Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

Environmental risks and sphingolipid signatures in adult asthma and its phenotypic clusters: a multicentre study.

BACKGROUND: Adult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. METHODS: Environmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables. FINDINGS: In the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28-3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108-0.311, p<0.05), but not with the accumulated levels of PM2.5 exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (p<0.001 and p<0.05, respectively), correlating with the levels of PAH (r=0.196, p<0.01) and metal exposure (r=0.202-0.323, p<0.05), respectively, and both correlating with circulating inflammatory markers (r=0.186-0.427, p<0.01). Analysis of six phenotypic clusters and those cases with comorbid type 2 diabetes mellitus (T2DM) revealed cluster-selective environmental risks and biosignatures. INTERPRETATION: These results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Lower starting dose of afatinib for the treatment of metastatic lung adenocarcinoma harboring exon 21 and exon 19 mutations.

BACKGROUND: Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib. METHODS: We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan. RESULTS: A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001). CONCLUSION: Patients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.

Associations of dermal diethyl phthalate level with changes in lung function test value mediated by absolute eosinophil count: A panel study of adults in southern Taiwan.

Phthalate concentrations in indoor and outdoor dust are associated with respiratory disease. Both immunoglobulin E (IgE) and eosinophil count are associated with airway inflammation from exposure to environmental allergens. Dermal phthalate level can be used as a matrix for assessing personal exposure through direct absorption from the air, particle deposition, or contact with contaminated products. However, the association between dermal phthalate level and changes in lung function test values, as mediated by immunological response, remains unclear. In total, 237 adults in southern Taiwan were recruited. Spirometry measurements (in L) of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were taken on visits 1 (2016-2018) and 2 (2019). Dermal phthalate level, absolute eosinophil count, and IgE level were recorded on visit 1. Mean changes in FVC and FEV1 decrease pear year, as determined through pairwise comparisons, were significant (diffFVCper year: -0.46, 95% CI: -0.51, -0.41; p < 0.001; diffFEV1per year: -0.37, 95% confidence interval [CI]: -0.41, -0.34; p < 0.001). For FEV1 decrease, log-unit increases in dermal diethyl phthalate (DEP) were positively associated with diffFEV1per year (ß = 0.096; 95% CI: 0.042, 0.150; p = 0.001) and negatively associated with absolute eosinophil count (ß= -0.201; 95% CI: -0.380, -0.023; p= 0.027). Log-unit increases in absolute eosinophil count were negatively associated with diffFEV1per year (ß= -0.109; 95% CI: -0.150, -0.068; p < 0.001). Absolute eosinophil count mediated 19.70% of the association between dermal DEP level and diffFEV1per year. For FVC decrease, log-unit increases in dermal DEP were positively associated with diffFVCper year (ß = 0.095; 95% CI: 0.035, 0.155; p = 0.002) and negatively associated with absolute eosinophil count (ß = -0.243; 95% CI: -0.427, -0.060; p = 0.010). Log-unit increases in absolute eosinophil count were negatively associated with diffFVCper year (ß= -0.122; 95% CI: -0.168, -0.076; p < 0.001). Absolute eosinophil count mediated 29.98% of the association between dermal DEP level and diffFVCper year. The results suggest that dermal DEP level is positively associated with changes in lung function test values and is mediated by absolute eosinophil count.

Infection-provoked reversible posterior leukoencephalopathy syndrome in an adult with nephrotic syndrome: a case report.

BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare and heterogeneous clinico-neuroradiological syndrome characterized by headache, altered mental status, seizures, and visual disturbances. Hypertension and immunosuppression are two of the main factors that predispose an individual to RPLS. However, RPLS can develop when no major risk factors are present. RPLS has been reported in pediatric nephrotic patients, but rarely in adults. CASE PRESENTATION: A 42-year-old Asian woman with nephrotic syndrome presented with seizures, headaches, and nausea. Her blood pressure was controlled, and no immunosuppressants had been prescribed. All symptoms and tests indicated RPLS following infection with pneumonia, which was successfully treated by immediate administration antibiotic and anti-epileptic medications. Seizures did not recur during a 2-year follow-up period. CONCLUSIONS: When patients with nephrotic syndrome have an infection, RPLS symptoms should be investigated thoroughly. With early diagnosis and appropriate treatment of RPLS, morbidity and mortality can be prevented.

Better airway resistance reduction profile in intubated COPD patients by personalized bronchodilator dosing: A pilot randomized control trial.

