Satoru Fujiuchi

Resistin Is Closely Related to Systemic Inflammation in Obstructive Sleep Apnea

Background: Obstructive sleep apnea (OSA) is closely related to systemic inflammation. Resistin is an adipocyte-derived cytokine (adipokine) that may link obesity with inflammation. Objective: We aimed to investigate whether incremental changes in OSA severity, from normal to severe, primarily affect the levels of resistin and other adipokines. Methods: Serum levels of resistin, interleukin-6 (IL-6) and leptin were examined in 31 men with OSA and 10 men without OSA, matched for age, body mass index (BMI) and several metabolic profiles. In 11 of the 31 men with OSA, these mediators were reexamined after 3 months of nasal continuous airway pressure (nCPAP) therapy. Results: Levels of resistin and IL-6 were simultaneously elevated in men with OSA compared with those in men without OSA (p < 0.05), while levels of leptin did not differ. The resistin and IL-6 levels tended to increase with increasing disease severity (p < 0.05), which was based on the apnea-hypopnea index (AHI). The average oxyhemoglobin saturation during sleep (p < 0.01) and IL-6 (p < 0.05) emerged as significant determinants of resistin, even after adjustments for age, BMI, leptin levels and metabolic risk factors. After nCPAP therapy, the elevated levels of resistin and IL-6 decreased, reaching almost baseline levels of controls. Before treatment, AHI correlated positively with the reduction rate in resistin (p < 0.05). Conclusion: In OSA patients, resistin production can be enhanced by hypoxic stress during sleep, possibly mediating systemic inflammatory processes. nCPAP therapy may play a beneficial role in the control of resistin production.

Increased vascular endothelial growth factor in acute eosinophilic pneumonia

Acute eosinophilic pneumonia (AEP) is associated with the presence of diffuse pulmonary infiltrates on the chest radiograph and an increased number of eosinophils and an elevation of interleukin (IL)‐5 levels in bronchoalveolar lavage (BAL) fluid. Vascular endothelial growth factor (VEGF) is a constitutively expressed protein encoded by messenger ribonucleic acid in human eosinophils and is released following stimulation with IL‐5. However, the roles of IL‐5 and VEGF in the pathogenesis or activity of this disease have not been clarified. The authors investigated the cells and the levels of these two factors in BAL fluid in five AEP patients and five normal controls before and after corticosteroid treatment. The absolute number of eosinophils·mL−1, IL‐5 and VEGF levels in patients before treatment were higher than in controls (53.8 versus 0.3×104·mL−1, 490.1 versus 5.2 pg·mL−1 and 643.0 versus 133.9 pg·mL−1, respectively). IL‐5 and VEGF rapidly decreased to the control level in parallel with clinical improvement. The relationship between eosinophilia and IL‐5 and VEGF levels was strongly significant. Elevated interleukin‐5 in the lung may initiate the recruitment of eosinophils and enhance the release of mediators, such as vascular endothelial growth factor from eosinophils, which, in turn, increases the permeability of blood vessels.

Extrinsic allergic alveolitis induced by the yeast Debaryomyces Hansenii

A 65-yr-old female developed cough, fever and dyspnoea following repeated exposure to a home ultrasonic humidifier. High-resolution computed tomography showed ground-glass opacity in both lung fields. Arterial blood gas analysis gave an oxygen tension of 8.38 kPa (63 Torr). Pulmonary function testing revealed restrictive ventilatory impairment with a reduction in the diffusing capacity. The diagnosis of extrinsic allergic alveolitis (EAA) was confirmed by radiographic findings, pathological evidence of alveolitis and reproductive development by a provocation test to the humidifier water. The yeast Debaryomyces Hansenii was the only microorganism cultured from the water of the humidifier. The double diffusion precipitating test and lymphocyte proliferative response was positive for an extract of D. Hansenii, providing evidence to incriminate this fungus. This is the first described case of EAA caused by D. Hansenii.

Suramin Inhibits the Growth of Non-Small-Cell Lung Cancer Cells That Express the Epidermal Growth Factor Receptor

The epidermal growth factor (EGF) is a potent growth factor that is believed to enhance the proliferation of cancer cells by a paracrine or autocrine mechanism. EGF transduces various signals and finally stimulates cell proliferation upon binding to cell surface receptors. Prevention of the association of this peptide with its receptors might lead to the development of new modalities for treatment of lung cancer. Several investigators have reported that suramin has antiproliferative activity against cancer cells that express EGF receptors (EGF-R), and that it acts by blocking the binding of the ligand to its receptor. In this study, we analyzed the antitumor effect of suramin using two lines of lung cancer cells (A549 and PC-13), which express EGF-R, and a variety of assays. Receptor-binding assays confirmed that A549 and PC-13 cells have cell surface receptors for EGF. Suramin inhibited the binding of EGF to these receptors. EGF and fetal bovine serum (FBS) stimulated the proliferation of cells, but suramin inhibited these effects in a dose-dependent fashion. Suramin at 200 microg/ml reduced the growth of A549 and PC-13 cells by 25 and 15%, respectively, in medium that contained 1% FBS. Paradoxically, the concentrations of suramin that inhibited cell proliferation were lower than those that were effective in inhibiting the binding of EGF to its receptor. Although expression of c-fos and c-myc mRNA increased when cells were stimulated by EGF or FBS, suramin at 200 microg/ml did not markedly alter such expression. Suramin partially blocked the EGF-induced progression of the cell cycle from the G0/G1 to the S phase. These results suggest that suramin partially blocks EGF signal transduction. Suramin probably inhibits cell proliferation by inhibiting intranuclear enzymes, as well as by partial blockage of EGF signal transduction.

