Feasibility of 5-fluorouracil and imiquimod for the topical treatment of cervical intraepithelial neoplasias (CIN) 2/3.

OBJECTIVES: To determine the feasibility (as measured by tolerability and safety) and efficacy of topical 5-fluorouracil (5-FU) and imiquimod for the treatment of cervical intraepithelial neoplasia (CIN) 2/3. METHODS: This pilot prospective study was conducted in women aged 18-45 years with p16+ CIN 2/3. Participants underwent an 8-week alternating regimen of self-applied 5% 5-FU on weeks 1, 3, 5, and 7 and physician-applied imiquimod on weeks 2, 4, 6, and 8. Adverse events (AEs) were collected by symptom diary and clinical exam. Feasibility was measured by tolerability and safety (AEs) of the study intervention. Tolerability was assessed as the number of participants able to apply 50% or more of the treatment doses. The safety outcome was calculated as the number of participants who experienced "specified AEs" defined as possibly, probably, or definitely related grade 2 or worse AE or grade 1 genital AEs (blisters, ulcerations, or pustules) lasting more than 5 days. The efficacy of the intervention was determined by histology and high-risk human papillomavirus (hrHPV) testing was done after treatment. RESULTS: The median age of the 13 participants was 27 ± 2.9 years. Eleven (84.61%) participants applied 50% or more of the treatment. All participants reported grade 1 AEs; 6 (46.15%) reported grade 2 AEs; and 0 reported grade 3/4 AEs. Three (23.08%) participants had specified AEs. Histologic regression to normal or CIN 1 among those completing 50% or more of the treatment doses was observed in 10 (90.91%) participants, and 7 (63.63%) tested negative for hr-HPV at the end of the study. CONCLUSIONS: Topical treatment for CIN 2/3 with 5-FU/imiquimod is feasible, with preliminary evidence of efficacy. Topical therapies need further investigation as adjuncts or alternatives to surgical therapy for CIN 2/3.

The Association Between Antenatal Maternal Self-reported Substance Use, Maternal Characteristics, and Obstetrical Variables.

BACKGROUND: Substance use disorders during pregnancy are a concern both to the public and medical community, because the negative consequences can be detrimental to both mother and the fetus. The accurate identification of prenatal drug exposure is necessary to determine appropriate medical and psychosocial intervention, and to identify risk factors that may affect outcomes for the mother and her newborn. The prevalence of prenatal drug exposure is very difficult to estimate because of flaws in all methods of identification. OBJECTIVE: The study is designed to identify risk factors and demographic variables that contribute to nondisclosure of illicit and nonillicit substance use. In addition, this study aims to determine if nondisclosure leads to adverse neonatal outcomes. STUDY DESIGN: Newborns delivered with a positive meconium or urine toxicology, and/or known maternal exposure to illicit and nonillicit substances, were identified. Maternal records were reviewed for disclosure of substance use during pregnancy at admission for delivery along with other medical and demographic variables. Women with antenatal prescription drug use that may alter toxicology screens were excluded from analysis. Pediatric records were also reviewed to obtain neonatal variables. RESULTS: One hundred sixty-eight newborns were identified as having prenatal exposure to an illicit or nonillicit substance over the 4-year period. Eighty-six per cent (145/168) of women tested positive or their newborn tested positive for at least 1 illicit substance, and 49% (82/168) tested positive for multiple illicit substances. Fifty-four per cent (91/168) of women did not disclose using at least one illicit drug for which she or her newborn tested positive.With regards to maternal characteristics, there was no statistically significant difference between age (P = 0.958), parity (P = 0.300), or race (P = 0.531), and disclosure or failure to disclose about illicit drug use. However, patients who did not report prenatal illicit drug use (33/82 = 40%) were less likely (P = 0.049) to receive complete prenatal care (defined as 3 or more visits) compared with those who acknowledged their substance use (40/70 = 57%). CONCLUSION: Substance use disorders during pregnancy are an often underestimated cause of maternal, fetal, and neonatal complications. Limited studies have examined the relationship between maternal characteristics and associated illicit or nonillicit drug use. The absence of correlation between maternal demographics and disclosure of illicit substance use demonstrates the fact that all antepartum patients are at risk for these behaviors. Furthermore, the fact that women who did not disclose their illicit drug use were less likely to seek complete prenatal care reflects the need for physicians to provide a destigmatized healthcare environment, encouraging pregnant women to disclose their substance use so they can be provided with appropriate counseling and treatment.

Neurosteroid vitamin D system as a nontraditional drug target in neuropsychopharmacology.

