participated in an evaluation where his nonverbal IQ, fine motor, and receptive/expressive language skills were assessed. Language assessment included both formal and informal evaluation procedures. Language intervention was delivered across 7 weeks through focused stimulation. Results Evaluation findings supported diagnosis of a language disorder unexplained by other factors. Visual analysis revealed an improvement in some behaviors targeted during intervention (i.e., number of different verbs and pronouns), but not others. In addition, descriptive analysis indicated qualitative improvement in Lucas' language production. Parent satisfaction survey results showed a high level of satisfaction with therapy progress, in addition to a belief that Lucas improved in language areas targeted. Conclusions This study adds to the growing body of literature that unexplained language disorders in signed languages exist and provides preliminary evidence for positive outcomes from language intervention for a Deaf signing child. The case described can inform professionals who work with Deaf signing children (e.g., speech-language pathologists, teachers of the Deaf, and parents of Deaf children) and serve as a potential starting point in evaluation and treatment of signed language disorders. Supplemental Material https://doi.org/10.23641/asha.16725601.

"I wanted to participate in my own care": Evaluation of a Patient Navigation Program.

INTRODUCTION: Patient navigation programs can help people overcome barriers to outpatient care. Patient experiences with these programs are not well understood. The goal of this study was to understand patient experiences and satisfaction with an emergency department (ED)-initiated patient navigation (ED-PN) intervention for US Medicaid-enrolled frequent ED users. METHODS: We conducted a mixed-methods evaluation of patient experiences and satisfaction with an ED-PN program for patients who visited the ED more than four times in the prior year. Participants were Medicaid-enrolled, English- or Spanish-speaking, New Haven-CT residents over the age of 18. Pre-post ED-PN intervention surveys and post-ED-PN individual interviews were conducted. We analyzed baseline and follow-up survey responses as proportions of total responses. Interviews were coded by multiple readers, and interview themes were identified by consensus. RESULTS: A total of 49 participants received ED-PN. Of those, 80% (39/49) completed the post-intervention survey. After receiving ED-PN, participants reported high satisfaction, fewer barriers to medical care, and increased confidence in their ability to coordinate and manage their medical care. Interviews were conducted until thematic saturation was reached. Four main themes emerged from 11 interviews: 1) PNs were perceived as effective navigators and advocates; 2) health-related social needs were frequent drivers of and barriers to healthcare; 3) primary care utilization depended on clinic accessibility and quality of relationships with providers and staff; and 4) the ED was viewed as providing convenient, comprehensive care for urgent needs. CONCLUSIONS: Medicaid-enrolled frequent ED users receiving ED-PN had high satisfaction and reported improved ability to manage their health conditions.

Patient Navigation to Reduce Emergency Department (ED) Utilization Among Medicaid Insured, Frequent ED Users: A Randomized Controlled Trial.

BACKGROUND: Some Medicaid enrollees frequently utilize the emergency department (ED) due to barriers accessing health care services in other settings. OBJECTIVES: To determine whether an ED-initiated Patient Navigation program (ED-PN) designed to improve health care access for Medicaid-insured frequent ED users could decrease ED visits, hospitalizations, and costs. METHODS: We conducted a prospective, randomized controlled trial comparing ED-PN with usual care (UC) among 100 Medicaid-enrolled frequent ED users (defined as 4-18 ED visits in the prior year), assessing ED utilization during the 12 months pre- and post-enrollment. Secondary outcomes included hospitalizations, outpatient utilization, hospital costs, and Medicaid costs. We also compared characteristics between ED-PN patients with and without reduced ED utilization. RESULTS: Of 214 eligible patients approached, 100 (47%) consented to participate. Forty-nine were randomized to ED-PN and 51 to UC. Sociodemographic characteristics and prior utilization were similar between groups. ED-PN participants had a significant reduction in ED visits and hospitalizations during the 12-month evaluation period compared with UC, averaging 1.4 fewer ED visits per patient (p = 0.01) and 1.0 fewer hospitalizations per patient (p = 0.001). Both groups increased outpatient utilization. ED-PN patients showed a trend toward reduced per-patient hospital costs (-$10,201, p = 0.10); Medicaid costs were unchanged (-$5,765, p = 0.26). Patients who demonstrated a reduction in ED usage were older (mean age 42 vs. 33 years, p = 0.03) and had lower health literacy (78% low health literacy vs. 40%, p = 0.02). CONCLUSION: An ED-PN program targeting Medicaid-insured high ED utilizers demonstrated significant reductions in ED visits and hospitalizations in the 12 months after enrollment.

