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The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment-naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Calcium silicate-based materials have attracted a great deal of interest due to their osteogenesis and have been used as implant materials for bone repair and regeneration. The purpose of this study was to use gelatin with and without genipin cross-linking for controlling degradation, improving mechanical properties, and enhancing angiogenesis of calcium silicate bioceramics. The in vitro degradation of gelatin-containing scaffolds was analysed in a simulated body fluid (SBF) solution. Human mesenchymal stem cells (hMSCs) were used to examine angiogenesis. The results indicated that the gelatin-containing scaffolds showed a diametral tensile strength of about 2 MPa and a porosity of about 60% falling within the range of values reported for the cancellous bone. Apatite precipitation occurred on all scaffold surfaces after soaking in SBF for 1 week. The gelatin-containing scaffold without cross-linking exhibited a greater weight loss and porosity than the control without gelatin. The cross-linking agent, genipin, significantly improved the mechanical stability of the composite scaffold. The gelatin enhanced the viable cell populations. More importantly, gelatin actively promoted the secretion of angiogenic factors such as von Willebrand factor and angiopoietin-1 in hMSCs. It is concluded that combination of calcium silicate and gelatin may synergistically enhance clinically desirable functions in terms of controlled degradation, improved mechanical properties, and enhanced angiogenesis.

The surface properties of metallic implants play an important role in their clinical success. Improving upon the inherent shortcomings of Ti implants, such as poor bioactivity, is imperative for achieving clinical use. In this study, we have developed a Ti implant modified with Ca or dual Ca + Si ions on the surface using an electron cyclotron resonance ion source (ECRIS). The physicochemical and biological properties of ion-implanted Ti surfaces were analyzed using various analytical techniques, such as surface analyses, potentiodynamic polarization and cell culture. Experimental results indicated that a rough morphology was observed on the Ti substrate surface modified by ECRIS plasma ions. The in vitro electrochemical measurement results also indicated that the Ca + Si ion-implanted surface had a more beneficial and desired behavior than the pristine Ti substrate. Compared to the pristine Ti substrate, all ion-implanted samples had a lower hemolysis ratio. MG63 cells cultured on the high Ca and dual Ca + Si ion-implanted surfaces revealed significantly greater cell viability in comparison to the pristine Ti substrate. In conclusion, surface modification by electron cyclotron resonance Ca and Si ion sources could be an effective method for Ti implants.

Objective: Maternal drug abuse may influence neonatal outcomes. We compared neonatal outcomes of patients with urine screened positive for commonly abused drugs (CAD) versus those who were screened negative, and reviewed the pattern of drugs detected at a university teaching hospital., Methods: Urine samples collected from babies with suspected illicit drug exposure who were admitted to the neonatal unit were sent for comprehensive drug screen (CDS) performed by liquid chromatographytime- of-flight mass spectrometry (LC-TOF/MS). The screening library can detect more than 300 drugs and their metabolites. Fluorescence polarization immunoassay (FPIA) was also used to screen for cannabinoids which were not detected by the present LC-TOF/MS method. Symptoms suggestive of drug exposure and history of maternal substance misuse were recorded., Results: Commonly abused drugs (CAD) including methadone, morphine, codeine, methamphetamine, ketamine, midazolam and heroin were present in the urine specimens of 46 (24.2%) of 190 neonates. Eighty-one (42.6%) urine samples screened positive for other drugs, which include antibiotics, lidocaine and pethidine administered during delivery. Drugs were undetectable in 33.2% samples. Urine positive for CAD was independently associated with maternal history of substance misuse (0.0001), birth-weight 2.5 kg (OR 2.9,0.01), neonatal withdrawal symptomatology (OR=8.89, 0.0001); but not with risk of preterm delivery. Logistic regression demonstrated that neonates with maternal history of substance misuse and CAD positivity were 5.99 (p=0.021) and 5.91 (0.0005) times more likely to have withdrawal symptoms., Conclusions: CADs are isolated in the CDS of nearly one-fourth of neonates. Neonates with maternal history of CAD exposure as evidenced by positive urine CDS are associated with low birth weight, and symptoms of drug withdrawal.

