Isolation of three distinct carbapenemase-producing Gram-negative bacteria from a Vietnamese medical tourist.

Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli, multidrug-resistant Pseudomonas aeruginosa and vancomycin-resistant Enterococcus faecium were isolated from a single patient. The patient came to Japan for advanced medical treatment after having undergone laparoscopic cholecystectomy and hospitalization in Vietnam. Whole-genome sequence analysis revealed that K. pneumoniae harbored blaOXA-48 that was found on a Col156 -type small plasmid, E. coli harbored blaNDM-5 and P. aeruginosa harbored both blaNDM-1 and 16S rRNA methyltransferase (rmtB). To the best of our knowledge, this is the first report of detection of K. pneumoniae harboring blaOXA-48 on a Col156-type small plasmid in the world and P. aeruginosa coharboring genes encoding NDM-1 and RmtB in Japan.

Reduced HDAC2 in skeletal muscle of COPD patients.

BACKGROUND: Skeletal muscle weakness in chronic obstructive pulmonary disease (COPD) is an important predictor of poor prognosis, but the molecular mechanisms of muscle weakness in COPD have not been fully elucidated. The aim of this study was to investigate the role of histone deacetylases(HDAC) in skeletal muscle weakness in COPD. METHODS AND RESULTS: Twelve COPD patients, 8 smokers without COPD (SM) and 4 healthy non-smokers (NS) were recruited to the study. HDAC2 protein expression in quadriceps muscle biopsies of COPD patients (HDAC2/ß-actin: 0.59 ± 0.34) was significantly lower than that in SM (1.9 ± 1.1, p = 0.0007) and NS (1.2 ± 0.7, p = 0.029). HDAC2 protein in skeletal muscle was significantly correlated with forced expiratory volume in 1 s % predicted (FEV1 % pred) (rs = 0.53, p = 0.008) and quadriceps maximum voluntary contraction force (MVC) (rs = 0.42, p = 0.029). HDAC5 protein in muscle biopsies of COPD patients (HDAC5/ß-actin: 0.44 ± 0.26) was also significantly lower than that in SM (1.29 ± 0.39, p = 0.0001) and NS (0.98 ± 0.43, p = 0.020). HDAC5 protein in muscle was significantly correlated with FEV1 % pred (rs = 0.64, p = 0.0007) but not with MVC (rs = 0.30, p = 0.180). Nuclear factor-kappa B (NF-κB) DNA binding activity in muscle biopsies of COPD patients (10.1 ± 7.4) was significantly higher than that in SM (3.9 ± 7.3, p = 0.020) and NS (1.0 ± 1.2, p = 0.004and significantly correlated with HDAC2 decrease (rs = -0.59, p = 0.003) and HDAC5 (rs = 0.050, p = 0.012). HDAC2 knockdown by RNA interference in primary skeletal muscle cells caused an increase in NF-κB activity, NF-κB acetylation and basal tumour necrosis factor (TNF)-α production, as well as progressive cell death through apoptosis. CONCLUSION: Skeletal muscle weakness in COPD may result from HDAC2 down-regulation in skeletal muscle via acetylation and activation of NF-κB. The restoration of HDAC2 levels might be a therapeutic target for improving skeletal muscle weakness in COPD.

[A Case of Dengue Fever and Subsequent Long-lasting Depression Accompanied by Alopecia in a Japanese Traveler Returning from Bali, Indonesia].

