Disease Control and Treatment Satisfaction in Patients with Chronic Spontaneous Urticaria in Japan.

Background: Chronic spontaneous urticaria (CSU), characterized by the recurrence of pruritic hives and/or angioedema for >6 weeks with no identifiable trigger, has a negative impact on health-related quality of life (HRQoL). Methods: The objective of this web-based cross-sectional study was to evaluate disease control, disease burden, and treatment satisfaction in Japanese adults with CSU using the Urticaria Control Test (UCT), HRQoL outcomes, and the Treatment Satisfaction Questionnaire for Medication-9 items (TSQM-9). Results: In total, 529 adults were included in the analysis (59.9% female), with a mean ± standard deviation (SD) in CSU duration of 13.2 ± 13.0 years. Based on UCT scores, two-thirds of patients had poor (score of 0-7; 23.6%) or insufficient (score of 8-11; 43.3%) symptom control, and one-third had good control (score of 12-16; 33.1%). Overall treatment satisfaction was not high, with mean ± SD TSQM-9 scores of 55.5 ± 17.6% for effectiveness, 68.2 ± 18.8% for convenience, and 59.2 ± 18.4% for global satisfaction. No apparent differences in TSQM-9 scores were observed between patients receiving different medications. HRQoL outcomes were worse among patients with poor/insufficient symptom control. Conclusions: Japanese adults with CSU have a high disease burden, and better treatment options are needed to increase treatment satisfaction.

Serine metabolism contributes to cell survival by regulating extracellular pH and providing an energy source in Saccharomyces cerevisiae.

Changes in extracellular pH affect the homeostasis and survival of unicellular organisms. Supplementation of culture media with amino acids can extend the lifespan of budding yeast, Saccharomyces cerevisiae, by alleviating the decrease in pH. However, the optimal amino acids to use to achieve this end, and the underlying mechanisms involved, remain unclear. Here, we describe the specific role of serine metabolism in the regulation of pH in a medium. The addition of serine to synthetic minimal medium suppressed acidification, and at higher doses increased the pH. CHA1, which encodes a catabolic serine hydratase that degrades serine into ammonium and pyruvate, is essential for serine-mediated alleviation of acidification. Moreover, serine metabolism supports extra growth after glucose depletion. Therefore, medium supplementation with serine can play a prominent role in the batch culture of budding yeast, controlling extracellular pH through catabolism into ammonium and acting as an energy source after glucose exhaustion.

Effect of mometasone furoate on nasal congestion model in rats.

AIMS: The present study was performed to evaluate the effect of mometasone furoate on a nasal congestion model in Brown Norway rats. METHODS: Nasal congestion in rats sensitized with toluene-2,4-diisocyanate (TDI) was measured using whole-body plethysmography which allowed animals to move freely. RESULTS: Penh (enhanced pause), an index of nasal congestion, was significantly increased after 5% TDI challenge in sensitized rats compared with that in non-sensitized rats. The peak of the increase in Penh appeared at 1 and 5 h after TDI challenge. A single topical administration of mometasone furoate (0.05%) at 1 h before TDI challenge suppressed the increase of Penh in sensitized rats. A significant effect was observed 5-6 h after nasal administration. Almost the same results were obtained with fluticasone propionate (0.05%). CONCLUSION: Mometasone furoate may therefore be effective and have a rapid onset of action in nasal congestion when used clinically as with fluticasone propionate.

Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models.

Hepatocyte growth factor (HGF) promotes malignant development of cancer cells by enhancing invasion and metastasis. NK4, a competitive antagonist for HGF, is a bifunctional molecule that acts as a HGF antagonist and angiogenesis inhibitor. Although successful tumor inhibition by NK4 gene expression in tumor models has been demonstrated, the effects of systemic NK4 gene introduction are yet to be addressed. Here we show that systemic administration of a replication-defective adenovirus expressing NK4 (Ad.NK4) inhibits tumor growth and lung metastasis of B16F10 melanoma and Lewis lung carcinoma in syngeneic mice. Single tail-vein injection of Ad.NK4 achieved therapeutic levels of NK4 in the circulation and in multiple organs. Despite NK4 expression that was highest in the liver, toxicity in the liver was minimal. Ad.NK4-mediated growth inhibition was associated with decreased blood vessel density and increased apoptosis in tumor tissues, which suggests that NK4 suppressed tumor growth as an angiogenesis inhibitor. Metastasis of B16F10 melanoma and Lewis lung carcinoma cells to the lung was potently inhibited by systemic Ad.NK4-administration. Our results demonstrated that the adenovirus-mediated induction of high levels of circulating NK4 significantly inhibited in vivo tumor growth and distant metastasis without obvious side effects. NK4 gene therapy is thus a safe and promising strategy for the treatment of cancer patients, and further validation in clinical trials is needed.

Participation in cysteinyl leukotrienes and thromboxane A2 in nasal congestion model in Brown Norway rats.

The aim of this study was to investigate the involvement of chemical mediators in a nasal congestion model in Brown Norway (BN) rats. For the above purpose, we studied the effects of pranlukast and zafirlukast (cysteinyl leukotriene (cys-LT) receptor antagonists), seratrodast and ramatroban (thromboxane A(2) (TXA(2)) receptor antagonists) on nasal congestion and sneezing induced by toluene 2, 4-diisocyanate (TDI). All of these drugs suppressed the increase of enhanced pause (Penh), the index of nasal congestion, in both early and late phase responses; however, pranlukast, zafirlukast and seratrodast failed to suppress immediate sneezing caused by TDI challenge. These results indicate that cys-LTs and TXA(2) are responsible for the development of both early and late phase nasal congestion. Moreover, these chemical mediators contribute very little to immediate sneezing in a BN rat model of allergic rhinitis.

