Search

Pathologic mechanisms in cochleae immediately following the onset of noise-induced hearing loss (NIHL) remain unclear. In this study, mice were exposed to 120 dB of octave band noise for 2 h to induce NIHL. Three hours after noise exposure, expression levels of the whole mouse genome in cochleae were analyzed by RNA-seq and DNA microarray. Differentially expressed genes (DEGs) exhibiting >2-fold upregulation or downregulation in noise-exposed cochleae compared to controls without noise exposure were identified. RNA-seq and microarray analyses identified 273 DEGs regulated at 3 h post-noise (51 upregulated and 222 downregulated). Bioinformatic analysis revealed that these DEGs were associated with the functional gene pathway "neuroactive ligand-receptor interaction" and included 28 genes encoding receptors for neurotransmitters such as gamma-aminobutyric acid and glutamate. Other DEGs included 25 genes encoding transcription factors. Downregulation of 4 neurotransmitter receptors (Gabra3, Gabra5, Gabrb1, Grm1) and upregulations of 5 transcription factors (Atf3, Dbp, Helt, Maff, Nr1d1) were validated by RT-PCR. The differentially regulated transcription factor Atf3 immunolocalized to supporting cells and hair cells in the organ of Corti at 12-h post-noise. The present data serve as a basis for further studies aimed at developing medical treatments for acute sensorineural hearing loss., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS., Methods: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence., Results: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin., Conclusions: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16-40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum β-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS)., Methods: IgG4-positive cells in uncinate tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. Associations between the number of IgG4-positive cells and clinicopathological factors were analyzed. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of IgG4-positive cells in tissue that can predict the post-operative course., Results: IgG4 was mainly expressed in infiltrating plasma and plasmacytoid cells, and the number of IgG4-positive cells was significantly higher in NP, especially those from severe ECRS patients, than in UT. In CRS patients, the number of IgG4-positive cells significantly and positively correlated with blood and tissue eosinophilia, radiological severity, and serum level of total IgE. The number of infiltrating IgG4-positive cells was significantly higher in patients with a poor post-operative course (sustained sinus shadow 6 months after surgery) than in those with a good one. The number of IgG4-positive cells in NP could discriminate patients with a good or a poor post-operative course (area under the curve: 0.769). Also, 73.3% sensitivity and 82.5% specificity were achieved when the cut-off value was set at 17 cells/high-power field., Conclusions: Our results suggest that the local expression of IgG4 on cells may be used as a biomarker that reflects the pathophysiology of CRS, including the post-operative course., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis., Methods: Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT., Results: Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 μm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal., Conclusions: Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: IL-10 is a major anti-inflammatory cytokine that prevents inflammation-mediated tissue damage. We characterized the production of IL-10 by sinonasal tissue cells following exposure to Staphylococcus aureus enterotoxin B (SEB), which elicits cellular responses and is associated with the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS)., Methods: Dispersed nasal polyp (NP) cells and uncinate tissue (UT) cells were prepared from patients with CRS with and without NP, respectively. Cells were incubated with SEB, and then the levels of IL-10 in the cell supernatants were determined. The effect of neutralizing IL-10 on SEB-induced IL-5, IL-13, IFN-γ, and IL-17A production was examined. Expression of IL-10 in NPs was also determined., Results: IL-10 was expressed in infiltrating inflammatory cells in NPs. NP cells, especially non-adherent NP cells, produced substantial amounts of IL-10 in response to SEB. Although baseline production of IL-10 was significantly higher in NP cells than UT cells, the degree of IL-10 response to SEB was not significantly different between the cell types. The degree of IL-10 production was negatively correlated with the degree of eosinophilia both in tissues and peripheral blood whereas positively correlated with the 1-s forced expiratory volume/forced vital capacity ratio. Patients with severe ECRS displayed a significant decrease in IL-10 production compared with those with non-ECRS. IL-10 neutralization significantly augmented SEB-induced IL-13 and IFN-γ production by NP cells., Conclusions: Impaired IL-10 production in response to SEB in NP may exacerbate the pathophysiology of ECRS including eosinophilia and lower airway obstruction., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: In Asian population, there is limited information on the relevance between obesity and poor outcomes in acute pancreatitis (AP). The objective of this study was to examine the clinical impact of obesity based on body mass index (BMI) on prognosis of AP in Japanese patients., Methods: A total of 116 patients with AP were enrolled in this study. Univariate and multivariate logistic regression analyses were performed to examine relations between BMI and patients' outcomes. Additionally, to investigate whether including obesity as a prognostic factor improved the predictive accuracy of a Japanese prognostic factor score (PF score), a receiver-operating characteristic (ROC) curve analysis of mortality was conducted., Results: Multiple logistic regression analyses revealed that BMI =25 kg/m 2 was associated with a significant higher mortality [odds ratio (OR)=15.8; 95% confidence interval (CI): 1.1-227; P=0.043]. The area under the ROC curve (AUC) for the combination of PF score and BMI =25 kg/m 2 (AUC=0.881; 95% CI: 0.809-0.952) was higher than that for the PF score alone (AUC=0.820; 95% CI: 0.713-0.927) (P=0.034)., Conclusions: The negative impact of a high BMI on the prognosis of AP was confirmed in a Japanese population. Including BMI =25 kg/m 2 as an additional parameter to PF score enhanced the predictive value of the PF score for AP-related mortality., (Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.)