Recovery from dengue fever is generally rapid and uneventful. However, recuperation is often prolonged and may be accompanied by noticeable depression. We present herein on a traveler to Indonesia who developed long-lasting depression after the classic symptoms of dengue fever such as fever, arthralgia, and macropapular rash had resolved. A previously healthy 42-year old japanese woman presented to the Travel Clinic of Seirei Yokohama Hospital with complaints of 4 days of fever, joint aches, bone pain, and a macropapular rash on her torso. She had returned from Bali 5 days previously. During her 1-week stay, one day was spent in rural, mountainous areas where she was exposed to several mosquito bites. The 1st serum sample collected 4 days after the disease onset gave positive result in the rapid dengue IgM antibody test and the rapid dengue NS1 antigen immunechromatographic test. The DENV-1 genome was detected with RT-PCR. Her 13-year old son, who had accompanied her, was also diagnosed as having dengue fever and he recovered without event. The Above-mentioned symptoms resolved within one week. However, the patient suffered from prolonged depression. She also noticed loss of hair 3 months after the disease onset Administration of a Serotonin-Noradrenalin Reuptake Inhibitor and a minor tranquillizer required to allow her requied to lead a normal life. Although she gradually felt better, it took approximately 2 years until she had recovered completely without taking any antidepressant and minor tranquillizer. It is a well-known fact in endemic countries that dengue fever could have an significant impact on the patients' mental well-being. However, it appears that physicians in non-endemic countries are not fully aware of the prolonged depression, which can occur subsequent to the acute illness. Follow-up consultations of returing travelers who have recoverd from dengu fever should be arranged to monitor their mental and emotional states closely.

Usefulness of Combined Measurement of Surfactant Protein D, Thrombin-Antithrombin III Complex, D-Dimer, and Plasmin-α2 Plasmin Inhibitor Complex in Acute Exacerbation of Interstitial Lung Disease: A Retrospective Cohort Study.

Background/Objectives: The coagulation cascade due to tissue damage is considered to be one of the causes of poor prognostic outcomes in patients with acute exacerbations of interstitial lung disease (AE-ILD). This study aimed to confirm coagulopathy in AE-ILD by evaluating the differences in the clinical characteristics of coagulation/fibrinolysis markers between stable ILD and AE-ILD. Methods: Overall, 81 patients were enrolled in this retrospective study and categorized into the following two groups: a chronic ILD group comprising 63 outpatients and an acute ILD group comprising 18 inpatients diagnosed with AE-ILD. Serum markers, including thrombin-antithrombin III complex (TAT), D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), and surfactant protein D (SP-D), were compared between the groups. Results: Among the 18 patients with acute ILD, 17 did not meet the International Society of Thrombosis and Hemostasis scoring system for disseminated intravascular coagulation. In acute ILD, the SP-D levels were statistically significantly positively correlated with TAT, D-dimer, and PIC levels, while the Krebs von den Lungen 6 (KL-6) levels showed no correlation with any of these coagulation/fibrinolytic markers. A positive correlation was observed between SP-D levels and TAT, D-dimer, and PIC levels in acute ILD. Serum TAT, D-dimer, and PIC all showed good area under the receiver operating characteristic (ROC) curve (AUC) values in ROC analysis for the diagnosis of acute ILD. Conclusions: In the clinical setting of AE-ILD, it may be important to focus not only on alveolar damage markers such as SP-D but also on coagulation/fibrinolytic markers including TAT, D-dimer, and PIC.

[A case of Plasmodium ovale malaria--morphological diagnostic difficulty and utility of rapid diagnostic tests].

A 46-year-old Japanese man was referred to our travel clinic because of high fever for the past 7 days. He worked as an engineer for a month in Zambia and returned to Japan 2 days ago. He had a high-grade fever of 40.5 degrees C. Examination of the palpebral conjunctiva showed no evidence of anemia. Liver and spleen were not palpable. Blood sample was collected at the time of the febrile paroxysm. Malaria parasites were detected by examination of Giemsa-stained thin blood films. The dominant feature of parasite was early trophozoit with a low parasitemia (0.0469%, 1,857.6/microL). The James' stippling was absent. Schizonts and gametocytes were scarce. As ring morphology was quite variable, identification of species might not be possible. Identification of species is more difficult than usual, on the grounds that: 1) the blood sample contains rare early trophozoites, 2) the level of parasitemia is low, and 3) it is quite possible for parasites to be transformed due to the inappropriate treatment. Finally, the diagnosis was confirmed by nested PCR. Examination of Giemsa-stained blood films is the "gold standard" for detection and identification of organisms. However, in non-endemic countries, trained laboratory personnel are scarce and the most may be inexperienced in malaria diagnosis. It is recommended that personnel continue to gain experience by participating in external quality assurance schemes, and that routine laboratories utilize rapid diagnostic tests (RDTs) concurrently. The availability of simple and accurate RDTs could aid the diagnosis in no-endemic countries.

[Clinical and microbiological features of patients with pulmonary nontuberculous mycobacterial infection].