Identification and Quantitation of Potent Odorants in Spearmint Oils.

Potent odorants in Native spearmint, Scotch spearmint, and Macho mint oils were determined by the combined use of gas chromatography-olfactometry (GCO), gas chromatography-mass spectrometry (GC-MS), and aroma extract dilution analysis (AEDA). Of the 85 odorants detected, ( R)-(-)-carvone was the most potent odorant in all three spearmint oils. Additional predominant odorants in all spearmint oils included eugenol, ethyl ( S)-(+)-2-methylbutanoate, ( E)-ß-damascenone, and (3 E,5 Z)-1,3,5-undecatriene. Forty-six compounds were quantitated using various methods, including 19 by gas chromatography with flame ionization detection (GC-FID), 20 by stable isotope dilution analysis (SIDA), and 14 by GCO dilution analysis. Concentrations were used to calculate the odor activity values (OAVs) for predominant odorants in the oils. Among the compounds quantitated, those with the highest OAVs were ( R)-(-)-carvone, 1,8-cineole, ( E, Z)-2,6-nonadienal, ( E)-ß-damascenone, and (3 E,5 Z)-1,3,5-undecatriene.

A Closer Look at Rural-Urban Health Disparities: Associations Between Obesity and Rurality Vary by Geospatial and Sociodemographic Factors.

BACKGROUND: Obesity affects over one-third of older adults in the United States. Both aging and obesity contribute to an increased risk for chronic disease, early mortality, and additional health care utilization. Obesity rates are higher in rural areas than in urban areas, although findings are mixed. The objectives of this study are to assess potential nonlinearity in the association between rurality and obesity, and to evaluate the potential for socioeconomic status and geographic area to moderate the associations between rurality and obesity. METHODS: Using a representative sample of adults aged 65 and above from the Behavioral Risk Factor Surveillance System, obesity (BMI ≥ 30 kg/m2 ) was modeled against the primary exposure of rural-urban status, as measured by the Index of Relative Rurality. Binary logistic regression models were used to estimate the odds of obesity by rurality both as a continuous variable and by decile of rurality. Models were then stratified by per-capita income and state to assess potential moderation by these factors. RESULTS: The prevalence of obesity in older adults was highest in intermediate rurality areas (OR in rurality decile #5 1.134, 95% CI: 1.086-1.184) and lowest in the most rural and most urban areas. Obesity was highest in low- and middle-income areas, regardless of rural-urban status. In high-income areas, obesity among older adults was highest in areas of intermediate rurality and lowest in the most rural areas (OR 0.726, 95% CI: 0.606-0.870) and more urban areas, showing a J-shaped association. There were substantial differences in the associations between rurality and obesity in older adults among states. CONCLUSION: Associations between rurality and obesity varied by degree of rurality, socioeconomic status, and geography. Therefore, traditional "one-size-fits-all" approaches to reducing rural-urban health disparities in older adults may be more effective if tailored to the area-specific rural-urban gradients in health.

Reasons for Frequent Emergency Department Use by Medicaid Enrollees: A Qualitative Study.

