Properties of Achromobacter xylosoxidans highly resistant to aminoglycoside antibiotics.

We herein discovered a highly resistant clinical isolate of Pseudomonas aeruginosa with MICs to amikacin, gentamicin, and arbekacin of 128 µg/mL or higher in a drug sensitivity survey of 92 strains isolated from the specimens of Yoka hospital patients between January 2009 and October 2010, and Achromobacter xylosoxidans was separated from this P. aeruginosa isolate. The sensitivity of this bacterium to 29 antibiotics was investigated. The MICs of this A. xylosoxidans strain to 9 aminoglycoside antibiotics were: amikacin, gentamicin, arbekacin, streptomycin, kanamycin, neomycin, and spectinomycin, 1,024 µg/mL or ≥ 1,024 µg/mL; netilmicin, 512 µg/mL; and tobramycin, 256 µg/mL. This strain was also resistant to dibekacin. This aminoglycoside antibiotic resistant phenotype is very rare, and we are the first report the emergence of A. xylosoxidans with this characteristic.

Effects on asthma and induction of interleukin-8 caused by Asian dust particles collected in western Japan.

OBJECTIVE: Asian dust storms (ADS) contain various airborne particles that may augment airway inflammation by increasing the level of interleukin-8. The objective of the study was to investigate the association of exposure to an ADS with worsening of symptoms of adult asthma and the effect of ADS particles on interleukin-8 transcriptional activity. METHODS: The subjects were 112 patients with mild to moderate asthma who recorded scores for their daily upper and lower respiratory tract symptoms and measured morning peak expiratory flow (PEF) from March to May 2011. Interleukin-8 transcriptional activity was assessed in THP-G8 cells that were exposed to airborne particles collected during days of ADS exposure. RESULTS: Of the 112 patients, 31 had comorbid allergic rhinitis (AR) and/or chronic sinusitis (CS), and had worsened scores for upper respiratory tract symptoms on ADS days compared to non-ADS days. Scores for lower respiratory tract symptoms during ADS days were higher than non-ADS days in all patients. Three patients also had unscheduled hospital visits for exacerbation of asthma on ADS days. However, there was no significant difference in daily morning PEF between ADS and non-ADS days. Airborne particles collected on ADS days induced interleukin-8 transcriptional activity in THP-G8 cells compared to the original soil of the ADS. CONCLUSION: Exposure to an ADS aggravates upper and lower tract respiratory symptoms in patients with adult asthma. ADS airborne particles may increase airway inflammation through enhancement of interleukin-8 transcriptional activity.

[A case of lung abscess due to Aspergillus viridinutans in a patient with aplastic anemia].

A 75-year-old woman with aplastic anemia was admitted to our university hospital because of a dry cough that had persisted for a month. Chest computed tomography showed a mass shadow with a central low attenuation area in the lower lobe of the left lung. Filamentous fungus resembling Aspergillus fumigatus was cultured from the specimens obtained by transthoracic needle aspiration biopsy and bronchoalveolar lavage. The initial diagnosis was a lung abscess due to A. fumigatus, although the patient did not respond well to antifungal agents. Subsequently, the filamentous fungus was identified as Aspergillus viridinutans by sequence analysis of the ß-tubulin gene, and the patient was successfully treated with combination therapy along with granulocyte colony-stimulating factor. The incidence of A. viridinutans infection is very rare. A. viridinutans is morphologically similar to A. fumigatus; however, the response to antifungal agents is generally worse than that observed in A. fumigatus infections. Therefore, the selection of agents and supplemental therapy is of vital importance in cases of A. viridinutans infection.

[Chronotherapy of bronchial asthma].

Bronchial asthma is characterized by recurring symptoms, chronic inflammation of airway, reversible airflow limitation, and bronchial hyperresponsiveness. Lung function and symptoms of asthmatic patients frequently worsen between midnight and early morning. Currently, new drug delivery system based on chronopharmacology has been developed for the treatment of asthma. A night-time single dosing of anti-asthmatic drugs is clinically used for chronotherapy of asthma, which contributes to improve patient's adherence. This review focuses on chronotherapy of bronchial asthma.

