Chronic corticosterone exposure in rats induces sex-specific alterations in hypothalamic reelin fragments, MeCP2, and DNMT3a protein levels.

Women are disproportionately affected by stress-related disorders like depression. In our prior research, we discovered that females exhibit lower basal hypothalamic reelin levels, and these levels are differentially influenced by chronic stress induced through repeated corticosterone (CORT) injections. Although epigenetic mechanisms involving DNA methylation and the formation of repressor complexes by DNA methyl-transferases (DNMTs) and Methyl-CpG binding protein 2 (MeCP2) have been recognized as regulators of reelin expression in vitro, there is limited understanding of the impact of stress on the epigenetic regulation of reelin in vivo and whether sex differences exist in these mechanisms. To address these questions, we conducted various biochemical analyses on hypothalamic brain samples obtained from male and female rats previously treated with either 21 days of CORT (40 mg/kg) or vehicle (0.9 % saline) subcutaneous injections. Upon chronic CORT treatment, a reduction in reelin fragment NR2 was noted in males, while the full-length molecule remained unaffected. This decrease paralleled with an elevation in MeCP2 and a reduction in DNMT3a protein levels only in males. Importantly, sex differences in baseline and CORT-induced reelin protein levels were not associated with changes in the methylation status of the Reln promoter. These findings suggest that CORT-induced reelin decreases in the hypothalamus may be a combination of alterations in downstream processes beyond gene transcription. This research brings novel insights into the sexually distinct consequences of chronic stress, an essential aspect to understand, particularly concerning its role in the development of depression.

Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3µg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.

A Survey of Payer Perspectives on Cannabis Use Disorder.

BACKGROUND: Cannabis use disorder (CUD) as described/defined in DSM 5, is characterized by impaired control of marijuana use and related personal, health, and legal consequences. CUD is a serious public health problem, affecting nearly 6 million individuals in the United States. There are no FDA approved medications to treat this disorder. The lack of available treatment options contributes to uncertainties by drug sponsors about formulary and reimbursement decision-making for CUD pharmacotherapies. OBJECTIVE: To addresses this gap by presenting the first findings on managed care payers' perceptions of CUD treatments and clinical trial end points. METHODS: An online survey was conducted with 50 payers from managed care organizations. The survey inquired about perceptions of unmet need in CUD treatment, relevant clinical trial end points, disease knowledge, and likelihood of review of new pharmacotherapies. RESULTS: The majority of payers (62%) reported that they were at least moderately familiar with CUD treatment end points. Most (80%) rated the unmet need for new pharmacotherapies for CUD as at least moderately important. Payers rated the most important end points for clinical trials as abstinence and decreased resource utilization. Most participants said an FDA approved CUD treatment would be formally reviewed by payers within 6 months (58%) or a year (36%). CONCLUSIONS: Based on these findings, payers see an unmet need for CUD treatment. Furthermore, FDA-approved pharmacotherapies for CUD will likely be reviewed quickly by payers, especially if data are provided on the likelihood of achieving abstinence and reduced resource utilization.

Development and validation of The Personal Diabetes Questionnaire (PDQ): a measure of diabetes self-care behaviors, perceptions and barriers.

AIM: To develop and evaluate the validity and reliability of The Personal Diabetes Questionnaire (PDQ), a brief, yet comprehensive measure of diabetes self-care behaviors, perceptions and barriers. To examine individual items to provide descriptive and normative information and provide data on scale reliability and associations between PDQ scales and concurrently assessed HBA(1c) and BMI. METHOD: Items were written to address nutritional management, medication utilization, blood glucose monitoring, and physical activity. The initial instrument was reviewed by multidisciplinary diabetes care providers and items subsequently revised until the measure provided complete coverage of the diabetes care domains using as few items as possible. The scoring scheme was generated rationally. Subjects were 790 adults (205 with type 1 and 585 with type 2 diabetes) who completed the PDQ while waiting for clinic appointments. RESULTS: Item completion rates were high, with few items skipped by participants. Subscales demonstrated good internal consistency (Cronbach α=.650-.834) and demonstrated significant associations with BMI (p ≤.001) and HbA(1c) (p ≤.001). CONCLUSIONS: The PDQ is a useful measure of diabetes self-care behaviors and related perceptions and barriers that is reliable and valid and feasible to administer in a clinic setting. This measure may be used to obtain data for assessing diabetes self-management and barriers and to guide patient care.

Six-minute walk distance in patients with severe end-stage COPD: association with survival after inpatient pulmonary rehabilitation.