INTRODUCTION: The optimal dose of inhaled metered-dose bronchodilators for intubated patients with chronic obstructive pulmonary disease (COPD) is unknown. In this study, we proposed a bronchodilator dosing schedule based on an individual's airway resistance (Raw) and tested its efficacy in reducing Raw. METHODS: A total of 51 newly admitted patients with invasively ventilated COPD were randomly assigned to receive personalized or fixed bronchodilator dosing. Personal target Raw was defined by measuring each individual's Raw after maximal pharmacologic bronchodilatation. Thereafter, Raw was measured every 8 h until the 28th day. Patients in the fixed-dosing group received only predetermined doses. Additional doses of bronchodilators were given to patients in the personalized-dosing group when the measured Raw exceeded their target Raw. RESULTS: The median daily doses of salmeterol/fluticasone were 9.2 (personalized-dosing) vs 7.6 (fixed-dosing) puffs (P < 0.001). The relative deviation of Raw from the personal target was expressed as (measured Raw - target Raw)/target Raw. The experimental group showed a smaller relative Raw deviation than the control group (0.09 ±â€¯0.10 vs 0.44 ±â€¯0.11, P = 0.02). There were no differences between the two groups in terms of ventilator-free days from day 1 to day 28, number of episodes of nosocomial pneumonia, total number of puffs of rescue bronchodilator, number of drug-related adverse effects or mortality rate at day 180. CONCLUSION: Personalized dosing of inhaled bronchodilator administered to invasively ventilated COPD patients can produce a better reduction in Raw. Further studies with larger sample size are required to verify the conclusion of this pilot study.

Exposure to cooking oil fumes and chronic bronchitis in nonsmoking women aged 40 years and over: a health-care based study.

BACKGROUND: Little is known about the effect of exposure to cooking oil fumes (COFs) on the development of non-malignant respiratory diseases in nonsmoking women. This study investigated the relationship between exposure to COFs and chronic bronchitis in female Taiwanese non-smokers. METHODS: Searching the 1999 claims and registration records maintained by Taiwan's National Health Insurance Program, we identified 1846 women aged 40 years or older diagnosed as having chronic bronchitis (ICD-9 code: 491) at least twice in 1999 as potential study cases and 4624 women who had no diagnosis of chronic bronchitis the same year as potential study controls. We visited randomly selected women from each group in their homes, interviewed to collect related data including cooking habits and kitchen characteristics, and them a spirometry to collect FEV1 and FVC data between 2000 and 2009. RESULTS: After the exclusion of thirty smokers, the women were classified those with chronic bronchitis (n = 53), probable chronic bronchitis (n = 285), and no pulmonary disease (n = 306) based on physician diagnosis and American Thoracic Society criteria. Women who had cooked ≥ 21 times per week between the ages of 20 and 40 years old had a 4.73-fold higher risk of chronic bronchitis than those cooking < 14 times per week (95% CI = 1.65-13.53). Perceived kitchen smokiness was significantly associated with decreased FEV1 (- 137 ml, p = 0.021) and FEV1/FVC ratio (- 7.67%, p = 0.008). CONCLUSIONS: Exposure to COF may exacerbate the progression of chronic bronchitis in nonsmoking women.

Sagittally malrotated kidney: a case series of two patients.

Renal malrotation along the horizontal plane with the long axis of the kidney in the vertical plane can be classified according to an anomalous rotation of the embryologic kidney during ascent. However, renal malrotation along the sagittal plane with the long axis of the kidney in the horizontal plane cannot be explained embryologically and had only been previously reported in one case. Here we report two cases of renal malrotation with the long axis of the kidney in the horizontal plane. Case 1 was a 43-year-old woman with acute pyelonephritis. Right unilateral malrotated kidney was accidentally found in abdominal CT scan and she recovered uneventfully. Case 2 was a 63-year-old diabetic woman with atrial fibrillation, cerebral hemorrhage, sepsis, acute respiratory failure, acute renal failure and right renal infarction. Right unilateral malrotated kidney was accidentally found in abdominal CT scan and she expired within a few days. Thus, these two patients were the 2nd and the 3rd cases of sagittally malrotated kidneys worldwide.

Significant Correlation between Brachial Pulse Pressure Index and Renal Resistive Index.