BACKGROUNDS: The prevalence of pulmonary nontuberculous mycobacterial infection (pNTM) is currently increasing. Furthermore, its clinical feature is reported to be gradually changing. However, few reports to clarify the current features of pNTM have been published. The aim of this study is to investigate microbiological and clinical features of pNTM. PATIENTS AND METHODS: This study was a retrospective observational study. Patients with pNTM visited to Dokkyo Medical University Koshigaya Hospital between January 2009 and December 2010 were enrolled. All patients fulfilled the diagnostic criteria in Japanese guidelines for nontuberculous mycobacterial pulmonary disease published in 2008. Medical records were reviewed to obtain information about the enrolled patients. RESULTS: Total 143 patients (49 males and 94 females, age 67 +/- 10 yrs) were enrolled in this study. Only 11.9% of patients had malignant diseases and 5.6% had diabetes mellitus whereas 79% had no comorbidity. Nearly 60% of patients showed normal BMI. At the time of diagnosis, 52.0% of patients had no symptom whereas 22.3% had cough and/or sputum, and 7.1% had hemoptysis. The results of smear examination with acid-fast staining were negative in 80.4%, +/- in 9.8%, 1 + in 7.7% and 2 + in 2.1%. Causative pathogens detected with acid-fast bacillus culture were Mycobacterium avium (M. avium) (74.8%), M. intracellulare (14.0%), M. fortuitum (3.5%), M. abscessus (2.8%), M. kansasii (2.8%) and others. CONCLUSION: This study showed that majority of patients had no symptoms and/or negative results of smear examination with acid-fast staining. It is crucial to consider these facts when a diagnostic test of pNTM is performed.

Clinical characteristics and cytokine profiles of adult obese asthma with type2 inflammation.

Obesity-related non-eosinophilic asthma has been identified as a phenotype of asthma. However, mepolizumab and omalizumab improve asthma control in severe asthma with obesity, implying that type-2 cytokines may be involved in the deterioration of control in obese asthma. Despite this, the clinical details of obese asthma with positive type-2 inflammation markers have not yet been reported. The objective of this study was to investigate the clinical characteristics of patients with obese asthma with positive type-2 inflammation markers. Adult obese asthmatic patients were enrolled and were classified into two groups: obese asthma with positive type-2 inflammation markers (T2) and obese asthma with negative type-2 inflammation markers (NT2), then data were compared. In total, 434 patients were enrolled (85% of patients were at GINA therapy step 4-5). The T2 group had a higher proportion of patients with persistent asthma since childhood and with allergic rhinitis. A higher percentage of patients used high-dose inhaled corticosteroids (ICS) and experienced acute exacerbations (annual exacerbation ratio ≥ 1) in the T2 group. Multivariate logistic regression analysis showed that the T2 group was independently associated with younger age, comorbidity of allergic rhinitis, persistent asthma since childhood, use of high-dose ICS, and acute exacerbation rate ≥ 1. Adipocytokine levels were similar between the groups. Collectively, obese asthma with positive type-2 inflammation markers is characterised by a higher percentage of persistent asthma since childhood and more severe asthma.

Risk factors of local oropharyngeal and laryngeal adverse effects from use of single inhaled corticosteroids and long-acting beta-agonists.

BACKGROUND: Single inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) are clinically effective and safe. However, if local oropharyngeal and laryngeal adverse effects (LOLAE) appear, adherence to the use of ICS is impaired. To minimize the development of adverse effects, it is essential to identify the underlying risk factors. METHODS: The study included 481 asthmatic patients who were prescribed ICS/LABA for the first time in their life between January and September of 2010. Patients ranged in age from 14 to 86 years old and consisted of 281 never smokers and 200 smokers. All data were collected retrospectively by respirologists. RESULTS: Seventy-three out of 481 patients suffered from one or more adverse effects, with 54 of these exhibiting LOLAE. Patients with LOLAE (51.4 ± 16.2 yrs) were significantly older than those without LOLAE (43.7 ± 15.9 yrs) (p = 0.0011) and were also prescribed a significantly higher dose of ICS. The pack-years of patients with LOLAE (2.1 ± 4.9) were significantly lower than those without LOLAE (6.0 ± 13.0) (p = 0.0087). The type of administered ICS was also significantly associated with a risk of developing LOLAE. CONCLUSIONS: Our survey indicated that a greater age, a higher dose of ICS, and the type of ICS were potential risk factors of LOLAE. The identified factors should be considered in a clinical setting in order to prevent the development of LOLAE and provide optimal treatment to patients.