Analysis of chest CT in patients with Mycobacterium avium complex pulmonary disease.

Background: The radiographic changes of Mycobacterium avium complex (MAC) pulmonary disease during therapy have not been studied well. Objective: To assess the efficacy of antituberculous drug therapy against MAC pulmonary disease using computed tomography (CT). Method: We analyzed chest CT scans before and after antituberculous therapy in 30 patients (21 women, 9 men) with MAC pulmonary disease. To evaluate radiographic changes during therapy, we defined a ‘degree of improvement’ (DI) that is calculated according to the CT appearance. Results: DI was better (1.35 ± 0.21) in patients who had converted sputum culture than in those who had not (0.44 ± 0.25) (p < 0.05). In patients who were diagnosed by bronchial washing, DI was better (1.60 ± 0.22) than in patients who were diagnosed by sputum (0.67 ± 0.20) (p < 0.01). We categorized the CT appearance into 6 types: small nodules, cavities, bronchial wall thickening, infiltration, pleural thickening and atelectasis. Patients who showed pleural thickening had a significantly worse DI (0.12 ± 0.40) than those who did not (1.23 ± 0.18) (p < 0.01). Most of the lesions that disappeared after therapy were small nodules. Conclusion: These results indicate that chest CT might be a useful tool for the prediction or assessment of drug therapy for MAC pulmonary disease.

Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection.

Objective:  Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection.

Pharmacokinetics of garenoxacin in elderly patients with respiratory tract infections.

The pharmacokinetics of the new oral des-fluoroquinolone antimicrobial garenoxacin (GRNX) was investigated in elderly patients with respiratory tract infections. Patients were treated with GRNX (200 mg or 400 mg) once daily for 7 days. Plasma GRNX concentrations were determined and pharmacokinetic parameters were estimated by Bayesian predictions using reported population pharmacokinetic parameters. At each dose, the maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC) were comparable with those reported in young subjects, except that the estimated C(max) and AUC values in one patient receiving the 200 mg dose whose body weight and creatinine clearance rate (CL(Cr)) were 38 kg and 17 mL/min, respectively, were higher than those of the other patients given 200 mg GRNX and were comparable with those of patients who received the 400mg dose. These results suggest that the recommended dose of GRNX should be 400 mg for most elderly and young patients, but only 200 mg in patients whose body weight and CL(Cr) are < 40 kg and < 30 mL/min, respectively.

Evaluation of a Quantitative Serological Assay for Diagnosing Chronic Pulmonary Aspergillosis

ABSTRACT The purpose of this study was to evaluate the clinical utility of a quantitative Aspergillus IgG assay for diagnosing chronic pulmonary aspergillosis. We examined Aspergillus-specific IgG levels in patients who met the following criteria: (i) chronic (duration of >3 months) pulmonary or systemic symptoms, (ii) radiological evidence of a progressive (over months or years) pulmonary lesion with surrounding inflammation, and (iii) no major discernible immunocompromising factors. Anti-Aspergillus IgG serum levels were retrospectively analyzed according to defined classifications. Mean Aspergillus IgG levels were significantly higher in the proven group than those in the possible and control groups (P < 0.01). Receiver operating characteristic curve analysis revealed that the Aspergillus IgG cutoff value for diagnosing proven cases was 50 mg of antigen-specific antibodies/liter (area under the curve, 0.94; sensitivity, 0.98; specificity, 0.84). The sensitivity and specificity for diagnosing proven cases using this cutoff were 0.77 and 0.78, respectively. The positive rates of Aspergillus IgG in the proven and possible groups were 97.9% and 39.2%, respectively, whereas that of the control group was 6.6%. The quantitative Aspergillus IgG assay offers reliable sensitivity and specificity for diagnosing chronic pulmonary aspergillosis and may be an alternative to the conventional precipitin test.

Successful alectinib treatment after crizotinib-induced interstitial lung disease.

A 70‐year‐old woman with lung adenocarcinoma, harbouring anaplastic lymphoma kinase gene rearrangement, was treated with crizotinib as third‐line chemotherapy. After 2 months, crizotinib was discontinued because of the development of crizotinib‐induced interstitial lung disease (ILD). Steroid treatment was then introduced and tapered off. Following complete resolution of the interstitial shadow, cytotoxic chemotherapy was initiated, and continued for over 2 years, until new intrapulmonary lesions developed. Although there was a risk of drug‐induced interstitial pneumonia, alectinib was initiated as the fifth‐line therapy, without steroid supplementation, as there was no alternative treatment. No recurrence of ILD was noted at 10 months. To our knowledge, this is the first report of successful alectinib treatment after the development of crizotinib‐induced ILD without the use of prednisolone.

Hypoxic ventilatory depression in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

We describe a case of a 21‐year‐old man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS) who presented with hypoxic ventilatory depression. He had chronic hypoventilation, which was not explained by weakness of respiratory muscles. His hypercapnic ventilatory response was not impaired. In contrast, hypoxic ventilatory depression was observed in the isocapnic progressive hypoxic response test. After exposure to hypoxic conditions, his respiratory frequency decreased and tidal volume was unchanged. The hypoxic ventilatory depression was partially blocked by pretreatment with aminophylline. In conclusion, we need to be careful with patients with MELAS who are hypoxaemic because a vicious circle of hypoxia and hypoventilation can occur.