Background: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: IL-22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real-time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined., Results: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin-induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV 1 )/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs., Conclusions: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Vascular endothelial growth factor (VEGF) is known to be associated with the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). VEGF is produced by a variety of cells including fibroblasts. It was recently reported that prostaglandin (PG) E 2 induces VEGF release by nasal polyp fibroblasts. However, little is known regarding possible regulation of VEGF by other PGs. We have reported that molecules that regulate PGD 2 metabolism play roles in the pathogenesis of CRS including in local eosinophilia and type 2 cytokine production. In the present study, we sought to determine whether PGD 2 regulates VEGF release by nasal polyp fibroblasts., Methods: Nasal polyp fibroblasts were established from nasal polyps. These fibroblasts were stimulated with serial dilutions of PGD 2 or PGD 2 receptor (DP/CRTH2)-selective agonists in the presence or absence of receptor-selective antagonists. The concentration of VEGF in the culture supernatants was determined using ELISA., Results: 5 μM of PGD 2 significantly induced VEGF release by nasal polyp fibroblasts. VEGF release was also obtained by stimulation with a DP receptor-selective, but not with a CRTH2 receptor-selective agonist. In addition, PGD 2 -induced VEGF release was significantly inhibited by pre-treatment with DP receptor-selective antagonists. In contrast, pre-treatment with a CRTH2 receptor-selective antagonist significantly enhanced PGD 2 -induced VEGF release., Conclusions: PGD 2 stimulates VEGF production via DP but not CRTH2 receptors in nasal polyp fibroblasts., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Minimal persistent inflammation (MPI) contributes to hyperreactivity in allergic rhinitis. However, little is known regarding whether pre-onset activation of eosinophils and mast cells is present or not in Japanese cedar pollinosis (JCP). Furthermore, a prophylactic effect of intranasal corticosteroids on such MPI in JCP has not been investigated., Methods: We designed a double-blinded, randomized, placebo-controlled, crossover trial. Twenty patients with JCP were examined outside the pollen season (UMIN000008410). Nasal provocation with paper discs containing extracts of Japanese cedar pollen was performed once a day for 3 consecutive days. Onset of nasal symptoms was monitored over 15 min after each provocation. The levels of eosinophil cationic protein (ECP) and tryptase in nasal secretions were examined. Fluticasone furoate nasal spray or placebo treatment was started one day before the first provocation., Results: In the placebo group, 25% of the patients showed onset of nasal symptoms following provocation on the first day. In addition, 75% and 68% of the patients showed symptom onset on the second and third day of provocation, respectively. After the first provocation, the levels of ECP and tryptase in nasal secretions were significantly increased. These increases were seen not only in symptomatic but also in asymptomatic subjects in response to provocation, and the levels were similar between these subjects. Prophylactic treatment with fluticasone significantly suppressed the increase in nasal ECP and tryptase associated with repeated provocations., Conclusions: These results suggest that pre-onset activation of eosinophils and mast cells is present in experimental JCP, and that prophylactic treatment with intranasal corticosteroids has the potential to control such activation., (Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Toll-like receptor 3 (TLR3) is expressed in upper airways, however, little is known regarding whether Toll-like receptor 3 (TLR3) signals exert a regulatory effect on the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), especially on eosinophilic inflammation. We sought to investigate the effect of Poly(IC), the ligand for TLR3, on cytokine production by dispersed nasal polyp cells (DNPCs)., Methods: DNPCs were pretreated with or without Poly(IC), and were then cultured in the presence or absence of staphylococcal enterotoxin B (SEB), following which the levels of IL-5, IL-10, IL-13, IL-17A and interferon (IFN)-γ in the supernatant were measured. To determine the involvement of IL-10 and cyclooxygenase in Poly(IC)-mediated signaling, DNPCs were treated with anti-IL-10 monoclonal antibody and diclofenac, the cyclooxygenase inhibitor, respectively. Poly(IC)-induced prostaglandin E2 (PGE2) production was also determined., Results: Exposure to Poly(IC) induced a significant production of IL-10, but not of IL-5, IL-13, IL-17A or IFN-γ by DNPCs. Pretreatment with Poly(IC) dose-dependently inhibited SEB-induced IL-5, IL-13 and IL-17A, but not IFN-γ production. Neutralization of IL-10 significantly abrogated the inhibitory effect of Poly(IC). Treatment with diclofenac also abrogated the inhibitory effect of Poly(IC) on SEB-induced IL-5 and IL-13 production. However, unlike exposure of diclofenac-treated DNPCs to lipopolysaccharide, the ligand for TLR4, exposure of these cells to Poly(IC) did not enhance IL-5 or IL-13 production. Poly(IC) did not significantly increase PGE2 production by DNPCs., Conclusions: These results suggest that TLR3 signaling regulates eosinophilia-associated cytokine production in CRSwNP, at least in part, via IL-10 production., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