BACKGROUND: The Affordable Care Act initiated several care coordination programs tailored to reduce emergency department (ED) use for Medicaid-enrolled frequent ED users. It is important to clarify from the patient's perspective why Medicaid enrollees who want to receive care coordination services to improve primary care utilization frequently use the ED. METHODS: We conducted a qualitative data analysis of patient summary reports obtained from Medicaid enrolled frequent ED users who agreed to participate in a randomized control trial (RCT) evaluating the impact of patient navigation intervention compared with standard of care on ED use and hospital admissions. We defined frequent ED users as those who used the ED four to 18 times in the past year. The study was conducted at an urban, teaching hospital ED with approximately 90,000 visits per year. The research staff conducted interviews (~30-40 minutes), regarding the patient's medical history, reasons for ED visits, health care access issues, and social distresses. The aforementioned findings were summarized in a 1- to 2-page report and presented to the RCT's project team (social worker, emergency medicine physician, primary care physician, and patient navigators) on a weekly basis to further understand the needs of this patient population. A diverse team of researchers (program staff and physicians) coded all reports and reached consensus using reflexive team analysis. We reconciled differences in code interpretations and generated themes. RESULTS: One-hundred patients enrolled in the RCT from March 2013 to February 2014, and all 100 patient summary reports were evaluated. We identified three key themes associated with Medicaid enrollee frequent ED use: 1) negative personal experiences with the healthcare system, 2) challenges associated with having low socioeconomic status, and 3) significant chronic mental and physical disease burden. CONCLUSIONS: Medicaid frequent ED users engaged in receiving patient navigation services with the goal to reduce ED use and hospital admissions describe barriers that go beyond timely primary care access issues. These include sociodeterminants of health, lack of trust in primary care providers, and healthcare system.

Spatiotemporal Discordance in Five Common Measures of Rurality for US Counties and Applications for Health Disparities Research in Older Adults.

INTRODUCTION: Rural populations face numerous barriers to health, including poorer health care infrastructure, access to care, and other sociodemographic factors largely associated with rurality. Multiple measures of rurality used in the biomedical and public health literature can help assess rural-urban health disparities and may impact the observed associations between rurality and health. Furthermore, understanding what makes a place truly "rural" versus "urban" may vary from region to region in the US. PURPOSE: The objectives of this study are to compare and contrast five common measures of rurality and determine how well-correlated these measures are at the national, regional, and divisional level, as well as to assess patterns in the correlations between the prevalence of obesity in the population aged 60+ and each of the five measures of rurality at the regional and divisional level. METHODS: Five measures of rurality were abstracted from the US Census and US Department of Agriculture (USDA) to characterize US counties. Obesity data in the population aged 60+ were abstracted from the Behavioral Risk Factor Surveillance System (BRFSS). Spearman's rank correlations were used to quantify the associations among the five rurality measurements at the national, regional, and divisional level, as defined by the US Census Bureau. Geographic information systems were used to visually illustrate temporal, spatial, and regional variability. RESULTS: Overall, Spearman's rank correlations among the five measures ranged from 0.521 (percent urban-urban influence code) to 0.917 (rural-urban continuum code-urban influence code). Notable discrepancies existed in these associations by Census region and by division. The associations between measures of rurality and obesity in the 60+ population varied by rurality measure used and by region. CONCLUSION: This study is among the first to systematically assess the spatial, temporal, and regional differences and similarities among five commonly used measures of rurality in the US. There are important, quantifiable distinctions in defining what it means to be a rural county depending on both the geographic region and the measurement used. These findings highlight the importance of developing and selecting an appropriate rurality metric in health research.

The Effectiveness of a Patient-Centred Assessment with a Solution-Focused Approach (DIALOG+) for Patients with Psychosis: A Pragmatic Cluster-Randomised Controlled Trial in Community Care.