BACKGROUND: The renal resistive index (RI) is calculated as (peak systolic velocity - minimum diastolic velocity)/peak systolic velocity, and has been significantly associated with renal function. Pulse pressure index (PPI) is derived from a formula similar to renal RI, i.e. (systolic blood pressure - diastolic blood pressure)/systolic blood pressure. The purpose of this study was to investigate whether brachial PPI had a significant correlation with renal RI and could be used in identifying patients with impaired renal function. METHODS: We consecutively enrolled 255 patients referred for echocardiographic examination. The renal RI was measured from Doppler ultrasonography and blood pressure was measured from an ABI-form device. RESULTS: Patients with brachial PPI ≥ 0.428 (mean value of brachial PPI) had a lower estimated glomerular filtration rate (eGFR) than those with brachial PPI < 0.428 (p < 0.001). After the multivariate analysis was completed, brachial PPI had a significant correlation with renal RI (unstandardized coefficient ß = 0.53, p < 0.001). The areas under the curve for brachial PPI and renal RI in prediction of eGFR < 45 mL/min/1.73 m(2) were 0.682 and 0.893 (both p < 0.001), respectively. CONCLUSIONS: Brachial PPI was significantly correlated with renal RI. Patients with higher brachial PPI had a more reduced renal function. Hence, brachial PPI may be able to quickly reflect the intrarenal vascular hemodynamics, and may serve as an important tool for screening and follow-up for patients with abnormal renovascular resistance. KEY WORDS: Chronic kidney disease; Pulse pressure index; Resistive index.

Developing a machine-learning model for real-time prediction of successful extubation in mechanically ventilated patients using time-series ventilator-derived parameters.

Background: Successful weaning from mechanical ventilation is important for patients admitted to intensive care units. However, models for predicting real-time weaning outcomes remain inadequate. Therefore, this study aimed to develop a machine-learning model for predicting successful extubation only using time-series ventilator-derived parameters with good accuracy. Methods: Patients with mechanical ventilation admitted to the Yuanlin Christian Hospital in Taiwan between August 2015 and November 2020 were retrospectively included. A dataset with ventilator-derived parameters was obtained before extubation. Recursive feature elimination was applied to select the most important features. Machine-learning models of logistic regression, random forest (RF), and support vector machine were adopted to predict extubation outcomes. In addition, the synthetic minority oversampling technique (SMOTE) was employed to address the data imbalance problem. The area under the receiver operating characteristic (AUC), F1 score, and accuracy, along with the 10-fold cross-validation, were used to evaluate prediction performance. Results: In this study, 233 patients were included, of whom 28 (12.0%) failed extubation. The six ventilatory variables per 180 s dataset had optimal feature importance. RF exhibited better performance than the others, with an AUC value of 0.976 (95% confidence interval [CI], 0.975-0.976), accuracy of 94.0% (95% CI, 93.8-94.3%), and an F1 score of 95.8% (95% CI, 95.7-96.0%). The difference in performance between the RF and the original and SMOTE datasets was small. Conclusion: The RF model demonstrated a good performance in predicting successful extubation in mechanically ventilated patients. This algorithm made a precise real-time extubation outcome prediction for patients at different time points.

Arsenic exposure associated with lung interstitial changes in non-smoking individuals living near a petrochemical complex: A repeated cross-sectional study.

Arsenic exposure is associated with airway inflammation and decreased lung function tests. Whether arsenic exposure associated with lung interstitial changes remains unknown. We conducted this population-based study in southern Taiwan during 2016 and 2018. Our study recruited individuals aged over 20 years, residing in the vicinity of a petrochemical complex and with no history of cigarette smoking. In both the 2016 and 2018 cross-sectional studies, we conducted chest low-dose computed tomography (LDCT) scans, as well as urinary arsenic and blood biochemistry analyses. Lung interstitial changes included lung fibrotic changes that were defined as the presence of curvilinear or linear densities, fine lines, or plate opacity in specific lobes; additionally, other interstitial changes were defined as the presence of ground-glass opacity (GGO) or bronchiectasis on the LDCT images. In both cross-sectional studies conducted in 2016 and 2018, participants with lung fibrotic changes exhibited a statistically significant increase in the mean urinary arsenic concentrations compared to those without fibrotic changes (geometric mean = 100.1 vs. 82.8 µg/g creatinine, p < 0.001 for cross-sectional study 2016, and geometric mean = 105.6 vs. 71.0 µg/g creatinine, p < 0.001 for cross-sectional study 2018). After controlling for age, gender, body mass index, platelet counts, hypertension, aspartate aminotransferase, cholesterol, HbA1c, and educational levels, we observed a significant positive association between a unit increase in log urinary arsenic concentrations and the risk of lung fibrotic changes in both cross-sectional study 2016 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.04-1.90, p = 0.028) and cross-sectional study 2018 (OR = 3.03, 95% CI = 1.38-6.63, p = 0.006). Our study did not find a significant association between arsenic exposure and bronchiectasis or GGO. It is imperative for the government to take significant measures to reduce arsenic exposure levels among individuals living near petrochemical complexes.