This review discussed the contribution of eosinophilic upper airway inflammation includes allergic rhinitis (AR) and chronic rhinosinusitis (CRS) to the pathophysiology and course of asthma, the representative counterpart in the lower airway. The presence of concomitant AR can affect the severity of asthma in patients who have both diseases; however, it is still debatable whether the presence of asthma affects the severity of AR. Hypersensitivity, obstruction and/or inflammation in the lower airway can be detected in patients with AR without awareness or diagnosis of asthma, and AR is known as a risk factor for the new onset of wheeze and asthma both in children and adults. Allergen immunotherapy, pharmacotherapy and surgery for AR can contribute to asthma control; however, a clear preventive effect on the new onset of asthma has been demonstrated only for immunotherapy. Pathological similarities such as epithelial shedding are also seen between asthma and CRS, especially eosinophilic CRS. Abnormal sinus findings on computed tomography are seen in the majority of asthmatic patients, and asthmatic patients with CRS show a significant impairment in Quality of Life (QOL) and pulmonary function as compared to those without CRS. Conversely, lower airway inflammation and dysfunction are seen in non-asthmatic patients with CRS. Treatments for CRS that include pharmacotherapy such as anti-leukotrienes, surgery, and aspirin desensitization show a beneficial effect on concomitant asthma. Acting as a gatekeeper of the united airways, the control of inflammation in the nose is crucial for improvement of the QOL of patients with co-existing AR/CRS and asthma., (Copyright © 2015 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP)., Methods: Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC)., Results: Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics, Conclusions: S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.