Assessing Autonomic Nervous System Function by Pulse Rate Variability in Patients with Chronic Obstructive Pulmonary Disease.

Heart rate variability (HRV) is measured to analyze autonomic nervous system function in humans, and pulse rate variability (PRV) assessed using the photoplethysmography method with a pulse oximeter has been proposed as a surrogate for HRV. To examine whether PRV is compatible with HRV in patients with chronic obstructive pulmonary disease (COPD), we simultaneously measured HRV with an electrocardiogram and PRV with a pulse oximeter in patients with COPD, and compared low-frequency and high-frequency components computed from HRV and PRV as indicators of autonomic nervous system function. In a Bland-Altman analysis, the low-frequency component computed from HRV exhibited good consistency with that computed from PRV. The high-frequency component showed a significant fixed error but relatively good consistency. Our results indicate that autonomic nervous system function may be estimated with the low-frequency component by measuring PRV with a pulse oximeter in patients with COPD.

Rapid Multiplex RT-PCR for Influenza A and B by Genesoc®, a Microfluidic PCR System.

Background: Rapid antigen tests are widely used to diagnose influenza. However, despite their simplicity and short turnover time, the sensitivity of these tests is relatively low, and molecular tests with greater sensitivity are being sought. In this study, we developed and clinically evaluated a protocol for the rapid multiplex testing of influenza A and B, using a rapid real-time PCR system, GeneSoC®, that is based on microfluidic thermal cycling technology. Methods: The specificity of the developed assay was validated using cultured viral strains of influenza A/B, human metapneumovirus, and respiratory syncytial virus. Analytical sensitivity was evaluated using serially diluted RNA synthesized via in vitro transcription and nasopharyngeal swab samples collected from consecutive patients seeking medical attention for a combination of upper respiratory and general symptoms. Cross-validation of GeneSoC® based on comparisons with conventional real-time RT-PCR and rapid antigen tests was performed by parallel testing of influenza-positive clinical specimens. Results: The GeneSoC® assay detected the target sequences of influenza A and B at minimum concentrations of 38 and 65 copies/µL in reaction, respectively. For the analysis of clinical specimens, the positive, negative, and overall agreement between GeneSoC® RT-PCR and a conventional real-time RT-PCR was in all cases 100%, whereas for the comparison between GeneSoC® RT-PCR and the rapid antigen test, the agreements for positive, negative, and overall findings were 100%, 90.9%, and 95.7%, respectively. The mean time for completing GeneSoC® RT-PCR was 16 min 29 s (95% confidence interval, 16 min 18 s to 16 min 39 s). Conclusion: The microfluidic real-time PCR system, GeneSoC®, has an analytical performance comparable to that of conventional real-time RT-PCR with rapid turnover time, and represents a promising alternative to rapid antigen tests for diagnosing influenza A and B.

Diagnostic and prognostic impact of serum-soluble UL16-binding protein 2 in lung cancer patients.

UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the (51) Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ≥ 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ≥ 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC.

Pollen augments the influence of desert dust on symptoms of adult asthma patients.

BACKGROUND: East Asian desert dust storms that occur during mainly spring are called Asian dust storms (ADS). Our objective was to study the association of pollen and ADS with symptoms of adult asthma patients in Japan. METHODS: We designed a telephone survey to investigate the upper and lower respiratory, ocular, and skin symptoms of asthma patients during ADS in February, March, and December on 2009. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: We surveyed 106 patients in February, 101 patients in March, and 103 patients in December. In February and March, Japanese cedar and/or cypress pollen was also in the atmosphere during ADS, but no pollen was identified during December survey. Worsening of upper or lower respiratory, ocular, or skin symptoms was noted by 20.8% of patients in February, 33.7% in March, and 16.5% in December. Worsening of symptoms was significantly more common in March than in February or December. Two patients needed emergency treatment for exacerbation during ADS in March, but no patient needed hospitalization in any period. There was no significant difference of the daily morning PEF/personal best PEF ratio between ADS days and control days. However, in patients with worsening of upper and/or lower respiratory tract symptoms, the daily morning PEF/personal best ratio was significantly associated with the atmospheric level of particulate matter, but not with levels of pollen or other air pollutants. CONCLUSIONS: Pollen augmented symptoms in adult asthma patients, but ADS on its own also were able to aggravate symptoms and pulmonary function.