Effect of Usuhiratake (Pleurotus pulmonarius) on sneezing and nasal rubbing in BALB/c mice.

The anti-rhinitis properties of Pleurotus pulmonarius were investigated in BALB/c mice. A single administration of Pleurotus Pulmonarius caused no significant effect on antigen-induced nasal rubbing and sneezing at a dose of 500 mg/kg, but a significant inhibition was observed after 2 weeks of repeated treatment at this dose, and at a dose of 200 mg/kg, it also caused a significant inhibition after repeated administration for 4 weeks. Pleurotus pulmonarius showed no significant inhibitory effect on the production of IgE. In addition, Pleurotus pulmonarius caused no inhibition of histamine-induced nasal rubbing and sneezing at a dose of 500 mg/kg, but in vitro study, it inhibited histamine release from rat mast cells induced by compound 48/80 at the soluble supernatant solution of 30 and 100 microg/ml of Pleurotus pulmonarius suspended in PBS. These results demonstrated that Pleurotus pulmonarius may be effective in the relief of symptoms of allergic rhinitis through inhibition of histamine release.

Involvement of Raf-1/MEK/ERK1/2 signaling pathway in zinc-induced injury in rat renal cortical slices.

Zinc is an essential nutrient that can also be toxic. We have previously reported that zinc-related renal toxicity is due, in part, to free radical generation in the renal epithelial cell line, LLC-PK(1) cells. We have also shown that an MEK1/2 inhibitor, U0126, markedly inhibits zinc-induced renal cell injury. In this study, we investigated the role of an upstream MEK/ERK pathway, Raf-1 kinase pathway, and the transcription factor and ERK substrate Elk-1, in rat renal cortical slices exposed to zinc. Immediately after preparing slices from rat renal cortex, the slices were incubated in medium containing Raf-1 and MEK inhibitors. ERK1/2 and Elk-1 activation were determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 and phosphorylated Elk-1 (pElk-1) in nuclear fractions prepared from slices exposed to zinc. Zinc caused not only increases in 4-hydroxynonenal (4-HNE) modified protein and lipid peroxidation, as an index of oxidant stress, and decreases in PAH accumulation, as that of renal cell injury in the slices. Zinc also induced a rapid increase in ERK/Elk-1 activity accompanied by increased expressions of pERK and pElk-1 in the nuclear fraction. A Raf-1 kinase inhibitor and an MEK1/2 inhibitor U0126 significantly attenuated zinc-induced decreases PAH accumulation in the slices. The Raf-1 kinase inhibitor and U0126 also suppressed ERK1/2 activation in nuclear fractions prepared from slices treated with zinc. The present results suggest that a Raf-1/MEK/ERK1/2 pathway and the ERK substrate Elk-1 are involved in free radical-induced injury in rat renal cortical slices exposed to zinc.

Nasal congestion model in Brown Norway rats and the effects of some H1-antagonists.

The aim of this study was to develop and characterize a new model for evaluating nasal congestion in rats by using whole body plethysmography (WBP)-free moving application. Brown Norway rats were sensitized with 10% toluene-2, 4-diisocyanate (TDI) solution, and nasal congestion was provoked with 5% TDI. An increase in the enhanced pause (Penh) was recognized after being challenged with TDI. In addition, a significant increase in the Penh was observed following the intranasal application of histamine in TDI sensitized rats. Histamine H1 antagonists, such as chlorpheniramine and ketotifen suppressed the increase of Penh during the early-phase response. On the other hand, epinastine suppressed the increase of Penh in both the early and late phase responses. In conclusion, we developed an allergic rhinitis model that includes nasal congestion symptoms in Brown Norway rats, and this model may be useful for evaluating the effects of drugs on nasal congestion.

Molecular cloning, expression and partial characterization of Xksy, Xenopus member of the Sky family of receptor tyrosine kinases.

We isolated a cDNA encoding the Xenopus member of Sky/Axl/Mer receptor tyrosine kinase family (referred as Sky family), termed Xksy. The predicted Xksy protein has conserved structural characteristics of the Sky family: an unique extracellular domain of two immunoglobulin (Ig)-like repeats, two fibronectin type III (FNIII)-like repeats and an intracellular tyrosine kinase. Homology analysis of Xksy showed the highest identity to mammalian Sky protein. In contrast to the predominant expression of sky mRNA in the adult mammalian nervous system, Northern blot analysis showed ubiquitous expression of a single 5.2-kb Xksy mRNA in tissues of the adult Xenopus. RNase protection assays revealed that, during development, Xksy mRNA is expressed from mid neurulation stage. Levels increase through the tadpole stage and become restricted to the head region in embryos by stage 40. Whole-mount in situ hybridization analyses revealed that expression of Xksy is localized to the nervous system of the tadpole stage, including origins of sensory organs and branchial arches. When a chimeric receptor (EGFR-Xksy), composed of the extracellular region of epidermal growth factor (EGF) receptor and the transmembrane/intracellular regions of Xksy, was expressed in a doxycycline repressive manner in HEK 293 cells, EGF-stimulus without doxycycline induced tyrosine phosphorylation of the chimeric receptor and evoke morphological changes. EGF treatment also induced growth modifications of EGFR-Xksy cells. And doxycycline pre-treatment eliminated these activities. These findings suggest that Xksy may play an important role in growth, differentiation and the accurate migration of cells during embryogenesis and early neural development.