Blood lead (Pb) is associated with lung fibrotic changes in non-smokers living in the vicinity of petrochemical complex: a population-based study.

Lead (Pb) is a toxic metal that has been extensively used in various industrial processes, and it persists in the environment, posing a continuous risk of exposure to humans. This study investigated blood lead levels in participants aged 20 years and older, who resided in Dalinpu for more than two years between 2016 to 2018, at Kaohsiung Municipal Siaogang Hospital. Graphite furnace atomic absorption spectrometry was used to analyze the blood samples for lead levels, and the LDCT (Low-Dose computed tomography) scans were interpreted by experienced radiologists. The blood lead levels were divided into quartiles, with Q1 representing levels of ≤1.10 µg/dL, Q2 representing levels of >1.11 and ≤1.60 µg/dL, Q3 representing levels of >1.61 and ≤2.30 µg/dL, and Q4 representing levels of >2.31 µg/dL. Individuals with lung fibrotic changes had significantly higher (mean ± SD) blood lead levels (1.88±1.27vs. 1.72±1.53 µg/dl, p< 0.001) than those with non-lung fibrotic changes. In multivariate analysis, we found that the highest quartile (Q4: >2.31 µg/dL) lead levels (OR: 1.36, 95% CI: 1.01-1.82; p= 0.043) and the higher quartile (Q3: >1.61 and ≤2.30 µg/dL) (OR: 1.33, 95% CI: 1.01-1.75; p= 0.041) was significantly associated with lung fibrotic changes compared with the lowest quartile (Q1: ≤1.10 µg/dL) (Cox and Snell R2, 6.1 %; Nagelkerke R2, 8.5 %). The dose-response trend was significant (Ptrend= 0.030). Blood lead exposure was significantly associated lung fibrotic change. To prevent lung toxicity, it is recommended to maintain blood lead levels lower than the current reference value.

Arsenic exposure and lung fibrotic changes-evidence from a longitudinal cohort study and experimental models.

Introduction: Arsenic (As) exposure is associated with lung toxicity and we aim to investigate the effects of arsenic exposure on lung fibrotic changes. Methods: Participants (n= 976) enrolled via a general health survey underwent chest low-dose computed tomography (LDCT), spirometry forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and urinary arsenic examination during 2016 and 2018. Lung fibrotic changes from LDCT were defined. AsLtoL, low arsenic levels in both 2016 and 2018; AsLtoH, low arsenic in 2016 but high levels in 2018; AsHtoL, high arsenic in 2016 but low levels in 2018; AsHtoH, high arsenic levels in both 2016 and 2018. Mice exposed to 0. 0.2mg/L, 2 mg/L, 50 mg/L of sodium arsenite (NaAsO2) through drinking water for 12 weeks and 24 weeks were applied for histological analysis. Cultured lung epithelial cells were exposed to NaAsO2 and the mesenchymal changes were examined. Results: AsHtoH increased the risk (OR= 1.65, 95% CI 1.10, 2.49) of Lung fibrotic positive to positive (reference: Lung fibrotic negative to negative) compared with AsLtoL. Moreover, the predicted mean of FVC and FEV1 in AsHtoH (-0.09 units, 95% CI: -0.27, -0.09; -0.09 units, 95% CI: -0.17, -0.01) and AsLtoH (-0.13 units, 95% CI: -0.30, -0.10; -0.13 units, 95% CI: -0.22, -0.04) was significantly lower than ASLtoL. Significant lung fibrotic changes including the increase of the alveolar septum thickness and collagen fiber deposition were observed upon 2 mg/L NaAsO2 treatment for 12 weeks, and the damage was dose- and time-dependent. In vitro, sodium arsenite treatment promotes the epithelial-mesenchymal transition (EMT)-like changes of the normal human bronchial epithelial cells, including upregulation of several fibrotic and mesenchymal markers (fibronectin, MMP-2, and Snail) and cell migration. Inhibition of reactive oxygen species (ROS) and MMP-2 impaired the arsenic-induced EMT changes. Administration of a flavonoid, apigenin, inhibited EMT in vitro and pulmonary damages in vivo with the reduction of mesenchymal markers. Discussion: we demonstrated that continued exposure to arsenic causes lung fibrosis in humans and mice. Targeting lung epithelial cells EMT is effective on the development of therapeutic strategy. Apigenin is effective in the inhibition of arsenic-induced pulmonary fibrosis and EMT.