Background: Statistically significant results of medical intervention trials are not always clinically meaningful. We sought to estimate the minimal clinically important difference (MCID) (the smallest change in a given endpoint that is meaningful to a patient) during seasonal alteration of Japanese cedar/cypress pollinosis (JCCP)., Methods: Results of a double-blinded, placebo-controlled trial of JCCP patients conducted between 2008 and 2010 were analyzed using an anchor-based method in which a face scale for Japanese rhinoconjunctivitis quality-of-life questionnaire (JRQLQ) was set as an anchor. MICDs were calculated as changes of average scores, including those for naso-ocular symptoms with 5 items in diary cards (T5SS), naso-ocular symptoms with 6 items (T6SS) and QOL with 17 items on the JRQLQ when face scale scores either improved or deteriorated by one point., Results: In 2009 and 2010, 3,698 and 374, respectively, grains/cm(2) of pollens were dispersed. The MCIDs for T5SS in 2009 and 2010 were 1.426 (0.285 per item) and 1.441 (0.288), respectively. The MCIDs for T6SS were 4.115 (0.686) and 3.183 (0.531) in 2009 and 2010, respectively. The MCIDs for QOL were 10.469 (0.616) and 6.026 (0.354) in 2009 and 2010, respectively., Conclusions: For T5SS in the diary, T6SS and QOL in JRQLQ, unit differences of 1.5 (0.3 per item), 3.6 (0.6) and 8.2 (0.5), respectively, were considered clinically meaningful by JCCP patients. The MCID for symptoms recorded in the diary was stable irrespective of the dispersed pollen level.

We conducted the Miyazaki Olmesartan Therapy for Hypertension in the EldeRly (MOTHER) study, which suggested that there are preferable effects of an angiotensin receptor blocker (ARB), olmesartan, plus a calcium channel blocker (CCB) over the ARB plus a diuretic, in elderly patients with hypertension. In this subanalysis, we examined whether obesity influences the efficacies of these combination therapies. The study subjects were 58 hypertensive patients ages 65 to 85, who had been randomly assigned to either group treated with olmesartan plus a CCB or a diuretic and completed the treatment for 6 months. Systolic and diastolic blood pressures were reduced following these combination treatments in nonobese and obese patients. In the CCB combination, blood pressure reductions in nonobese patients were larger than in obese patients at 1 and 3 months, and serum creatinine remained unchanged despite the greater reduction of blood pressure. Meanwhile, such differences were not noted in the diuretic groups. Plasma aldosterone was significantly reduced in nonobese patients of two combination groups, but not in those with obesity. ARB plus CCB combination therapy might be preferably chosen for nonobese elderly patients, whereas the influence of obesity seems smaller in the efficacy of ARB plus a diuretic., (Copyright © 2012 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the safety and effectiveness of early interventional treatment (EIT) with intranasal corticosteroids for seasonal allergic rhinitis. We designed a double-blinded, randomized, placebo-controlled 12-week trial of EIT with mometasone furoate nasal spray (MFNS) for Japanese cedar/cypress pollinosis (JCCP)., Methods: A total of 50 JCCP patients received MFNS (200μg once daily: n = 25) or placebo (n = 25) starting on February 1, 2010. Treatments continued until the end of April. The primary endpoint was the comparison of the total nasal symptom score (TNSS) between the MFNS and placebo groups. The secondary endpoints included comparisons of QOL, daytime sleepiness, nasal ECP levels, and safety., Results: Continuous dispersion of Japanese cedar pollen began on February 22. Although the placebo group showed a significant worsening of symptoms after the start of the continuous dispersion, no worsening occurred in the MFNS group. A significant difference in the TNSS between the two groups was seen starting at 4 weeks after the treatment. Similar results were seen for QOL and sleepiness. Nasal ECP levels in March were significantly lower in the MFNS group. A total of 56% of the MFNS group progressed to a persistent allergic rhinitis state in accordance with the ARIA classification, as opposed to 84% of the placebo group. MFNS was well tolerated, and the plasma cortisol concentrations were similar between the two groups., Conclusions: EIT with MFNS for JCCP is both safe and effective. This treatment can potentially lessen symptoms and help pollinosis patients remain in the intermittent state.

