Exposure to ozone enhances antigen-presenting activity concentration dependently in rats

The effect of ozone (O(3)) on the symptoms of allergic asthma and the mechanisms underlying have not yet been fully elucidated. Antigen presentation is one of the factors contributing to the allergic reaction. Therefore, we investigated the effects of repeated exposure to O(3) on antigen-presenting (AP) activity, on the expression of cell-surface molecules associated with antigen presentation (Ia, B7.1, B7.2 and CD11b/c) in bronchoalveolar lavage cells (BAL cells), and on allergic asthma-like symptoms. Rats were exposed to 0.3, 0.56, 1ppm O(3) or filtered air for a 3-day period every 2 weeks, this was replicated three times. AP activity was assessed by measuring antigen-specific T-cell proliferation; and the expression of cell-surface molecules, by flow cytometry. Rats were also made to inhale aerosolized 1% ovalbumin (OVA) or saline for 10min post-exposure to O(3), and allergic asthma-like symptoms were measured by determining the increase in enhanced pause (Penh), which correlates well with lung resistance. O(3) increased both AP activity and expression of Ia and costimulatory molecules in BAL cells concentration dependently. It also increased lung resistance, and the increase in lung resistance after O(3) exposure was significantly higher in the OVA-inhaled group than in the saline-inhaled group. The present results show that O(3) increased AP activity concentration dependently and suggest that O(3) might aggravate allergy symptoms by enhancing AP activity.     

Vascular pseudoinvasion in a solitary Peutz‐Jeghers polyp in the ileum

A Peutz‐Jeghers polyp (PJP) is a hamartomatous lesion characterized by arborescent smooth muscle bundles covered with mucosa native to the site of involvement. PJPs in the small intestine may represent misplacement of non‐neoplastic epithelium into the submucosa, muscularis propria and subserosa. Although epithelial misplacement in PJPs is a well‐documented phenomenon, pseudoinvasion even into the vascular space in PJPs has not previously been reported. We report a case of a 22‐year‐old Japanese woman with a solitary PJP in the ileum. The ileal PJP in this patient showed epithelial herniation even into the vascular space. All the herniated epithelium, including the epithelial components invaginated into the vascular space, demonstrated features of pseudoinvasion, that is, presence of normal small intestinal type mucosa accompanied by the lamina propria, absence of any stromal desmoplastic reaction, and retention of the basal‐luminal gradient. Pathologists must be aware of the possibility of vascular pseudoinvasion in small intestinal PJPs to avoid overdiagnosis of carcinoma and resulting unnecessary major surgery.     

Change of cross-sectional area of the right internal jugular vein: effect of Trendelenburg position and valsalva maneuver]

To compare the effect of Valsalva maneuver and 10 degrees Trendelenburg position on the right internal jugular vein (RIJV), we measured RIJV cross-sectional area using ultrasound imaging during these procedures. The study group consisted of 13 normal healthy volunteers (6 males, 7 females, aged 25-47) with no history of neck surgery or right internal jugular vein (RIJV) puncture. All ultrasound images were obtained at the level of the cricoid cartilage. The subjects were positioned supine, and the measurements were taken with the subjects supine, under Valsalva maneuver, and under 10 degrees Trendelenburg tilt position. The cross-sectional areas of the RIJV during Valsalva maneuver and 10 degrees Trendelenburg position compared to those with supine position were 314 +/- 162%, and 192 +/- 96%, respectively. We conclude that both procedures increase cross-sectional area of IRJV significantly and in this respect Valsalva maneuver is more effective than Trendelenburg position.     

Clinical evaluation of combination therapy with cefoxitin and amikacin in complicated urinary tract infections

The clinical efficacy of combination therapy using Cefoxitin (CFX) and Amikacin (AMK) was studied in 19 patients with complicated urinary tract infections. Patients received 2 g of CFX i.v. and 100 mg of AMK i.m. twice a day. The overall clinical efficacy of treatment was evaluated by the criteria proposed by the UTI Committee, Japan, as excellent, moderate or poor. The overall clinical efficacy was excellent in 89%, moderate in 5% and poor in 5% of the patients. Of the 21 strains isolated from the patients, 20 strains (95%) were eradicated. No subjective side effects were observed. Drug-related aggravation in laboratory tests were observed slight elevations of glutomic-oxalacefic transaminase, glutamic-pyruvic transaminase and alkaliphosphatase in 2 cases, but all of them were minimal and reversible. Underlying condition-related aggravation was observed a slight elevation of BUN and creatinine clearance in 1 case. These results suggest that the combination therapy with CFX and AMK might be useful in the treatment of complicated urinary tract infections.     

Transgenic rescue of insulin receptor-deficient mice

The role of different tissues in insulin action and their contribution to the pathogenesis of diabetes remain unclear. To examine this question, we have used genetic reconstitution experiments in mice. Genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis. We show that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescues insulin receptor knockout mice from neonatal death, prevents diabetes in a majority of animals, and normalizes adipose tissue content, lifespan, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells are rescued from neonatal death, but develop lipoatrophic diabetes and die prematurely. These data indicate, surprisingly, that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes.     