Correlation between Asian dust storms and worsening asthma in Western Japan.

BACKGROUND: Severe wind storms during spring in East Asia, called Asian dust storms (ADS), have been assessed in the past for their effect on health in Asian countries. Our objective was to study the ADS association with asthma symptoms in adult patients in Japan. METHODS: We designed a telephone survey to assess ADS influence on upper and lower respiratory, ocular and cutaneous symptoms in 98 patients with adult asthma from April to May 2007. Peak expiratory flow (PEF) was also measured from February to May. RESULTS: Worsening lower respiratory symptoms were noted by 22 of 98 patients during ADS in April, when Japanese cedar pollen levels also increased. During ADS in May, however, Japanese cedar and cypress pollen levels were not elevated, 11 patients had worsening of lower respiratory symptoms. None required emergency treatment for the exacerbation. Lower respiratory symptoms worsening most were cough and sputum; this was more common in patients with allergic rhinitis or atopy than in those without (P < 0.05). Min%Max differed significantly at 88.7 ± 6.6% during dust dispersion period, defined as the ADS day plus the next 6 days, versus 92.0 ± 5.3% during the 7-day period before a dust storm. CONCLUSIONS: We found that ADS aggravated lower respiratory symptoms in adult patients with asthma, but this influence was mild.

[Clinical evaluation of an oxygen concentrator and humidifier that does not require additional reservoir water].

A conventional humidifier with a reservoir of water for humidification can produce micro-aerosols contaminated with bacteria. The present study was undertaken to determine the clinical efficiency of a membrane humidifier that does not require additional reservoir water. We analyzed relative room air humidity and oxygen levels obtained from 2 pressure-swing adsorption (PSA)-type oxygen concentrators with membrane humidifiers. A significant correlation was found between relative room air humidity and that of oxygen moistened by a membrane humidifier. Several patients with chronic respiratory failure experienced improvements in subjectively reported nasal dryness using an oxygen concentrator with a membrane humidifier. This device avoids the need to change reservoir water, and may improve patient quality of life in the home.

Telemonitoring of Home Oxygen Therapy: A Review of the State of the Art and Introduction of a New Cloud-based System.

Home oxygen therapy allows patients requiring long-term oxygen therapy to receive care at home and helps improve the prognosis of patients with chronic respiratory failure. The usage conditions of oxygen concentrators, which are used to supply gaseous oxygen, and the effects of oxygen inhaled at a prescribed flow rate have not been confirmed in adequate detail. As a result of advances in information and communications technology, internet communication functions can now be incorporated into medical devices installed in patients' homes. This allows time-series data on oxygen concentrator usage and biological variables to be stored on a server and accessed remotely by health care providers, enabling them to check the validity of home oxygen therapy and intervene appropriately. In Japan, telemonitoring of home oxygen therapy is covered by social insurance systems and is recognized as a new medical technology. This article reviews the usefulness of telemonitoring of home oxygen therapy and describes the cloud-based analytical system we have developed.

Health-Related Quality of Life in Patients on Home Oxygen Therapy with Telemonitoring.

Home oxygen therapy (HOT) is an important treatment for patients with chronic respiratory diseases. Recently, telemonitoring of HOT has been become available. In the present study, we examined whether telemonitoring of HOT could improve health-related quality of life (HRQOL). Twelve patients receiving HOT participated in this study. The oxygen flow rates, use of the oxygen concentrator, and the values of percutaneous arterial oxygen saturation measured by each patient with a pulse oximeter were checked using a telemonitoring system for a period of one month. Interventions based on the results obtained were carried out in order to optimize oxygen use in this patient cohort. We evaluated the results of the SF-36 questionnaire before the initiation of telemonitoring and at 3 months after completion of the study. We identified significant improvements in SF-36 sub-scores after completion of this intervention. We conclude that telemonitoring may be a useful method to improve HRQOL.

A Randomized Controlled Trial of Telemedicine for Long-Term Sleep Apnea Continuous Positive Airway Pressure Management.