BACKGROUND: DIALOG+ was developed as a computer-mediated intervention, consisting of a structured assessment of patients' concerns combined with a solution-focused approach to initiate change. This study tested the effectiveness of DIALOG+ in the community treatment of patients with psychosis. METHOD: This was a pragmatic, exploratory, parallel-group, cluster-randomised controlled trial. Clinicians within community teams - along with patients with psychosis under their care - were randomised to use DIALOG+ once per month for 6 months or an active control. The primary outcome (subjective quality of life, SQOL) and secondary outcomes were assessed after 3, 6 and 12 months by blinded assessors and analysed using mixed-effect models. RESULTS: A total of 49 clinicians and 179 patients were randomised. Implementation of DIALOG+ was variable, with an average of 1.8 sessions (SD = 1.6) in the first 3 months and 1.1 (SD = 1.2) in the following 3 months. Patients in the DIALOG+ arm had better SQOL at 3, 6 and 12 months (p = 0.035, 0.058 and 0.014, respectively; Cohen's d = 0.29-0.34). They also had significantly fewer unmet needs at 3 and 6 months, fewer general psychopathological symptoms at all time points and better objective social outcomes at 12 months, with no significant differences in other outcomes. Overall care costs were lower in the intervention group. CONCLUSION: Despite variable implementation, DIALOG+ is a beneficial intervention for community patients with psychosis. As a non-expensive and potentially cost-saving, generic intervention, DIALOG+ may be widely used and may improve the effectiveness of community treatment. Further trials should test DIALOG+ in different patient groups and contexts.

Psychosocial factors of caregiver burden in child caregivers: results from the new national study of caregiving.

BACKGROUND: Over 50 million informal caregivers in the United States provide care to an aging adult, saving the economy hundreds of billions of dollars annually from costly hospitalization or institutionalization. Despite the benefits associated with caregiving, caregiver stress can lead to negative physical and mental health consequences, or "caregiver burden". Given these potential negative consequences of caregiver burden, it is important not only to understand the multidimensional components of burden but to also understand the experience from the perspective of the caregiver themselves. Therefore, the objectives of our study are to use exploratory factor analysis to obtain a set of latent factors among a subset of caregiver burden questions identified in previous studies and assess their reliability. METHODS: All data was obtained from the 2011 National Study of Caregiving (NSOC). Exploratory factor analysis (EFA) was performed to identify a set of latent factors assessing four domains of caregiver burden in "child caregivers": those informal caregivers who provide care to a parent or stepparent. Sensitivity analysis was also conducted by repeating the EFA on demographic subsets of caregivers. RESULTS: After multiple factor analyses, four consistent caregiver burden factors emerged from the 23 questions analyzed: Negative emotional, positive emotional, social, and financial. Reliability of each factor varied, and was strongest for the positive emotional domain for caregiver burden. These domains were generally consistent across demographic subsets of informal caregivers. CONCLUSION: These results provide researchers a more comprehensive understanding of caregiver burden to target interventions to protect caregiver health and maintain this vital component of the US health care system.

Do Adult Medicaid Enrollees Prefer Going to Their Primary Care Provider's Clinic Rather Than Emergency Department (ED) for Low Acuity Conditions?

BACKGROUND: The rates of annual visits for adult Medicaid enrollees to the emergency department (ED) are increasing. Many programs throughout the country are focused on engaging patients in the use of their primary care providers (PCP) rather than the ED for low acuity conditions. It is unclear, however, the proportion of patients who are willing to use primary care services rather than the ED if they are given the choice. METHODS: Cross-sectional study of adult Medicaid enrollees (18 y and older) presenting to a large, urban, academic ED from June to August 2012 with a low acuity condition was performed. We excluded patients who did not have a PCP or active Medicaid insurance. Our primary goal was to determine the proportion of patients who prefer to use the ED, rather than their PCP clinic, if an appointment was immediately available. Our second goal was to understand why patients would prefer ED over PCP care. RESULTS: A total of 150 patients agreed to complete the survey, and 95 (63.3%) met our inclusion criteria. Forty-three patients (45.3%) stated preferring to use their PCPs rather than the ED if an appointment was available at that time. Thirteen (48.1%) cited that the ED had more technology or specialty care services available when compared with their PCP's clinic, 8 (15.4%) were in significant pain, and 6 (11.5%) felt the care they received in the ED was better than what they would receive in their PCP clinic. CONCLUSIONS: Our study shows that a little less than half of adult Medicaid enrollees presenting to the ED with low acuity conditions would have preferred to use their PCP rather than the ED, if an appointment had been immediately available.