Cigarette smoke-induced impairment of autophagy in macrophages increases galectin-8 and inflammation.

Cigarette smoke impairs autophagy, an intracellular protein degradation system, but the consequences of this defect have not been fully elucidated, especially in macrophages. Dysfunctional alveolar macrophages play an important role in chronic obstructive pulmonary disease (COPD). Here we show that galectin-8, a danger receptor that identifies damaged intracellular host vesicles and initiates autophagosome engulfment, is elevated due to activation of autophagy by cigarette smoke extract (CSE) in macrophages. CSE impaired autophagic flux in PMA-differentiated U937 macrophage-like cells, resulting in intracellular accumulation of galectin-8 and the autophagic adaptor protein NDP52. COPD patients showed elevated levels of galectin-8 and NDP52 in the lung homogenates with significant increase in the serum galectin-8 levels in patients with frequent acute exacerbations. Soluble galectin-8 induced interleukin (IL)-6 release in bronchial epithelial cells via PI3Kα signalling. Thus, increased galectin-8 due to CSE-induced impaired autophagy may be involved in the pathogenesis of COPD and may be a biomarker of this disease.

Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription.

Corticosteroids are potent anti-inflammatory agents, but corticosteroid insensitivity is a major barrier for the treatment of some chronic inflammatory diseases. Here, we show that hypoxia induces corticosteroid-insensitive inflammation via reduced transcription of histone deacetylase-2 (HDAC2) in lung epithelial and macrophage cells. HDAC2 mRNA and protein expression was reduced under hypoxic conditions (1% O(2)). Hypoxia enhanced interleukin-1beta-induced interleukin-8 (CXCL8) production in A549 cells and decreased the ability of dexamethasone to suppress the CXCL8 production. Deletion or point mutation studies revealed that binding of the transcription factor hypoxia-inducible factor (HIF) 1alpha to a HIF response element at position -320, but not HIF-1beta or HIF-2alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.

Pulmonary emphysema is associated with fungal sensitization in asthma.

BACKGROUND: Fungal sensitization is a risk factor for severe asthma. Colonization in the lower respiratory tract is one of the forms of fungal exposure, and it is related to fungal sensitization. Pulmonary emphysema was recently reported to be an underlying disease of fungal colonization. The aim of study was to evaluate the prevalence of pulmonary emphysema in asthmatic patients with and without fungal sensitization. METHODS: We enrolled 108 patients with allergic asthma and divided them into the patients sensitized to Aspergillus and/or Candida (n=56) and those not sensitized to both Aspergillus and Candida (n=52). The presence of pulmonary emphysema on chest CT was evaluated retrospectively. RESULTS: The frequency of pulmonary emphysema was significantly higher in the patients sensitized to Aspergillus and/or Candida compared to the patients not sensitized to both fungi (P=0.0040). The frequency of pulmonary emphysema was also significantly higher in the patients sensitized to either Aspergillus or Candida compared to the patient not sensitized to the fungi (P=0.0398 and P=0.0198, respectively). A multivariate logistic regression analysis demonstrated that the presence of pulmonary emphysema was independently associated with the sensitization to Aspergillus and/or Candida (OR 7.84, 95% CI: 1.20-51.10). CONCLUSIONS: Pulmonary emphysema is associated with sensitization to Aspergillus and/or Candida.

Persistent Asthma from Childhood to Adulthood Presents a Distinct Phenotype of Adult Asthma.

