Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study).

BACKGROUND: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 µg/day. METHODS: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 µg b.i.d.) or an FP group (100 µg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored. RESULTS: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups. CONCLUSIONS: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches.

Association of Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma2 gene with small dense low-density lipoprotein in the general population.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene has been reported to predict a lower risk for developing type 2 diabetes mellitus. However, its effect on the lipid profile has been disputable. Among low-density lipoproteins, small dense low-density lipoprotein (sdLDL) particles have been linked to a greater risk for coronary artery disease. The purpose of this study was to investigate the genetic effect of the Pro12Ala polymorphism in the PPARgamma2 gene on the presence of sdLDL in the general Japanese population. In 379 subjects (aged 54 +/- 13 years), body mass index, percentage of body fat, blood pressure, and biochemical profiles were measured. Pro12Ala polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The area of sdLDL subfractions (sdLDL4-7) was analyzed by high-resolution polyacrylamide gel electrophoresis. The frequency of the Ala12 allele in PPARgamma2 was 0.04. There was no difference in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels between genotypes. However, subjects with the X/Ala genotype (Pro/Ala + Ala/Ala) had significantly higher serum triglyceride levels (P = .001) and a larger area of sdLDL4-7 (P = .002) than those with the Pro/Pro genotype. Multiple regression analysis revealed that the Ala12 allele was a significant variable contributing to the variance in the increased area of sdLDL4-7 (P = .040). In conclusion, the Pro12Ala polymorphism in the PPARgamma2 gene was positively associated with an enlarged area of sdLDL4-7. This polymorphism may play a role in the genetic predisposition to increases in sdLDL4-7.

The uncoupling protein-1 gene -3826A/G polymorphism and hypertension in Japanese subjects.

BACKGROUND: The possible effects of the uncoupling protein-1 (UCP-1) gene -3826A/G polymorphism on hypertension (HT) have yet to be elucidated. METHODS: A total of 578 Japanese subjects (231 males and 347 females, mean age 58.4 years) were enrolled in the study to investigate the association between HT and the -3826A/G polymorphism by genomic PCR and Bcl1-restriction fragment length polymorphism methods. RESULTS: Multivariate logistic regression analysis for HT, adjusted for genotype (recessive model, AA+AG vs. GG) and other covariates such as cardiovascular risk factors [e.g., smoking, body mass index (BMI), dyslipidemia and diabetes] showed age [odds ratio (OR) 1.11 (95% confidence interval 1.08-1.13)] and BMI [OR 1.13 (1.06-1.21)] as independent significant factors. In the subgroup analysis, as well as age and BMI, GG genotype [OR 2.32 (1.08-4.99)] was also an independent significant factor for HT in males. Similarly, as well as age and BMI, GG genotype [OR 1.89 (1.00-3.57)] was also an independent significant factor for HT in the relatively older subgroup (> or =60 years). CONCLUSIONS: The results suggest that the GG genotype may be associated with the presence of HT in Japanese males and older subjects. Further investigation is needed to confirm our hypothesis.

Application of a quick-freezing and deep-etching method to pathological diagnosis: a case of elastofibroma.

A case of elastofibroma in a middle-aged Japanese woman was examined by the quick-freezing and deep-etching (QF-DE) method, as well as by immunohistochemistry and conventional electron microscopy. The slowly growing tumor developed at the right scapular region and was composed of fibrous connective tissue with unique elastic materials called elastofibroma fibers. A normal elastic fiber consists of a central core and peripheral zone, in which the latter has small aggregates of 10 nm microfibrils. By the QF-DE method, globular structures consisting of numerous fibrils (5-20 nm in width) were observed between the collagen bundles. We could confirm that they were microfibril-rich peripheral zones of elastofibroma fibers by comparing the replica membrane and conventional electron microscopy. One of the characteristics of elastofibroma fibers is that they are assumed to contain numerous microfibrils. Immunohistochemically, spindle tumor cells showed positive immunoreaction for vimentin, whereas alpha-smooth muscle actin, desmin, S-100 protein and CD34 showed negative immunoreaction. By conventional electron microscopy, the tumor cell had thin cytoplasmic processes, pinocytotic vesicles and prominent rough endoplasmic reticulum. Abundant intracytoplasmic filaments were observed in some tumor cells. Thick lamina-like structures along with their inner nuclear membrane were often observed in the tumor cell nuclei. The whole image of the tumor cell was considered to be a periosteal-derived cell, which would produce numerous microfibrils in the peripheral zone of elastofibroma fibers. This study indicated that the QF-DE method could be applied to the pathological diagnosis and analysis of pathomechanism, even for surgical specimens obtained from a patient.

Relationships between hematological recovery and overall survival in older adults undergoing allogeneic bone marrow transplantation.