Although numerous studies have investigated gender-related differences in patients who have had an acute myocardial infarction (AMI), few studies have examined the gender-related differences among inpatients receiving Phase I inpatient cardiac rehabilitation following AMI.Using data from the Taiwan National Health Insurance Research Database, this study analyzed 6713 adult patients who received inpatient cardiac rehabilitation following AMI between 2002 and 2011. The differences in comorbidity, medical service use, and prognosis between the male and female patients were analyzed to determine whether the comorbidities affecting their prognoses differed.Female patients accounted for 23.18% of the sample, had a higher average age, and exhibited severe comorbidities; furthermore, they had significantly more days of hospitalization and days in an intensive care unit than did male patients. The gender-related differences in hospital mortality rate and 30-day mortality rate were nonsignificant, but female patients exhibited a significantly higher 1-year mortality rate. Moreover, the risk for 1-year mortality was higher among female patients with moderate or severe renal disease (odds ratio: 1.94, 95% confidence interval: 1.29-2.92) than among their male counterparts. However, the 1-year mortality rate for the female patients did not increase after all risk factors were adjusted.Gender-related differences in age, comorbidity, and prognosis were confirmed in AMI patients receiving Phase I inpatient cardiac rehabilitation. In addition, gender-related differences were observed in the comorbidity risk factors affecting prognosis. However, being female did not affect the prognosis., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background: The role of adiponectin in arterial stiffness and its relationship to cardiovascular disease is not fully demonstrated and needs further elaboration. In this study, the association between adiponectin level and arterial stiffness is studied among kidney transplant patients., Material and Methods: Anthropometric data and biochemical data including fasting glucose, lipid profile, renal function and serum adiponectin were determined in 55 kidney transplant patients. Central arterial stiffness was measured and presented by carotid-femoral pulse wave velocity., Results: Univariate linear analysis showed that body weight, waist circumference, brachial pulse pressure and body mass index were correlated positively with carotid-femoral pulse wave velocity in this patient group. However, logarithmically transformed adiponectin level (log-adiponectin) correlated negatively with carotid-femoral pulse wave velocity. In multivariate regression analysis of factors significantly associated with carotid-femoral pulse wave velocity, it showed that both log-adiponectin (β = -0.427; R(2) = 0.205, p = 0.001) and body weight (β = 0.327; R(2 )=( )0.106, p = 0.007) were independently predictive of central arterial stiffness., Conclusion: Our study suggests that fasting serum adiponectin is negatively associated with carotid-femoral pulse wave velocity, hence arterial stiffness, in kidney transplant patients.

Background: Asthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC)., Methods: This study was a nested case-control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected., Results: From the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56-3.04) and 1.77 (1.22-2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16-1.84) and 1.55 (95 %CI, 1.22-1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteroid was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22-20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05-9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50-5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69-16.81)., Conclusion: Corticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC.

Background: Leptomeningeal carcinomatosis (LC) is a detrimental complication of patients with non-small-cell lung cancer (NSCLC). The effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on the clinical outcome of these patients, particularly those with EGFR mutations, has not been studied yet., Methods: We searched the database for lung cancer patients diagnosed from 2003 to 2010 in one Asian medical center. NSCLC patients who also had LC diagnosed by either cytology or brain neuroimaging studies were identified. The treatments and clinical outcomes were reviewed., Results: Of 5526 lung cancer patients, we identified 212 (3.8%) NSCLC patients with LC. Most patients (88.7%) had adenocarcinoma histology, and 129 (60.9%) patients had been treated with at least one regimen of EGFR TKI before the diagnosis of LC. One hundred and twenty-four (58.5%) patients were treated with EGFR TKI, and 128 (60.4%) patients were treated with whole-brain radiation therapy (WBRT) after the diagnosis of LC. The median overall survival was 4.5 months (95% confidence interval, 3.5-7.3). Multivariate analysis suggested that EGFR TKI therapy, WBRT, and cytotoxic chemotherapy were independent predictors for longer survival. Mutational status of EGFR was evaluated in 101 patients, and 75 mutations (74.3%) were detected. Among the 75 patients with EGFR mutations, EGFR TKI therapy and cytotoxic chemotherapy after diagnosis of LC remained the independent factors predictive of extended survival in the multivariate analysis., Conclusions: Treatment of LC with EGFR TKI, cytotoxic chemotherapy, or WBRT in selected patients is associated with prolong survival period. These treatment options, especially EGFR TKIs, should be studied in patients with EGFR mutation-positive NSCLC and LC.