Rationale: The effects of telemedicine on adherence in patients with obstructive sleep apnea with long-term continuous positive airway pressure (CPAP) use have never been investigated.Objectives: To examine effects of a telemedicine intervention on adherence in long-term CPAP users.Methods: In a prospective, randomized, multicenter noninferiority trial conducted in 17 sleep centers across Japan, patients who had used CPAP for >3 months and were receiving face-to-face follow-up by physicians every 1 or 2 months were randomized by a coordinating center in a blind manner to the following three groups: 1) follow-up every 3 months accompanied by a monthly telemedicine intervention (telemedicine group: TM-group), 2) follow-up every 3 months (3-month group: 3M-group), or 3) monthly follow-up (1-month group: 1M-group). Each group was followed up for 6 months. The change in percentage of days with ≥4 h/night of CPAP use from baseline to the end of the study period was evaluated. A decline of ≥5% from baseline was considered deterioration of adherence. Noninferiority of TM- and 3M-groups compared with the 1M-group according to the number of patients with deterioration of adherence was evaluated with the Farrington and Manning test (noninferiority margin 15%).Results: A total of 483 patients were analyzed (median duration of CPAP use, 29 [interquartile range, 12-71] mo), and deterioration of adherence was found in 41 of 161 (25.5%), 55 of 166 (33.1%), and 35 of 156 (22.4%) patients in the TM-, 3M-, and 1M-groups, respectively. The noninferiority of the TM-group compared with the 1M-group was verified (difference in percentage of patients with adherence deterioration, 3.0%; 95% confidence interval [CI], -4.8% to 10.9%; P < 0.01). Conversely, the 3M-group did not show noninferiority to the 1M-group (percentage difference, 10.7%; 95% CI, 2.6% to 18.8%; P = 0.19). In the stratified analysis, adherence in TM- and 1M-group patients with poor adherence at baseline improved (TM: 45.8% ± 18.2% to 57.3% ± 24.4%; P < 0.01; 1M: 43.1% ± 18.5% to 53.6% ± 24.3%; P < 0.01), whereas that of the 3M-group did not (39.3% ± 20.8% to 39.8% ± 24.8%; P = 0.84).Conclusions: Intensive telemedicine support could help to optimize CPAP adherence even after long-term CPAP use.Clinical trial registered with www.umin.ac.jp/ctr/index.htm (trial number: UMIN000023118).

[Acute bird-related hypersensitivity pneumonitis: radiological findings in a case in the early phase after onset].

A 71-year-old woman was admitted to our hospital four times because of high fever and dyspnea from September to November in 2007. We treated her with antibiotics on her first two admissions. HOwever, we suspected hypersensitivity pneumonitis on the third admission because she suffered from fever and dyspnea soon after she had been discharged and returned home. She recovered only with the oxygen therapy on the last two admissions. Computed tomography of the chest showed early phase localized consolidation but changed to ground-glass opacities spreading over the entire lung field later during her third and fourth admissions. Bronchial alveolar lavage showed increases in total cell count, lymphocytes and IgA of pigeon-dropping extracts' and budgerigar-dropping extracts. TBLB showed epithelioid cell granulomas without caseous necrosis and alveolar septal inflammation. Inhalation challenge test using freeze-dried pigeon-dropping extracts was positive, therefore we finally established a diagnosis of acute bird related hypersensitivity pneumonitis. This is apparently the first report of acute bird-related hypersensitivity pneumonitis showing localized consolidation initially and later changing to diffuse ground-glass opacities. These radiological observations are significant in considering the onset and the progression of this disease.

Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.

PURPOSE: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines. EXPERIMENTAL DESIGN: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h (51)Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells. RESULTS: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 microg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients. CONCLUSIONS: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.

