Efficacy of mometasone furoate nasal spray for nasal symptoms, quality of life, rhinitis-disturbed sleep, and nasal nitric oxide in patients with perennial allergic rhinitis.

Intranasal corticosteroid therapy has exhibited effectiveness for improving nasal symptoms and quality of life (QOL) scores associated with seasonal allergic rhinitis. We prospectively investigated the efficacy of mometasone furoate nasal spray (MFNS) for improving the total nasal symptom score, QOL score, and sleep quality in subjects with perennial allergic rhinitis (PAR). Nasal airway conditions were also objectively assessed by measuring nasal nitric oxide (NO). Fifty-seven patients with PAR were randomized to MFNS or placebo for a 14-day, double-blind, crossover study. The subjects recorded their symptoms on nasal symptom forms and a visual analog scale. QOL and sleep quality were surveyed in accordance with the Japanese version of the Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) and the Japanese version of the Epworth Sleepiness Scale. Nasal NO was measured during a single exhalation using a chemiluminescence analyzer. MFNS treatment achieved significant reductions versus placebo for total nasal symptoms (p < 0.001). There were significant decreases of the usual daily activity domain (p < 0.005), outdoor activities (p < 0.01), social function (p < 0.05), and the overall QOL score (p < 0.05) of JRQLQ with MFNS therapy versus placebo. A significant reduction of the sleepiness scale was also observed in the MFNS group with high sleep disturbance (p < 0.01). A significant decrease of nasal NO was found in the MFNS group (p < 0.01), especially among patients with severe nasal symptoms (p < 0.005). This prospective study indicated that MFNS therapy significantly improves nasal symptoms, QOL, sleep quality, and upper airway condition in Japanese subjects with PAR.

Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein.

Alpha-tocopherol transfer protein (TTP) regulates the retention and secretion of alpha-tocopherol (alpha-T) by the liver. Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of alpha-T and neurological dysfunctions described in patients with mutated Ttpa. We have explored genome-wide changes in mRNAs from brain cortex and liver of Ttpa-deficient (Ttpa(-/-)) mice and wild-type (Ttpa(+/+)) mice. Selective inductions of genes regulated by antioxidant response elements were detected in Ttpa(-/-) livers compared to Ttpa(+/+) livers, suggesting increased oxidant stress in Ttpa(-/-) livers. The activation of cell proliferation pathways in Ttpa(-/-) livers was indicated by the induction of genes that encode growth factor-binding proteins, mitogen-activated protein kinase kinase 3, and apoptosis inhibitor 6. The induction of synuclein-alpha and repression of synuclein-beta genes was detected in Ttpa(-/-) cortex. This may predispose Ttpa(-/-) cortex to increased formation of synuclein-alpha aggregates and Lewy body, often associated with oxidant stress. Cortex of Ttpa(-/-) mice revealed repression of genes encoding synaptic proteins, protein kinase C family members, and myelin proteins. A 13-fold decrease in the expression of retinoic acid receptor-related orphan receptor-alpha mRNA predicts staggerer-like phenotype (ataxia and deficits of motor coordination) of Ttpa(-/-) mice. The repression of specific genes that determine synaptic plasticity and neuronal development may account for suppressed electrophysiological activities of cortex and impaired behavior in Ttpa(-/-) mice.

Incorporation of deuterated RRR- or all-rac-alpha-tocopherol in plasma and tissues of alpha-tocopherol transfer protein--null mice.