Background: The associations between pulmonary diseases (asthma, chronic obstructive pulmonary disease [COPD], and tuberculosis [TB]) and subsequent lung cancer risk have been reported, but few studies have investigated the association with different histologic types of lung cancer., Methods: Patients newly diagnosed with lung cancer from 2004 to 2008 were identified from the National Health Insurance Research Database in Taiwan. Histologic types of lung cancer were further confirmed using the Taiwan Cancer Registry Database. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of asthma, COPD, and TB and to estimate the risk of specific types of lung cancer., Results: During the study period, 32,759 cases of lung cancer were identified from 15,219,024 insurants aged 20 years and older. In men and women, the adjusted HR estimates of squamous cell carcinoma were respectively 1.37 (95 % confidence interval [CI], 1.21-1.54) and 2.10 (95 % CI, 1.36-3.23) for TB, 1.52 (95 % CI, 1.42-1.64) and 1.50 (95 % CI, 1.21-1.85) for asthma, and 1.66 (95 % CI, 1.56-1.76) and 1.44 (95 % CI, 1.19-1.74) for COPD. Similarly, the adjusted HR estimates of adenocarcinoma were respectively 1.33 (95 % CI, 1.19-1.50) and 1.86 (95 % CI, 1.57-2.19) for TB, 1.13 (95 % CI, 1.05-1.21) and 1.18 (95 % CI, 1.09-1.28) for asthma, and 1.50 (95 % CI, 1.42-1.59) and 1.33 (95 % CI, 1.25-1.42) for COPD. The HRs of small cell carcinoma were respectively 1.24 (95 % CI, 1.01-1.52) and 2.23 (95 % CI, 1.17-4.25) for TB, 1.51 (95 % CI, 1.35-1.69) and 1.63 (95 % CI, 1.16-2.27) for asthma, and 1.39 (95 % CI, 1.26-1.53) and 1.78 (95 % CI, 1.33-2.39) for COPD., Conclusions: Asthma, COPD, and TB were associated with an increased risk of all major subtypes of lung cancer. The risk was the highest among women with TB.

Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of (65)ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm (65)ZnO NPs and zinc nitrate ((65)Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of (65)ZnO NPs were greater than those of (65)Zn(NO3)2, particularly the lung partition coefficient of 10 nm (65)ZnO NPs. Sensitivity analysis revealed that 71 nm (65)ZnO NPs and (65)Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for (65)ZnO NPs and (65)Zn(NO3)2. The simulation of (65)Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of (65)ZnO NPs with those of (65)Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to (65)ZnO NPs <10 nm because those small (65)ZnO NPs tend to accumulate in the body for a relatively longer time than 71 nm (65)ZnO NPs and (65)Zn(NO3)2 do.