OBJECTIVE: The advancement of hematopoietic stem cell transplantation techniques and the increase in frequency of hematological malignancy in older patients are expected to expand the indications to include more elderly patients. We investigated the problem of allogeneic bone marrow transplantation (allo-BMT) in patients over 40 years old. PATIENTS AND METHODS: We retrospectively analyzed 21 consecutive patients (13 males and 8 females) over 40 years old who underwent allo-BMT at our center during the past 12 years. RESULTS: The patients had a median age of 46 years, and 5 patients were over 50 years old. There were 8 cases of acute myelogenous leukemia (AML), 5 cases of acute lymphocytic leukemia (ALL), 6 cases of chronic myelogenous leukemia (CML) and 2 cases of myelodysplastic syndrome (MDS). The 3-year overall survival rate was 43.0%. Overall survival was associated with recovery of platelets in less than 30 days and recovery of neutrophil counts in less than 15 days. We did not observe any severe graft-versus-host disease (GVHD) or regimen-related toxicities. Twelve patients died of transplantation-related diseases. CONCLUSION: A faster recovery of the neutrophil and platelet counts was significantly associated with overall survival. Decreasing transplantation-related death, particularly by infection control, in allo-BMT in patients over age 40 is an important problem.

Maturational changes in airway remodeling after chronic exposure to ovalbumin in sensitized guinea pigs: role of cell renewal of airway resident cells.

We wanted to know whether airway remodeling caused by chronic exposures to antigen differed depending on the degree of maturation of animals. We sensitized guinea pigs at different stages of maturation: juvenile (approximately 200 g in body weight), adult (400 g), and old animals (800 g). Then, animals were repeatedly challenged with inhaled ovalbumin (0.3% or 3%) or vehicle twice a week for 6 wk. After the final challenge, the lungs were excised for the histologic evaluation of changes in the thickness of the inner wall area (Ti), the smooth muscle area (Tm), and the outer wall area (To) in noncartilaginous airway dimensions. To clarify whether or not the observed changes were due to renewal of airway cells, we stained the samples with labeled nucleotide 5'-bromo-2'-deoxyuridine (BrdU), which we injected repeatedly during the challenge periods. Chronic exposures to antigen induced airway wall thickening regardless of their stages of maturation. However, prominent areas of thickening differed between the three groups. Ti increased more remarkably in juvenile and adult animals than in old ones. By contrast, Tm significantly increased only in old animals. BrdU staining revealed more renewal of epithelial cells in juvenile and adult animals than in old ones (juvenile >or=adult > old), suggesting that increased renewal of epithelial cells contributed to the thickening of Ti in juvenile and adult animals. By contrast, only a slight increase in smooth muscle cell renewal was found even in old animals, indicating that an increase in Tm was due to factors such as hypertrophy. These results show that the development of antigen-induced airway remodeling is partly modified by the degree of maturation of animals in vivo.

Involvement of serotonin and nitric oxide in endotoxin-induced gastric motility changes in conscious rats.

Severe bacterial infection causes gastrointestinal dysmotility by an unknown mechanism. We investigated the possible involvement of serotonin (5-HT) and nitric oxide (NO) in endotoxin-induced motility disturbance, using an in vivo rat model. Six days prior to the experiment, a force transducer was sutured to the gastric antrum of rats. Lipopolysaccharide induced strong repetitive contractions in the gastric antrum within 2 to 3 min in all rats tested. After 15 min of hypermotility, motility decreased and remained low for more than 60 min. The initial increase in motility was suppressed by atropine, FK1052, or SB204070, whereas it was not affected by granisetron. The subsequent decrease was inhibited by L-NAME and S-methylisothiourea sulfate. These results indicate that in conscious rats, lipopolysaccharide induces a transient increase in gastric motility followed by suppression. The increase might be mediated by 5-HT4 receptors, and the decrease by inducible NOS.

Developmental changes in cyclooxygenase mRNA expression in the gastric mucosa of rats.

BACKGROUND: In newborn rats, gastric mucosa is more susceptible to various damaging agents and recovers from injury more quickly than in older animals. To determine whether metabolism of prostaglandins is responsible for this mucosal protective mechanism in developing rats, we studied cyclooxygenase (COX) mRNA expression in the mucosa using quantitative real-time polymerase chain reaction (PRC). METHODS: Cyclooxygenase-1 and COX-2 mRNA was extracted from the gastric mucosa of rats of various ages and quantitatively analyzed using real-time PCR with dual-labeled fluorogenic probes. The copy numbers of cDNA for COX-1 and COX-2 were standardized to glyceraldehyde-3-phosphate dehydrogenase from the same sample. RESULTS: Cyclooxygenase-1 mRNA expression was lowest in 1-week-old rats and highest in 4-week-old rats. Mucosal damage produced by 150 mmol/L HCl and 60% ethyl alcohol did not increase COX-1 mRNA expression in any age group. Cyclooxygenase-2 mRNA expression increased significantly with age. Mucosal injury increased COX-2 mRNA in each age group, especially in 1-week-old rats. Intraperitoneal lipopolysaccharide also increased COX-2 mRNA in both 1- and 4-week old rats. CONCLUSION: The high level of COX-2 mRNA expression in the gastric mucosa of 1-week-old rats may be responsible for the physiologic characteristics of gastric mucosal defenses in this age group.