BACKGROUND: In approximately 30% of children with asthma, the condition persists into adulthood. The longer duration of asthma in these patients is a risk factor for poor asthma control. However, the characteristics of adult patients with asthma that has persisted since childhood are not well documented. OBJECTIVE: We sought to compare the clinical characteristics among patients with adult-onset asthma, patients who outgrew childhood asthma but relapsed, and patients with persistent asthma since childhood. METHODS: We conducted a cross-sectional study of adult patients with asthma who visited our hospital. We classified them into 3 groups: those with adult-onset asthma (adult-onset), those who had remitted childhood asthma that relapsed (relapsed), and those who had asthma that had persisted since childhood (persistent). The clinical characteristics of these groups were compared. RESULTS: A total of 1443 patients were enrolled. The persistent group was younger and included fewer patients with a smoking history. There were statistically significant differences among the 3 groups in the percentages of patients with a family history of asthma and comorbidities of allergic rhinitis and atopic dermatitis. The proportion of patients with severe asthma differed among the 3 groups (31% in the adult-onset group, 34% in the relapsed group, and 40% in the persistent group; P = .015). The values of forced expiratory flow at 75% of vital capacity were lower in the persistent group than the relapsed or adult-onset group. A multivariable logistic regression analysis (dependent variable: severe asthma) in each group revealed that the factors associated with severe asthma differed among the adult-onset, relapsed, and persistent groups. When we established an overall model that included interaction terms of cohort-by-other factors, there was a trend that comorbidity of allergic rhinitis affected the severity of asthma differently in the relapsed group compared with the other groups. CONCLUSION: The clinical phenotype of asthma that persists from childhood to adulthood seems to be a distinct phenotype of adult asthma.

Obesity-associated severe asthma in an adult Japanese population.

BACKGROUND: Severe asthma is increasingly being recognized as an important public health issue. Obesity has been identified as a risk factor for poor asthma control and for worsening of asthma severity. However, most studies investigating obese patients with asthma have been performed in Western countries. Reports on the characteristics of obese Japanese individuals with severe asthma are lacking. Herein, we investigated the clinical characteristics of patients with obesity-associated severe asthma in a Japanese population and the association between obesity and poor asthma control. METHODS: We conducted a retrospective observational study of adult patients with severe asthma. Patients were classified into two groups based on the definition of obesity recommended by the Japan Society for the Study of Obesity: obese (OB) group (body mass index [BMI] ≥25 kg/m2) and non-obese (NOB) group (BMI <25 kg/m2). The two groups were compared. The characteristics of obesity and the metabolic functions are known to differ between males and females; therefore, we analyzed male-only and female-only cohorts separately. RESULTS: A total of 492 patients were enrolled. Age, smoking history in terms of number of pack-years, daily controller medications use, and spirometric data were not significantly different between the OB and NOB groups in either cohort. In the female cohort, the annual exacerbation ratio and the percentage of frequent exacerbators were significantly higher in the OB group compared to the NOB group. A multivariate logistic regression analysis showed that obesity was independently associated with frequent asthma exacerbations in the female cohort. CONCLUSIONS: Our study revealed that obesity, defined as a BMI ≥25 kg/m2, was independently associated with poor asthma control (including acute exacerbations) in adult Japanese females with severe asthma.

Influence of inhaled corticosteroids on community-acquired pneumonia in patients with bronchial asthma.

OBJECTIVE: The aim of the present study was to evaluate the influence of inhaled corticosteroids (ICS) on community-acquired pneumonia (CAP) in patients with asthma. PATIENTS AND METHODS: All asthmatic patients who required hospitalization for CAP from the beginning of 1989 through December 2001 were enrolled in this retrospective study. Patients who used oral corticosteroids daily were excluded. Patients were divided into two groups based on whether or not they used ICS, and we analyzed clinical characteristics of the pneumonia. Sixty-two patients (28 males, 34 females; mean age, 54.5 years) were enrolled in this study. Thirty-seven of 62 patients used ICS, with the mean dosage being 777.9 microg/day. RESULTS: We found no significant differences between the two groups with regard to mean age, serum albumin level, duration of asthma, pulmonary function and frequency of intravenous infusion of corticosteroids in the outpatient department. There were no significant differences in body temperature, white blood cell count, and CRP value upon admission between the two groups. Differences were not significant in the period of resolution of the pneumonia or in the frequency of pathogens identified between the two groups. CONCLUSION: ICS therapy appears to have no influence on CAP in patients with asthma. We recommend that ICS should be continued to control asthma with adequate antibiotic therapy when asthmatic patients have CAP.