Bioactives from Artemisia dracunculus L. enhance insulin sensitivity via modulation of skeletal muscle protein phosphorylation.

OBJECTIVES: A botanical extract from Artemisia dracunculus L., termed PMI 5011, has been shown to improve insulin sensitivity by increasing cellular insulin signaling in in vitro and in vivo studies. These studies suggest that PMI 5011 effects changes in phosphorylation levels of proteins involved in insulin signaling. The aim of this study was to explore the effects of this promising botanical extract on the human skeletal muscle phosphoproteome, by evaluating changes in site-specific protein phosphorylation levels in primary skeletal muscle cultures from obese, insulin-resistant individuals stimulated with and without insulin. METHODS: Insulin resistance is a condition in which a normal or elevated insulin level results in an abnormal biologic response, e.g., glucose uptake. Using isobaric tagging for relative and absolute quantification (iTRAQ™) followed by phosphopeptide enrichment and liquid chromatography-tandem mass spectrometry, 125 unique phosphopeptides and 159 unique phosphorylation sites from 80 unique proteins were identified and quantified. RESULTS: Insulin stimulation of primary cultured muscle cells from insulin-resistant individuals resulted in minimal increase in phosphorylation, demonstrating impaired insulin action in this condition. Treatment with PMI 5011 resulted in significant up-regulation of 35 phosphopeptides that were mapped to proteins participating in the regulation of transcription, translation, actin cytoskeleton signaling, caveolae translocation, and translocation of glucose transporter 4. These data further showed that PMI 5011 increased phosphorylation levels of specific amino acids in proteins in the insulin-resistant state that are normally phosphorylated by insulin (thus, increasing cellular insulin signaling) and PMI 5011 also increased the abundance of phosphorylation sites of proteins regulating anti-apoptotic effects. CONCLUSION: This phosphoproteomics analysis demonstrated conclusively that PMI 5011 effects changes in phosphorylation levels of proteins and identified novel pathways by which PMI 5011 exerts its insulin-sensitizing effects in skeletal muscle.

Characteristics of Medicaid enrollees with frequent ED use.

BACKGROUND: Medicaid enrollees are disproportionately represented among patients with frequent Emergency Department (ED) visits, yet prior studies investigating frequent ED users have focused on patients with all insurance types. METHODS: This was a single center, retrospective study of Medicaid-insured frequent ED users (defined as ≥4 ED visits/year not resulting in hospital admission) to assess patients' sociodemographic and clinical characteristics and evaluate differences in these characteristics by frequency of use (4-6, 7-17, and ≥18 ED visits). RESULTS: Twelve percent (n = 1619) of Medicaid enrollees who visited the ED during the 1-year study period were frequent ED users, accounting for 38% of all ED visits (n = 10,337). Most frequent ED users (n = 1165, 72%) had 4-6 visits; 416 (26%) had 7-17 visits, and 38 (2%) had ≥18 visits. Overall, 67% had a primary care provider and 56% had at least one chronic medical condition. The most common ED diagnosis among patients with 4-6 visits was abdominal pain (7%); among patients with 7-17 and ≥18 ED visits, the most common diagnosis was alcohol-related disorders (11% and 36%, respectively). Compared with those who had 4-6 visits, patients with ≥18 visits were more likely to be homeless (7% vs 42%, P < .05) and suffer from alcohol abuse (15% vs 42%, P < .05). CONCLUSION: One out of 8 Medicaid enrollees who visited the ED had ≥4 visits in a year. Efforts to reduce frequent ED use should focus on reducing barriers to accessing primary care. More tailored interventions are needed to meet the complex needs of adults with ≥18 visits per year.

Effectiveness of structured patient-clinician communication with a solution focused approach (DIALOG+) in community treatment of patients with psychosis--a cluster randomised controlled trial.