Whole-genome sequencing and identification of Morganella morganii KT pathogenicity-related genes.

BACKGROUND: The opportunistic enterobacterium, Morganella morganii, which can cause bacteraemia, is the ninth most prevalent cause of clinical infections in patients at Changhua Christian Hospital, Taiwan. The KT strain of M. morganii was isolated during postoperative care of a cancer patient with a gallbladder stone who developed sepsis caused by bacteraemia. M. morganii is sometimes encountered in nosocomial settings and has been causally linked to catheter-associated bacteriuria, complex infections of the urinary and/or hepatobiliary tracts, wound infection, and septicaemia. M. morganii infection is associated with a high mortality rate, although most patients respond well to appropriate antibiotic therapy. To obtain insights into the genome biology of M. morganii and the mechanisms underlying its pathogenicity, we used Illumina technology to sequence the genome of the KT strain and compared its sequence with the genome sequences of related bacteria. RESULTS: The 3,826,919-bp sequence contained in 58 contigs has a GC content of 51.15% and includes 3,565 protein-coding sequences, 72 tRNA genes, and 10 rRNA genes. The pathogenicity-related genes encode determinants of drug resistance, fimbrial adhesins, an IgA protease, haemolysins, ureases, and insecticidal and apoptotic toxins as well as proteins found in flagellae, the iron acquisition system, a type-3 secretion system (T3SS), and several two-component systems. Comparison with 14 genome sequences from other members of Enterobacteriaceae revealed different degrees of similarity to several systems found in M. morganii. The most striking similarities were found in the IS4 family of transposases, insecticidal toxins, T3SS components, and proteins required for ethanolamine use (eut operon) and cobalamin (vitamin B12) biosynthesis. The eut operon and the gene cluster for cobalamin biosynthesis are not present in the other Proteeae genomes analysed. Moreover, organisation of the 19 genes of the eut operon differs from that found in the other non-Proteeae enterobacterial genomes. CONCLUSIONS: This is the first genome sequence of M. morganii, which is a clinically relevant pathogen. Comparative genome analysis revealed several pathogenicity-related genes and novel genes not found in the genomes of other members of Proteeae. Thus, the genome sequence of M. morganii provides important information concerning virulence and determinants of fitness in this pathogen.

5-Methoxytryptophan Sensitizing Head and Neck Squamous Carcinoma Cell to Cisplatitn Through Inhibiting Signal Transducer and Activator of Transcription 3 (STAT3).

Head and neck squamous cell carcinoma (HNSCC) is a common cancer of the oral cavity. Cisplatin (CDDP) is the ideal chemo-radiotherapy used for several tumor types, but resistance to the drug has become a major obstacle in treating patients with HNSCC. 5-methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, reduces inflammation-mediated proliferation and metastasis. This study aimed to assess the anti-oral cancer activity of 5-MTP when used alone or in combination with CDDP. Results showed that CDDP dose dependently reduced the growth of SSC25 cells but not 5-MTP. The combination of CDDP and 5-MTP exerted additional inhibitory effect on the growth of SSC25 cells by attenuating the phosphorylation of STAT3. In the 4-nitroquinoline-1-oxide-induced oral cancer mouse model, 5-MTP sensitized the reduction effect of CDDP on tumorigenesis, which restricted the tongue tissue in hyperkeratotic lesion rather than squamous cell carcinoma. The combination of CDDP and 5-MTP may be a potent therapeutic strategy for HNSCC patients with radiotherapy.

The prenatal and postnatal effects of air pollution on asthma in children with atopic dermatitis.