Increased serum triglyceride clearance and elevated high-density lipoprotein 2 and 3 cholesterol during treatment of primary hypertriglyceridemia with bezafibrate

Background

Hypertriglyceridemia accompanied by low levels of high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. High-density lipoprotein 2 (HDL₂) and 3 (HDL₃) are believed to suppress the progress of atherosclerosis through reverse cholesterol transport. As a result, peripheral tissues can be protected against excessive accumulation of cholesterol. Although bezafibrate is known to accelerate the increase of HDL-C, results are not standardized regarding increases of HDL₃ and HDL₂ subfractions.

Objective

This study assessed the effects of bezafibrate on serum triglyceride (TG) fractional clearance rate (K₂) and HDL₂ and HDL₃ cholesterol (HDL₂-C and HDL₃-C, respectively) levels in patients with primary hypertriglyceridemia (serum TG ≥150 mg/dL).

Methods

Outpatients with primary hypertriglyceridemia were enrolled in this 8-week study conducted at the Third Department of Internal Medicine, Nagoya City University Hospital (Nagoya, Japan). Oral bezafibrate was administered at a dose of 400 mg/d (200-mg tablet BID, morning and evening) for 8 weeks. After 8 weeks, serum levels of total cholesterol (TC), TG, HDL-C, HDL₂-C, and HDL₃-C were measured. A fat emulsion tolerance test to assess K₂ and measurements of plasma lipoprotein lipase (LPL) mass, LPL activity, and hepatic triglyceride lipase (HTGL) activity in postheparin plasma were performed before bezafibrate administration and after the course of treatment.

Results

Sixteen patients (10 men, 6 women; mean [SD] age, 54 [12] years [range, 30-69 years]; mean [SD] body mass index, 23 [2] kg/m²) entered the study. The following findings were observed in male and female patients after 8 weeks of treatment. A statistically significant reduction was observed in mean serum TG level (P<0.01). Significant increases were seen in HDL-C, HDL₂-C, and HDL₃-C (all P<0.01), K₂ (P<0.01), and in plasma LPL mass (P<0.01) and LPL activity (P<0.05). TC level and HTGL activity did not change significantly. No adverse effects related to the use of bezafibrate were documented.

Conclusions

In this study, bezafibrate treatment resulted in significant decreases in serum TG level and significant increases in HDL₂-C and HDL₃-C levels and plasma LPL mass and activity. We hypothesize that bezafibrate may increase HDL₃-C by promoting TG-rich lipoprotein catabolism and may increase HDL₂-C by promoting the conversion of HDL₃ to HDL₂.     

In vitro marker gene expression analyses in human peripheral blood mononuclear cells: A tool to assess safety of influenza vaccines in humans

Vaccines are inoculated in healthy individuals from children to the elderly, and thus high levels of safety and consistency of vaccine quality in each lot must meet the required specifications by using preclinical and lot release testing. Because vaccines are inoculated into humans, recapitulation of biological reactions in humans should be considered for test methods. We have developed a new method to evaluate the safety of influenza vaccines using biomarker gene expression in mouse and rat models. Some biomarker genes are already known to be expressed in human lymphocytes, macrophages and dendritic cells; therefore, we considered some of these genes might be common biomarkers for human and mice to evaluate influenza vaccine safety. In this study, we used human peripheral blood mononuclear cells (PBMC) as a primary assessment tool to confirm the usefulness of potential marker genes in humans. Analysis of marker gene expression in PBMC revealed biomarker gene expressions were dose-relatedly increased in toxic reference influenza vaccine (RE)-stimulated PBMC. Although some marker genes showed increased expression in hemagglutinin split vaccine-stimulated PBMC, their expression levels were lower than that of RE in PBMC from two different donors. Many marker gene expressions correlated with chemokine production. Marker genes such as IRF7 were associated with other Type 1 interferon (IFN)-associated signals and were highly expressed in the CD304⁺ plasmacytoid dendritic cell (pDC) population. These results suggest PBMC and their marker genes may be useful for vaccine safety evaluation in humans.     

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia

OBJECTIVES: Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. METHODS: Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. RESULTS: CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). CONCLUSION: We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.     

Video‐assisted segmental resection of an intrapulmonary bronchogenic cyst mimicking a middle mediastinal cystic tumor

We report a case of an intrapulmonary bronchogenic cyst that radiologically mimicked a cystic tumor of the middle mediastinum. During video‐assisted thoracoscopic surgery, the lesion was confirmed to be in the lung parenchyma rather than in the mediastinum. A video‐assisted thoracoscopic anterior basal segmentectomy was eventually performed, and an intrapulmonary bronchogenic cyst was the diagnosis based on histology.