BACKGROUND: Large numbers of patients with psychosis have regular meetings with key clinicians in the community. There is little evidence on how these meetings should be conducted to be therapeutically effective. DIALOG, a computer mediated procedure, was shown to improve outcomes in a European multi-centre trial. DIALOG structures the patient-clinician communication and makes it patient-centred, but does not guide clinicians as to how to respond to patients' concerns. DIALOG has been further developed into DIALOG+, which uses advanced software and, additionally, provides a four step approach--based on a solution focused model--for addressing patients' concerns. We designed a cluster randomised controlled trial to test the effectiveness of DIALOG+ in improving treatment outcomes of patients with psychosis in the community. METHODS/DESIGN: Key workers are recruited from community mental health teams in East London and randomly allocated to either the intervention or control group. Out of their case loads, we identify patients with schizophrenia (F 20-29) and a moderate or lower level of subjective quality of life (MANSA score <5), who are treated according to the allocation of their key workers. Key workers in the intervention group are trained in using DIALOG+ and use it with each patient over a six-month period. Control patients rate their satisfaction with life and treatment on a tablet to control for the effect of regular ratings and the use of modern technology. We are recruiting up to 42 key workers to reach a total sample size of 180 patients. Clinical and social outcomes including costs are assessed after 3, 6 and 12 months. Primary outcome is subjective quality-of-life at 6 months. DISCUSSION: The trial aims to evaluate the effectiveness of a novel intervention (DIALOG+) which uses modern technology to support routine patient-clinician meetings in community care, makes the communication patient centred and guides patients and clinicians to address concerns. DIALOG+ is a generic and widely applicable intervention. If shown as effective, it can be used to improve outcomes of community care on a large scale, ensuring that routine encounters are therapeutically effective. DIALOG+ can also be implemented across services at relatively low additional costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34757603.

A "successful allele" at Campylobacter jejuni contingency locus Cj0170 regulates motility; "successful alleles" at locus Cj0045 are strongly associated with mouse colonization.

Campylobacter jejuni is an important foodborne pathogen of humans and its primary reservoir is the gastrointestinal (GI) tract of chickens. Our previous studies demonstrated that phase variation to specific "successful alleles" at C. jejuni contingency loci Cj0045 (successful alleles carry 9G or 10G homopolymeric tracts) and Cj0170 (successful allele carries a 10G homopolymeric tract) in C. jejuni populations is strongly associated with colonization and enteritis in C57BL/6 IL-10 deficient mice. In the current study, we strengthened the association between locus Cj0170, Cj0045, and mouse colonization. We generated 8 independent strains derived from C. jejuni 11168 strain KanR4 that carried a Cj0170 gene disruption and these were all non motile. Two randomly chosen strains with the Cj0170 gene disruption (DM0170-2 and DM0170-6) were gavaged into mice. DM0170-2 and DM0170-6 failed to colonize mice while the control strain that carried a "successful"Cj0170 10G allele was motile and did colonize mice. In parallel studies, when we inoculated C. jejuni strain 33292 into mice, the "unsuccessful"Cj0045 11G allele experienced phase variation to "successful" 9G and 10G alleles in 2 independent experiments prior to d4 post inoculation in mice while the "successful" 9G allele in the control strain remained stable through d21 post inoculation or shifted to other successful alleles. These data confirm that locus Cj0170 regulates motility in C. jejuni strain KanR4 and is a virulence factor in the mouse model. The data also support a possible role of locus Cj0045 as a virulence factor in strain 33292 in infection of mice.

Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene.

