Hisanao Yoshihara

Diagnostic and Prognostic Value of Procalcitonin in Community-Acquired Pneumonia

Introduction:The value of measuring procalcitonin (PCT) in patients with community-acquired pneumonia (CAP) is unclear. The aim of this study was to determine the value of PCT as a marker for microbial etiology and a predictor of outcome in CAP patients. Methods:A single-center observational study was conducted with CAP patients. On admission, their leukocyte count, serum C-reactive protein level, and serum PCT level were determined, and microbiological tests were performed. Patients were classified into 4 groups according to the A-DROP scoring system, which assesses the severity of CAP. Results:A total of 102 patients were enrolled. The pathogen was identified in 60 patients, and 31 patients had streptococcal pneumonia. The PCT levels were significantly higher in those patients with pneumococcal pneumonia than in those patients with other bacterial pneumonias (P < 0.0001). Multivariate regression analysis revealed that high PCT levels were associated with a pneumococcal etiology [odds ratio, 1.68; 95% confidence interval (CI): 1.02–2.81; P = 0.04] after adjustment for disease severity and demographic factors. The PCT levels were correlated with the A-DROP score (r = 0.49; P < 0.0001). The area under the curve for predicting mortality was highest for the A-DROP score (0.97; 95% CI: 0.92–0.99), followed by the area under the curve for PCT (0.82; 95% CI: 0.74–0.89) and C-reactive protein (0.77; 95% CI: 0.67–0.84). Conclusions:High PCT levels indicate that pneumococcal pneumonia and PCT levels depend on the severity of pneumonia. PCT measurements may provide important diagnostic and prognostic information for patients with CAP.

Transduction of Phosphatase and Tensin Homolog Deleted on Chromosome 10 into Eosinophils Attenuates Survival, Chemotaxis, and Airway Inflammation

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is part of a complex signaling system that affects a variety of important cell functions. PTEN antagonizes the action of PI3K by dephosphorylating the signaling lipid phosphatidylinositol 3,4,5-triphosphate. In the present study, we used a TAT fusion protein transduction system to elucidate the role of PTEN in eosinophils and airway inflammation. A small region of the HIV TAT protein (YGRKKRRQRRR), a protein transduction domain known to enter mammalian cells efficiently, was fused to the N terminus of PTEN. Flow cytometric analysis of annexin V- and propidium iodide-stained cells was used to assess eosinophil survival. A chemotaxis assay was performed using a Boyden chamber. Cell analysis in bronchoalveolar lavage fluid and histological examinations were performed using OVA-challenged A/J mice. We found that TAT-PTEN was successfully internalized into eosinophils and functioned as a phosphatase in situ. TAT-PTEN, but not a TAT-GFP control protein, blocked the ability of IL-5 to prevent the apoptosis of eosinophils from allergic subjects. The eotaxin-induced eosinophil chemotaxis was inhibited by TAT-PTEN in a dose-dependent manner. Intranasal pretreatment with TAT-PTEN, but not TAT-GFP, significantly inhibited the OVA-induced eosinophil infiltration in bronchoalveolar lavage fluid. Histological examination of the lung, including H&E and Alcian blue/periodic acid-Schiff staining, revealed that TAT-PTEN, but not TAT-GFP, abrogated eosinophilic inflammation and mucus production. Our results suggest that PTEN negatively regulates eosinophil survival, chemotaxis, and allergic inflammation. The pharmacological targeting of PTEN may constitute a new strategy for the treatment of eosinophilic disorders.

Effect of Procaterol, a β2 Selective Adrenergic Receptor Agonist, on Airway Inflammation and Hyperresponsiveness

BACKGROUND β-agonists are frequently used as bronchodilators for asthma as not only a reliever but also a controller, and their utility has increased with the development of long-acting β2 selective drugs. Although antiinflammatory effects of β2 selective-agonists have been reported in vitro, side effects on augmentation of airway hyperresponsiveness by chronic use of β2 selective-agonists have been described in several reports. In this study, we investigated the effects of procaterol, a second-generation β2-agonist, on airway inflammation in vivo using an antigen-specific murine model of asthma. METHODS Mice immunized with ovalbumin (OVA) + alum and challenged with inhaled ovalbumin were orally administered procaterol during the challenge. After inhalation, the mice were tracheostomized and placed in a body box under controlled ventilation to measure airway resistance before and after acetylcholine inhalation. RESULTS Administration of procaterol at a clinical dose equivalent did not augment airway hyperresponsiveness, inflammation of the airway wall, or subsequent airway wall thickening induced by OVA inhalation. BALF cell analysis revealed that the eosinophil number in the BALF was significantly reduced in procaterol-treated mice compared to untreated mice. CONCLUSIONS Oral administration of procaterol at a clinical dose did not augment airway responsiveness, but did reduce eosinophil inflammation.