Vitamin D is becoming increasingly recognized as a nontraditional drug target for different brain pathologies. Although widely known for their role in calcium metabolism, vitamin D and its receptor have been linked to several brain disorders, including cognitive decline, epilepsy, affective disorders, and schizophrenia. Here we discuss mounting evidence, and parallel recent clinical and animal behavioral, genetic and pharmacological data to emphasize the emerging role of the neurosteroid vitamin D system in brain function.

Modeling withdrawal syndrome in zebrafish.

The zebrafish (Danio rerio) is rapidly becoming a popular model species in behavioral neuroscience research. Zebrafish behavior is robustly affected by environmental and pharmacological manipulations, and can be examined using exploration-based paradigms, paralleled by analysis of endocrine (cortisol) stress responses. Discontinuation of various psychotropic drugs evokes withdrawal in both humans and rodents, characterized by increased anxiety. Sensitivity of zebrafish to drugs of abuse has been recently reported in the literature. Here we examine the effects of ethanol, diazepam, morphine and caffeine withdrawal on zebrafish behavior. Overall, discontinuation of ethanol, diazepam and morphine produced anxiogenic-like behavioral or endocrine responses, demonstrating the utility of zebrafish in translational research of withdrawal syndrome.

Bronchial hyperreactivity in non-atopic children with asthma and reflux: effect of anti-reflux treatment.

INTRODUCTION: The prevalence of bronchial hyperreactivity (BHR) or the effect of anti-reflux treatment on BHR in children with asthma and gastroesophageal reflux disease (GERD) is not known. METHODS: Thirty non-atopic children with persistent asthma were studied. Extended esophageal pH monitoring was used to diagnose GERD and methacholine challenge test (MCT) was used as a marker of BHR and performed before and 2 years after anti-GERD treatment. RESULTS: Of the 21 patients positive for GERD (group A), 15 had positive MCT suggesting BHR. Of the 9 patients negative for GERD (group B), 5 had positive MCT. On repeat testing 2 years later, 11/15 group A patients and 3/5 group B patients tested negative for BHR. Group A patients were receiving fewer asthma medications and experienced fewer exacerbations than Group B patients. CONCLUSIONS: BHR is prevalent in children with asthma and GERD and improves with anti-GERD treatment.

Associated factors in children with chronic cough.

BACKGROUND: Children presenting with chronic cough are common to the primary care physicians, but data on the etiology are scant. METHODS: We evaluated 40 children (age range, 5 to 12 years) with chronic cough (> 8 weeks duration) with no obvious cause who were referred by their primary care physicians. All patients underwent an extensive multispecialty workup that included pulmonary, GI, allergy, immunology, and otorhinolaryngology testing. Response to treatment was quantified pretreatment and 8 weeks after treatment by using a visual analog scale. RESULTS: Positive diagnostic test results were noted for gastroesophageal reflux disease (27.5%), allergy (22.5%), asthma (12.5%), infection (5%), aspiration (2.5%), and multiple etiologies (20%). Appropriate treatment for these factors resulted in a significant improvement in cough. CONCLUSION: Reflux, allergy, and asthma accounted for > 80% of the likely etiologic factors of chronic cough in children and responded to appropriate treatment.

Understanding behavioral and physiological phenotypes of stress and anxiety in zebrafish.

The zebrafish (Danio rerio) is emerging as a promising model organism for experimental studies of stress and anxiety. Here we further validate zebrafish models of stress by analyzing how environmental and pharmacological manipulations affect their behavioral and physiological phenotypes. Experimental manipulations included exposure to alarm pheromone, chronic exposure to fluoxetine, acute exposure to caffeine, as well as acute and chronic exposure to ethanol. Acute (but not chronic) alarm pheromone and acute caffeine produced robust anxiogenic effects, including reduced exploration, increased erratic movements and freezing behavior in zebrafish tested in the novel tank diving test. In contrast, ethanol and fluoxetine had robust anxiolytic effects, including increased exploration and reduced erratic movements. The behavior of several zebrafish strains was also quantified to ascertain differences in their behavioral profiles, revealing high-anxiety (leopard, albino) and low-anxiety (wild type) strains. We also used LocoScan (CleverSys Inc.) video-tracking tool to quantify anxiety-related behaviors in zebrafish, and dissect anxiety-related phenotypes from locomotor activity. Finally, we developed a simple and effective method of measuring zebrafish physiological stress responses (based on a human salivary cortisol assay), and showed that alterations in whole-body cortisol levels in zebrafish parallel behavioral indices of anxiety. Collectively, our results confirm zebrafish as a valid, reliable, and high-throughput model of stress and affective disorders.