Sample Entropy in Electrocardiogram During Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an arrhythmia commonly encountered in clinical practice. There is a high risk of thromboembolism in patients with AF. Nonlinear analyses such as electroencephalogram (EEG), electrocardiogram (ECG), and respiratory movement have been used to quantify biological signals, and sample entropy (SampEn) has been employed as a statistical measure to evaluate complex systems. In this study, we examined the values of SampEn in ECG signals for patients with and without AF to measure the regularity and complexity. METHODS: ECG signals of lead II were recorded from 34 subjects without arrhythmia and 15 patients with chronic AF in a supine position. The ECG signals were converted into time-series data and SampEn was calculated. RESULTS: The SampEn values for the group without arrhythmia were 0.252 ± 0.114 [time lag (τ) = 1] and 0.533 ± 0.163 (τ = 5), and those for the chronic AF group were 0.392 ± 0.158 (τ = 1) and 0.759 ± 0.246 (τ = 5). The values of SampEn were significantly higher in the group with chronic AF than in the group without arrhythmia (P < 0.01 for τ = 1, P < 0.004 for τ = 5). The constructed three-dimensional vectors were plotted in time-delayed three-dimensional space. We used time lags of τ = 5 and τ = 1. The shape of the loops of the three-dimensional space was better for τ = 5. CONCLUSION: The values of SampEn from ECG for chronic AF patients were higher than for subjects without arrhythmia, suggesting greater complexity for the time-series from chronic AF patients. SampEn is considered a new index for evaluating complex systems in ECG.

Evaluation of antigen-positive toxin-negative enzyme immunoassay results for the diagnosis of toxigenic Clostridium difficile infection.

Clostridium difficile (C. difficile)-associated diarrhea (CDAD) is a challenging nosocomial infectious disease. C. DIFF Quik Chek Complete assay is widely used to detect glutamate dehydrogenase (GDH) antigen and toxin A/B of C. difficile simultaneously. However, the interpretation of GDH positive/toxin negative results is problematic. We performed a retrospective study of patients with GDH positive/toxin negative results to determine the probability of detecting toxigenic C. difficile and its risk factors. Between April 2012 and March 2017, we investigated cultures of fecal specimens followed by toxin detection tests. The clinical histories of patients with and without toxigenic C. difficile were compared using univariate- and multivariate-analyses. In total, 2675 patients were examined using C. Diff Quik Chek Complete assay. Among 356 GDH positive/toxin negative patients, cultures were performed in 220 cases and toxigenic C. difficile was recovered from 139 (63.2%) specimens. Patients with toxigenic C. difficile had significantly lower body mass index than those without. Over half the GDH positive/toxin negative patients were infected with toxigenic C. difficile. Lower BMI was a CDAD risk factor in this patient population. These data can be utilized to initiate isolation and clinical interventions before confirmatory test results are available. J. Med. Invest. 65:131-135, February, 2018.

Treatment with beta2-adrenoceptor agonist in vivo induces human clock gene, Per1, mRNA expression in peripheral blood.

This study examined whether in vivo exposure to a beta2-adrenoceptor agonist, tulobuterol, induces human Period1 (hPer1) mRNA expression in cells from peripheral whole blood. In one experiment, oral tulobuterol was administered to five healthy volunteers at 22:00 h, while in another, a transdermally tulobuterol patch was applied to the same five subjects at 20:00 h. In each experiment, serum tulobuterol concentrations were measured at four time points, and total RNA was isolated from peripheral blood cells for determinations of hPer1 mRNA expression by real-time polymerase chain reaction. Both the tulobuterol tablet and the transdermal patch increased hPer1 mRNA expression, suggesting that analyses of human peripheral blood cells could reliably represent peripheral clock gene mRNA expression in vivo.

Usefulness of Pulse Oximeter That Can Measure SpO2 to One Digit After Decimal Point.

Pulse oximeters are used to noninvasively measure oxygen saturation in arterial blood (SaO2). Although arterial oxygen saturation measured by pulse oximeter (SpO2) is usually indicated in 1% increments, the value of SaO2 from arterial blood gas analysis is not an integer. We have developed a new pulse oximeter that can measure SpO2 to one digit after the decimal point. The values of SpO2 from the newly developed pulse oximeter are highly correlated with the values of SaO2 from arterial blood gas analysis (SpO2 = 0.899 × SaO2 + 9.944, r = 0.887, P < 0.0001). This device may help improve the evaluation of pathological conditions in patients.