The Role of Platelet-Derived Growth Factor Receptor in Eotaxin Signaling of Eosinophils

Background: Receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) are capable of eliciting kinase activity after ligand binding. In several cells, RTKs are activated via the G-protein-coupled receptor independent of the ligand-RTK interaction. We have previously found that EGFR is transactivated via CC chemokine receptor 3 in bronchial epithelial cells and that this pathway is important for mitogen-activated protein (MAP) kinase activation and cytokine production. It has recently been suggested that hypereosinophilic syndrome results from the fusion tyrosine kinase FIP1L1-PDGFRA. Although it is possible that the PDGFR signal is involved in eosinophil function, the details are still unclear. Methods: Blood eosinophils were purified using Percoll and anti-CD16 antibody-coated magnetic beads. Expression of PDGFR mRNA was examined by RT-PCR. After stimulating eosinophils with eotaxin, the phosphorylation of MAP kinases was examined by Western blotting with the antiphosphospecific MAP kinase antibody. The eotaxin-induced eosinophil chemotaxis was studied using Boyden chambers. Results: Eosinophils expressed PDGFRβ mRNA in 4 out of 8 donors, while PDGFRα mRNA was expressed in only 1 donor. Protein expression of PDGFR was also detectable in eosinophils from some donors. AG1295, a specific inhibitor of PDGFR, showed dose-dependent inhibition of eotaxin-induced MAP kinase phosphorylation in the eosinophils expressing PDGFRβ mRNA. The chemotaxis of these eosinophils was significantly inhibited by AG1295 (n = 3). Conclusions: Our results suggest that PDGFR modifies the CCR3-MAP kinase signaling pathway and chemotactic response in some donors. The pharmacological targeting of PDGFR may be a new strategy to treat eosinophilic disorders.

Relationships among Smoking Habits, Airflow Limitations, and Metabolic Abnormalities in School Workers

Background Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality. Objective We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities. Methods Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history. Results Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012–1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010–1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975–0.994; p = 0.007). Conclusions Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities.

Primary Malignant Pericardial Mesothelioma Mimicking Pericardial Metastasis from Adenocarcinoma

An 85-year-old man was admitted with dyspnea on exertion and general fatigue. He was a retired school teacher without obvious history of asbestos exposure. Chest radiograph revealed cardiomegaly, and a large pericardial effusion was found from echocardiogram, which was subsequently drained by ultrasound-guided needle aspiration. Its hyaluronic acid level was 32,000 ng/ml (within normal range). Cytologic examination was positive, suggesting adenocarcinoma. The F-18 fluorodeoxyglucose positron emission tomography scan detected abnormal aggregations around the ascending aorta, pulmonary artery, and pericardium, but no primary focus was found (Figure 1). Pleural thickening and pleural plaques were not detected. A diagnosis of adenocarcinoma and pericardial metastasis of unknown origin was made. He died about 3 months after diagnosis due to right cardiac failure resulting from constrictive pericarditis. Autopsy revealed tumor had infiltrated and proliferated in the pericardium and myocardium and invaded the pericardial cavity (Figure 2a). Tumor was not found in the pleura. Pleural plaques were found, but asbestos bodies were not observed. Histologic examination revealed atypical proliferation of epithelioid cells (Figure 2b) and spindle cells (Figure 2c). Immunologic staining for calretinin was positive in the epithelioid and sarcomatous tumor cell nuclei and cytoplasm (Figure 2d). We diagnosed diffuse and biphasic primary malignant pericardial mesothelioma (PMPM). PMPM is extremely rare and represents 0.7% of all mesotheliomas.1 In this case, the patient was originally misdiagnosed with adenocarcinoma by pericardial effusion cytology. The reliability of body cavity fluid cytology is low for malignant mesothelioma; its sensitivity is reported to be 33 to 84%.2 Thus, histologic and immunohistochemical studies should be performed when PMPM is clinically suspected, even if adenocarcinoma is diagnosed by pericardial effusion cytology.