Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice.

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/- ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/- mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/- and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.

Acute asymmetric upper nasal quandrantanopsia caused by a chiasmal colloid cyst in a patient with multiple sclerosis and bilateral retrobulbar neuritis.

PURPOSE: To report a patient with multiple sclerosis and a history of sequential bilateral retrobulbar neuritis, who developed new onset of highly asymmetric upper quadrantanopsia. DESIGN: Interventional case report. METHOD: A 36-year-old woman with multiple sclerosis and bilateral retrobulbar neuritis developed an acute asymmetric upper nasal quadrantanopsia. RESULTS: Magnetic resonance imaging of the brain revealed a cyst that caused chiasmal compression and bilateral visual field defects. CONCLUSION: New onset of bilateral visual field defects in a patient with diagnosed multiple sclerosis is likely to be caused by a new attack of the demyelinating disease. In this case, a newly diagnosed chiasmal colloid cyst was the cause of visual field defects.

Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray.

OBJECTIVE: Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 microg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction. RESULTS: Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects. CONCLUSIONS: (ABSTRACT TRUNCATED)

A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis.

BACKGROUND: The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. OBJECTIVE: This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population. METHODS: This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100 microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate 84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29. RESULTS: The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P

Onset of action of mometasone furoate nasal spray (NASONEX) in seasonal allergic rhinitis.

BACKGROUND: Mometasone furoate nasal spray (MFNS, NASONEX ), is a new synthetic corticosteroid with considerable efficacy in the treatment of seasonal and perennial rhinitis and less than 0.1% systemic absorption. This study was designed to evaluate the time of onset of action of MFNS. The subjects were evaluated over the course of 2 weeks during the spring allergy season. METHODS: The effects of MFNS 200 microg given once daily for 2 weeks were evaluated in a randomized, multicenter, double-blind, placebo-controlled study in 201 patients with seasonal allergic rhinitis. Clinically significant onset of action was assessed prospectively by special patient diary cards kept during the first 3 days of treatment. RESULTS: By 12 h after initial dosage (the earliest evaluation), 28% of patients in the MFNS group experienced clinically significant relief, compared with 13% of those given placebo (P = 0.01). Median time to at least moderate symptom relief in patients who received MFNS was 35.9 h, compared with more than 72 h in patients given placebo (P<0.01). By 72 h, 64% of the patients receiving MFNS experienced at least moderate relief, compared with 40% of those treated with placebo (P<0.01). Both patient and physician ratings of symptom severity, response to treatment, and overall condition of rhinitis indicated significant (P<0.01) superiority of MFNS over placebo. MFNS was well tolerated, with adverse events comparable to placebo. CONCLUSIONS: MFNS provided rapid onset of clinically significant symptom relief in patients with seasonal allergic rhinitis.

Effect of mometasone furoate on early and late phase inflammation in patients with seasonal allergic rhinitis.

BACKGROUND: Mometasone furoate is a potent glucocorticoid that can markedly inhibit proinflammatory Th2 cytokines in vitro. An aqueous nasal spray formulation has been shown to be clinically active in reducing the symptoms of perennial and seasonal allergic rhinitis. OBJECTIVE: To determine whether pretreatment with mometasone furoate 200 microg once daily decreases specific indices of early and late phase nasal inflammation compared with placebo. METHODS: A randomized, double-blind, placebo-controlled crossover study was conducted using nasal provocation with ragweed antigen in 21 patients with ragweed-induced allergic rhinitis out of the ragweed season; the treatment period was 2 weeks. Symptom scores, rhinoprobe cytology, and nasal lavage fluid were collected during early and late phase periods for nasal cytokines (interleukin, 1, 4, 5, 6, and 8) and leukotriene B4 determinations using ELISA and RIA. RESULTS: Mean nasal symptom scores and sneezing frequency were consistently lower with mometasone furoate compared with placebo. Treatment was associated with a statistically significant early phase (30-minute time point) reduction in nasal lavage histamine levels compared with placebo (14.3 versus 20.2 ng/mL, P = .02). Within-treatment comparisons suggested that mometasone furoate reduced the antigen-induced late-phase response for IL-6, IL-8, and eosinophils compared with pretreatment. There were similar, but smaller, changes seen in the placebo group for these measurements. There were no statistically significant changes following antigen challenge in IL-1, IL-4, IL-5, LTB4, or in other nasal cytology parameters. CONCLUSION: These results suggest that the clinical activity of mometasone furoate nasal spray in seasonal allergic rhinitis is likely due, in part, to a reduction in the levels of histamine in nasal secretions related to the early phase response, and reductions in IL-6, IL-8, and eosinophils during the late phase response.

A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray.

BACKGROUND: Topical nasal corticosteroids have become a mainstay of treatment for the symptoms of seasonal allergic rhinitis (SAR). It is likely that topical corticosteroids, by blocking an initial influx of inflammatory cells in the nasal mucosa induced by aeroallergens, may have a preventive effect on nasal allergy symptoms when administered before the pollen season. OBJECTIVE: This study was designed to assess the efficacy and safety of an 8-week course of mometasone furoate nasal spray (MFNS), 200 micrograms once daily, in the treatment of SAR compared with beclomethasone dipropionate aqueous nasal spray (BDP), 168 micrograms twice daily, and placebo vehicle, when treatment is initiated before the anticipated onset of the ragweed season. METHODS: Three hundred forty-nine patients with SAR to ragweed pollen from nine centers in the Northeast and Midwest of the United States were randomized to one of the three intranasal study medications (MFNS, 200 micrograms once daily, BDP, 168 micrograms twice daily, or placebo vehicle), starting 4 weeks before the estimated start of the ragweed season. RESULTS: The proportion of "minimal symptom" days (total nasal symptom score < or = 2) was statistically significantly higher in both the MFNS and BDP groups when compared with the placebo vehicle group (p < 0.01). The two active treatment groups were not statistically significantly different from each other. MFNS and BDP displayed a similar safety profile that did not differ from placebo. CONCLUSIONS: This suggests that MFNS, 200 micrograms (once daily), is a useful therapy in the prophylactic treatment of SAR.