This study was conducted by the Japanese Society of Chemotherapy and is the first nationwide study on bacterial pathogens isolated from patients with urinary tract infections at 28 hospitals throughout Japan between January 2008 and June 2008. A total of 688 bacterial strains were isolated from adult patients with urinary tract infections. The strains investigated in this study are as follows: Enterococcus faecalis (n = 140), Escherichia coli (n = 255), Klebsiella pneumoniae (n = 93), Proteus mirabilis (n = 42), Serratia marcescens (n = 44), and Pseudomonas aeruginosa (n = 114). The minimum inhibitory concentrations of 39 antibacterial agents used for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. All Enterococcus faecalis strains were susceptible to ampicillin and vancomycin. Although a majority of the E. faecalis strains were susceptible to linezolid, 11 strains (7.8%) were found to be intermediately resistant. The proportions of fluoroquinolone-resistant Enterococcus faecalis, Escherichia coli, Proteus mirabilis, and S. marcescens strains were 35.7%, 29.3%, 18.3%, and 15.2%, respectively. The proportions of E. coli, P. mirabilis, K. pneumoniae, and S. marcescens strains producing extended-spectrum β-lactamase were 5.1%, 11.9%, 0%, and 0%, respectively. The proportions of Pseudomonas aeruginosa strains resistant to carbapenems, aminoglycosides, and fluoroquinolones were 9.2%, 4.4%, and 34.8%, respectively, and among them, 2 strains (1.8%) were found to be multidrug resistant. These data present important information for the proper treatment of urinary tract infections and will serve as a useful reference for periodic surveillance studies in the future.

The etiology of Parkinson's disease (PD) remains unclear; however, generation of reactive oxygen species during oxidation of dopamine (DA) could be one of the factors leading to selective loss of nigral dopaminergic neurons in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake and partition DA from neuronal cytoplasm into synaptic vesicles. Therefore, alterations of VMAT2 function may cause cytoplasmic accumulation of free DA, toxic to dopaminergic neurons. Upstream of a putative promoter region of the VMAT2 gene, there exist polymorphic sequences consisting of two microsatellites, (CA)n and (GA)n. We performed a case-control study of this polymorphic region to determine whether the VMAT2 gene is related to PD. We found six genotypes; however, there was no significant difference in the allele frequencies between patients with PD and control subjects. Our data suggest that the polymorphic region of the VMAT2 gene studied here is not closely related to PD.

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is an autosomal recessive form of cerebellar ataxia that occurs most commonly in Japan but is also frequently seen in Europe. This disease is caused by mutations in the aprataxin gene, but the functions of the gene product and the pathogenic mechanism remain unclear. The present study provides experimental evidence that the histidine triad (HIT) domain in aprataxin has enzymatic activity that is negatively regulated by the intramolecular interaction of the N-terminal domain. Furthermore, the reduction in HIT activity seen in all the disease-causing mutants tested, and the correlation between the reduced activity and the severe phenotype, support that aprataxin's physiological function is associated with its catalytic activity. Our findings suggest that the clinical phenotypes are caused by a loss of aprataxin function, attributable largely to diminished HIT activity but partially to a reduction in the levels of gene products.

A stereoselective high-performance liquid chromatographic method for the determination of the enantiomers of ketamine and its active metabolite, norketamine, in human plasma is described. The compounds were extracted from plasma by liquid-liquid extraction three times in a combination of cyclohexane with 2.5 M NaOH, 1 mM HCl and 1 M carbonate buffer. Stereoselective separation was achieved on a Chiralcel OD column with a mobile phase of n-hexane-2-propanol (98:2, v/v). The detection wavelength was 215 nm. The lower limits of the determination of the method were 5 ng/ml for ketamine and 10 ng/ml for norketamine. The intra- and inter-day coefficients of variation ranged from 2.9 to 9.8% and from 3.4 to 10.7% for all compounds, respectively. The method was sensitive and sufficiently reproducible for stereoselective monitoring of ketamine and norketamine in human plasma during pharmacokinetic studies after the administration of ketamine for analgesia.

Oxidative metabolism of cinnarizine (CZ) and its fluorine derivative flunarizine (FZ), both of which are selective calcium entry blockers, was examined in human liver microsomes. The ring-hydroxylations and the N-desalkylations constituted primary metabolic pathways in microsomal metabolism of CZ and FZ. Among these pathways, the ring-hydroxylase (p-hydroxylation) activities at the cinnamyl moiety of both drugs were highly correlated with debrisoquine 4-hydroxylase activity and CYP2D6 content. Quinidine, a selective inhibitor of CYP2D6, suppressed the ring-hydroxylase activities of CZ and FZ. These results suggest that CYP2D6 is involved in the ring-hydroxylation of the cinnamyl moiety of both CZ and FZ in human liver microsomes.