OBJECTIVES: Air pollution is strongly associated with asthma, but has not been determined to induce new-onset asthma development in children with atopic dermatitis (AD). WORKING HYPOTHESIS: To assess whether prenatal/postnatal exposure to air pollutants triggers new-onset asthma development in children with AD. STUDY DESIGN: Retrospective cohort study. PATIENT-SUBJECT SELECTION: Data of patients 3% were significantly influenced by prenatal exposure to PM2.5 , especially SO2 , NO, and NO2 . CONCLUSIONS: Prenatal and postnatal exposure to air pollution have an association with asthma development in AD patients.

Effects of Montelukast on Arsenic-Induced Epithelial-Mesenchymal Transition and the Role of Reactive Oxygen Species Production in Human Bronchial Epithelial Cells.

Background: Epithelial-mesenchymal transition (EMT) of airway lung epithelial cells is considered a major driver of fibrosis and airway remodeling. Arsenic exposure is well known to cause the malignant transformation of cells, including those in the lung. Accumulating studies have shown that arsenic exposure is associated with chronic pulmonary diseases. However, clinical treatment for arsenic-induced pulmonary damage has not been well investigated. Materials and Methods: The therapeutic effects of montelukast and its combination with fluticasone on sodium arsenite-induced EMT changes in normal human bronchial cells were investigated. The cell migration ability was evaluated by Transwell and wound healing assays. EMT marker expression was determined by immunoblotting. Furthermore, the role of reactive oxygen species (ROS) generation in arsenic-induced EMT and the effect of montelukast on this process were determined by ROS inhibitor treatment and ROS measurement, respectively. Results: Montelukast was effective at reducing arsenic-induced cell migration and mesenchymal protein (fibronectin, MMP-2, N-cadherin, ß-catenin, and SMAD2/3) expression. Arsenic-induced ROS production was attenuated by pretreatment with montelukast. Treatment with the ROS inhibitor N-acetyl cysteine reduced arsenic-induced NF-kB phosphorylation and the mesenchymal protein expression, indicating that ROS production is critical for arsenic-induced EMT. In addition, combined treatment with montelukast and fluticasone reversed the inhibitory effects of montelukast on cell migration. The expression of fibronectin, MMP-2 induced by arsenic was further enhanced by the combination treatment compared with montelukast treatment only. Conclusion: This study demonstrated that montelukast is effective at reducing arsenic-induced EMT in human bronchial epithelial cells. Through the inhibition of arsenic-induced ROS generation and NF-kB activation, which is critical for arsenic-induced EMT, montelukast inhibited arsenic-induced cell migration and the expression of extracellular matrix proteins and several EMT-regulating transcription factors. The combination of fluticasone with montelukast reversed the inhibitory effect of montelukast on arsenic-induced EMT. This study provides therapeutic strategies and mechanisms for arsenic-induced pulmonary epithelial damage.

Anxiety Is a Mediator between Heart Rate Variability and Quality of Life in Chronic Obstructive Pulmonary Disease.

Autonomic nervous system (ANS) dysregulation is an important pathophysiological mechanism in patients with chronic obstructive pulmonary disease (COPD). Heart rate variability (HRV) is a common index for ANS, and HRV has been used to explore the association between ANS and clinical illnesses. This study aimed to explore the group differences in HRV, depression, anxiety, and quality of life between participants with COPD and healthy controls (HC group), and whether emotion plays a mediating role between HRV and quality of life in participants with COPD. A total of ninety-six participants with COPD and 59 participants in the HC group completed the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and Saint George's Respiratory Questionnaire (SGRQ). Assessment of spirometry pulmonary function and five minute lead II electrocardiography (ECG) were also performed under the resting baseline. The COPD group had higher depression scores (F = 4.10, p = 0.008), and a lower quality of life (F = 14.44, p < 0.001) and HRV indices (such as standard deviation of RR intervals (F = 5.49, p < 0.05) and low frequency (F = 3.03, p < 0.05)) compared to the HC group. Sympathetic activation was positively correlated with depression (r = 0.312, p < 0.01), anxiety (r = 0.420, p < 0.001), and poor quality of life (r = 0.467, p < 0.001) in the COPD group. After controlling for age and sex, anxiety (ß = 0.585, p < 0.001) and sympathetic activation (ß = 0.231, p < 0.05) positively predicted poor quality of life, and lung function (ß = −0.251, p < 0.01) negatively predicted poor quality of life. Therefore, anxiety is a mediator between sympathetic activation and quality of life. Emotional and HRV screening should be applied to COPD patients in clinical practice, and emotional management or HRV biofeedback training can be used to improve anxiety and HRV for future studies.