BACKGROUND: Most vitamin E supplements contain synthetic all-rac-alpha-tocopherol [2,5,7,8-tetramethyl-2RS-(4'RS,8'RS,12-trimethyltridecyl)-6-chromanol] with 8 stereoisomers; only 1 is identical to the natural stereoisomer, RRR-alpha-tocopherol [2,5,7,8-tetramethyl-2R-(4'R,8'R,12-trimethyltridecyl)-6-chromanol]. In humans, 2R-alpha-tocopherol stereoisomers are preferentially maintained in the plasma, a function that has been attributed to hepatic alpha-tocopherol transfer protein (alpha-TTP), but this hypothesis has not been tested. OBJECTIVE: We sought to determine the functions of alpha-TTP by comparing mice that express alpha-TTP with mice that are genetically unable to express alpha-TTP. DESIGN: Adult alpha-TTP null (Ttpa(-/-); n = 5), heterozygous (Ttpa(+/-); n = 7), and wild-type (Ttpa(+/+); n = 3) mice consumed equimolar RRR-alpha-[5,7-(C(2)H(3))(2)]-(d(6))- and all-rac-alpha-[5-(C(2)H(3))]-(d(3))-tocopheryl acetates (30 mg/kg diet each) for 3 mo. Subsequently, we measured labeled and unlabeled alpha-tocopherols in plasma and 17 tissues. RESULTS: In all mice, plasma and tissue d(6)- + d(3)-alpha-tocopherols represented approximate 80-90% of total alpha-tocopherol. In the Ttpa(-/-) mice, low total alpha-tocopherol concentrations were found in plasma (5.4%) and most other tissues (2-20%), but liver concentrations were 39% of those of Ttpa(+/+) mice. Peripheral tissue ratios of d(6)- to d(3)-alpha-tocopherol were 1.1 plus minus 0.1 and 1.8 plus minus 0.2 in Ttpa(-/-) and Ttpa(+/+) mice, respectively (P < 0.0001), showing that alpha-TTP preferentially selects 2R-alpha-tocopherols for secretion into plasma. This 2:1 ratio does not support the currently defined international unit of 1.36:1 RRR-alpha-tocopherol to all-rac-alpha-tocopherol. CONCLUSION: Deletion of the alpha-TTP gene in mice results in an accumulation of dietary alpha-tocopherol in the liver and depletion of peripheral tissue alpha-tocopherol.

Sitosterolemia in ABC-transporter G5-deficient mice is aggravated on activation of the liver-X receptor.

BACKGROUND AND AIMS: Mutations in either adenosine triphosphate- binding cassette (ABC) half-transporter G5 or G8 cause sitosterolemia. It has been proposed that ABCG5/ABCG8 heterodimers mediate secretion of plant sterols and cholesterol by hepatocytes into bile and their efflux from enterocytes into the intestinal lumen. METHODS: To test whether deficiency of ABCG5 alone is sufficient to induce sitosterolemia, Abcg5-null mice were generated and characterized with respect to sterol metabolism. RESULTS: Abcg5 deficiency was associated with strongly elevated plasma levels of beta-sitosterol (37-fold) and campesterol (7.7-fold) as well as reduced plasma cholesterol concentrations (-40%). Retention of orally administered [(3)H]beta-sitosterol in the intestinal wall (+550%) and plasma (+640%) was higher in Abcg5-null mice than in wild-type controls. Surprisingly, high plasma beta-sitosterol and campesterol concentrations were even further elevated in Abcg5-null mice on treatment with the synthetic LXR agonist T0901317 (0.015% dietary supplementation, 10 days), whereas these concentrations were reduced by approximately 75% in wild-type mice. Both cholesterol and phospholipid concentrations in gallbladder bile were decreased, but, unexpectedly, cholesterol/phospholipid ratios were unchanged in the absence of Abcg5 and increased in both genotypes on LXR activation. Hepatic expression of Abcg8 was reduced by about 35% in Abcg5-deficient mice when compared with controls. No compensatory overexpression of other ABC transporters potentially involved in hepatic cholesterol trafficking was observed on messenger RNA level. CONCLUSIONS: Our data show that disruption of the Abcg5 gene alone is sufficient to cause hyperabsorption of dietary plant sterols and sitosterolemia in mice, whereas the ability to secrete cholesterol into bile is maintained.