PURPOSE: To evaluate the relationship between the 6-minute walk distance (6MWD) and survival in a cohort of patients with severe end-stage chronic obstructive pulmonary disease (COPD) who received inpatient pulmonary rehabilitation (IPR) from 1995 to 2007. METHODS: We retrospectively analyzed 815 patients with severe end-stage COPD who received IPR. 6MWDs before and after IPR (pre-6MWD, post-6MWD) were compared to assess whether 6MWD was significantly changed after IPR. The Kaplan-Meier survival curves were constructed to show the relationship between survival and 6MWD. The age- and or comorbidities-adjusted Cox proportional hazard model was applied to assess association between the survival and the pre-6MWD, post-6MWD, or difference in 6MWD from the pre-6MWD to post-6MWD (Delta6MWD). RESULTS: Baseline demographics demonstrated a median age 74.0 years, mostly women (60.1%), and white (89.9%) patients with significant comorbid diseases who were most recently hospitalized in acute care facilities (95.1%). IPR significantly increased the 6MWD (mean distance change: 86.4 m; 95% confidence interval [CI], 81.5-91.3 m). Pre-6MWD was not significantly associated with survival. However, post-6MWD was significantly associated with age- and comorbidity-adjusted survival (post-6MWD hazard ratio = 1.336; 95% CI, 1.232-1.449 [post-6MWD x m relative to post-6MWD 2x m]), and Delta6MWD was also significantly associated with age-, comorbidities-, and pre-6MWD-adjusted survival (Delta6MWD hazard ratio = 1.337; 95% CI, 1.227-1.457 [Delta6MWD x m relative to Delta6MWD 2x m]). CONCLUSIONS: In patients with severe end-stage COPD, IPR significantly improved 6MWD, and the post-6MWD and Delta6MWD were positively associated with the length of survival.

Stages of change and stuttering: a preliminary view.

UNLABELLED: As a way to better understand the process of change that occurs in stuttering, Craig [Craig, A. (1998). Relapse following treatment for stuttering: a critical review and correlative data. Journal of Fluency Disorders, 23, 1-30] compared the behavioral changes that people who stutter often experience with and without treatment to those that have been observed for certain (non)addictive behavior disorders such as smoking, overeating, phobia and anxiety disorder. The process underlying these behavioral changes has been described by the transtheoretical or "stages of change" model, which is a model of behavior change that can illuminate "where" a person is in the process of change, and how this may relate to the outcome of either treatment or self-change attempts [Prochaska, J. O., & DiClemente, C. C. (1986). The transtheoretical approach. In J. C. Norcross (Ed.), Handbook of eclectic psychotherapy. New York: Brunner/Mazel]. The purpose of the present study was to analyze the extent to which the responses of adults who stutter on a modified Stages of Change Questionnaire yield interrelations among questionnaire items that are consistent with a stage-based interpretation. Results of both confirmatory and exploratory factor analyses indicated that while the modified questionnaire was a relatively good fit for participant responses, the structure derived from the exploratory analysis provided a significantly better fit to the observed data. Results suggest that a questionnaire incorporating items that better reflect the unique behavioral, cognitive and affective variables that characterize stuttering may better discriminate stages of change in people who stutter as they move through therapy, or are engaged in self-directed change. EDUCATIONAL OBJECTIVES: After reading this paper, the learner will be able to: (1) describe the transtheoretical or "stages of change" model; (2) describe the various processes that are associated with different stages of change; (3) summarize research findings in stages of change as they apply to a variety of clinical populations; (4) discuss the applicability of the findings from the present study to stuttering treatment, and (5) relate conventional strategies and techniques used in stuttering therapy to different stages in the process of change.

A natural allele of Nxf1 suppresses retrovirus insertional mutations.

Endogenous retroviruses have shaped the evolution of mammalian genomes. Host genes that control the effects of retrovirus insertions are therefore of great interest. The modifier-of-vibrator-1 locus (Mvb1) controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, including the Pitpn(vb) tremor mutation and the Eya1(BOR) model of human branchiootorenal syndrome. Positional complementation cloning identifies Mvb1 as the nuclear export factor Nxf1, providing an unexpected link between the mRNA export receptor and pre-mRNA processing. Population structure of the suppressive allele in wild Mus musculus castaneus suggests selective advantage. A congenic Mvb1(CAST) allele is a useful tool for modifying gene expression from existing mutations and could be used to manipulate engineered mutations containing retroviral elements.