Building on gene-environment interaction (G × E) research, this study examines how the dopamine D4 receptor (DRD4) gene interacts with a situational prime of religion to influence prosocial behavior. Some DRD4 variants tend to be more susceptible to environmental influences, whereas other variants are less susceptible. Thus, certain life environments may be associated with acts of prosociality for some DRD4 variants but not others. Given that religion can act as an environmental influence that increases prosocial behavior, environmental input in the form of religion priming may have G × E effects. Results showed that participants with DRD4 susceptibility variants were more prosocial when implicitly primed with religion than not primed with religion, whereas participants without DRD4 susceptibility variants were not impacted by priming. This research has implications for understanding why different people may behave prosocially for different reasons and also integrates G × E research with experimental psychology.

Effects of prenatal stress and monoaminergic perturbations on the expression of serotonin 5-HT4 and adrenergic ß2 receptors in the embryonic mouse telencephalon.

The serotonin 5-HT(4) receptor (5-HT(4)R) is coded by a complex gene that produces four mRNA splice variants in mice (5-HT(4(a))R, 5-HT(4(b))R, 5-HT(4(e))R, 5-HT(4(f))R). This receptor has highly dynamic expression in brain development and its splice variants differ in their developmental trajectories. Since 5-HT(4)Rs are important in forebrain function (including forebrain control of serotonergic activity in the brainstem), we investigated the susceptibility of 5-HT(4)R expression in the mouse embryonic telencephalon to prenatal maternal stress and altered serotonin (5-hydroxytryptamine, 5-HT) levels. Because the gene coding the adrenergic ß(2) receptor (ß(2)AR) is embedded in the 5-HT(4)R gene, we also investigated whether 5-HT(4)R mRNA levels were modulated by selective ß(2)AR agents. Timed-pregnant C57BL/6 mice were treated beginning at embryonic day (E) 14 and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to assess the mRNA levels of all 5-HT(4)R splice variants and ß(2)AR in the embryonic telencephalon at E17. Maternal prenatal stress and 5-HT depletion with pCPA, a tryptophan hydroxylase inhibitor, reduced the levels of the 5-HT(4(b))R splice variant. Terbutaline (a selective ß(2)AR agonist) and ICI 118,551 (a selective ß(2)AR antagonist) had no effect on ß(2)AR and 5-HT(4)R mRNA levels. These results show that prenatal stress and reduced 5-HT levels can alter 5-HT(4)R expression in the developing forebrain and that some 5-HT(4)R splice variants may be more susceptible than others.

CIITA enhances HIV-1 attachment to CD4+ T cells leading to enhanced infection and cell depletion.

Activated CD4(+) T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4(+) T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, which results in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Further analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4(+) T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4(+) T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.

Class II transactivator (CIITA) enhances cytoplasmic processing of HIV-1 Pr55Gag.

BACKGROUND: The Pr55(gag) (Gag) polyprotein of HIV serves as a scaffold for virion assembly and is thus essential for progeny virion budding and maturation. Gag localizes to the plasma membrane (PM) and membranes of late endosomes, allowing for release of infectious virus directly from the cell membrane and/or upon exocytosis. The host factors involved in Gag trafficking to these sites are largely unknown. Upon activation, CD4+ T cells, the primary target of HIV infection, express the class II transcriptional activator (CIITA) and therefore the MHC class II isotype, HLA-DR. Similar to Gag, HLA-DR localizes to the PM and at the membranes of endosomes and specialized vesicular MHC class II compartments (MIICs). In HIV producer cells, transient HLA-DR expression induces intracellular Gag accumulation and impairs virus release. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that both stable and transient expression of CIITA in HIV producer cells does not induce HLA-DR-associated intracellular retention of Gag, but does increase the infectivity of virions. However, neither of these phenomena is due to recapitulation of the class II antigen presentation pathway or CIITA-mediated transcriptional activation of virus genes. Interestingly, we demonstrate that CIITA, apart from its transcriptional effects, acts cytoplasmically to enhance Pr160(gag-pol) (Gag-Pol) levels and thereby the viral protease and Gag processing, accounting for the increased infectivity of virions from CIITA-expressing cells. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that CIITA enhances HIV Gag processing, and provides the first evidence of a novel, post-transcriptional, cytoplasmic function for a well-known transactivator.