Recent studies suggest that actin filaments are essential in how a cell controls its nuclear shape. However, little is known about the relative importance of membrane tension in determining nuclear morphology. In this study, we used adhesive micropatterned substrates to alter the cellular geometry (aspect ratio, size, and shape) that allowed direct membrane tension or without membrane lateral contact with the nucleus and investigate nuclear shape remodeling and orientation on a series of rectangular shapes. Here we showed that at low cell aspect ratios the orientation of the nucleus was regulated by actin filaments while cells with high aspect ratios can maintain nuclear shape and orientation even when actin polymerization was blocked. A model adenocarcinoma cell showed similar behavior in the regulation of nuclear shape in response to changes in cell shape but actin filaments were essential in maintaining cell shape. Our results highlight the two distinct mechanisms to regulate nuclear shape through cell shape control and the difference between fibroblasts and a model cancerous cell in cell adhesion and cell shape control., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Unlabelled: Poultry exposure is a major risk factor for human H7N9 zoonotic infections, for which the mode of transmission remains unclear. We studied the transmission of genetically related poultry and human H7N9 influenza viruses differing by four amino acids, including the host determinant PB2 residue 627. A/Silkie chicken/HK/1772/2014 (SCk1772) and A/HK/3263/14 (HK3263) replicated to comparable titers in chickens, with superior oropharyngeal over cloacal shedding; both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Interspecies transmission via the airborne route was observed for ferrets exposed to the SCk1772- or HK3263-infected chickens, while low numbers of copies of influenza viral genome were detected in the air, predominantly at particle sizes larger than 4 μm. In ferrets, the human isolate HK3263 replicated to higher titers and transmitted more efficiently via direct contact than SCk1772. We monitored "intrahost" and "interhost" adaptive changes at PB2 residue 627 during infection and transmission of the Sck1772 that carried E627 and HK3263 that carried V/K/E polymorphism at 60%, 20%, and 20%, respectively. For SCk1772, positive selection for K627 over E627 was observed in ferrets during the chicken-to-ferret or ferret-to-ferret transmission. For HK3263 that contained V/K/E polymorphism, mixed V627 and E627 genotypes were transmitted among chickens while either V627 or K627 was transmitted to ferrets with a narrow transmission bottleneck. Overall, our results suggest direct contact as the main mode for H7N9 transmission and identify the PB2-V627 genotype with uncompromised fitness and transmissibility in both avian and mammalian species., Importance: We studied the modes of H7N9 transmission, as this information is crucial for developing effective control measures for prevention. Using chicken (SCk1772) and human (HK3263) H7N9 isolates that differed by four amino acids, including the host determinant PB2 residue 627, we observed that both viruses transmitted efficiently among chickens via direct contact but inefficiently via the airborne route. Chicken-to-ferret transmission via the airborne route was observed, along with the detection of viral genome in the air at low copy numbers. In ferrets, HK3263 transmitted more efficiently than SCk1772 via direct contact. During the transmission of SCk1772 that contained E and HK3263 that contained V/K/E polymorphism at PB2 residue 627, positive selections of E627 and K627 were observed in chickens and ferrets, respectively. In addition, PB2-V627 was transmitted and stably maintained in both avian and mammalian species. Our results support applying intervention strategies that minimize direct and indirect contact at the poultry markets during epidemics., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Macrophages in a tumor microenvironment have been characterized as M1- and M2-polarized subtypes. Here, we discovered the different macrophages' impacts on lung cancer cell A549. The M2a/M2c subtypes promoted A549 invasion and xenograft tumor growth. The M1 subtype suppressed angiogenesis. M1 enhanced the sensitivity of A549 to cisplatin and decreased the tube formation activity and cell viability of A549 cells by inducing apoptosis and senescence. Different macrophage subtypes regulated genes involved in the immune response, cytoskeletal remodeling, coagulation, cell adhesion, and apoptosis pathways in A549 cells, which was a pattern that correlated with the altered behaviors of the A549 cells. Furthermore, we found that the identified M1/M2 gene signatures were significantly correlated with the extended overall survival of lung cancer patients. These results suggest that M1/M2 gene expression signature may be used as a prognostic indicator for lung cancer patients, and M1/M2 polarization may be a target of investigation of immune-modulating therapies for lung cancer in the future.

Diabetes impairs copper (Cu) regulation, causing elevated serum Cu and urinary Cu excretion in patients with established cardiovascular disease; it also causes cardiomyopathy and chronic cardiac impairment linked to defective Cu homeostasis in rats. However, the mechanisms that link impaired Cu regulation to cardiac dysfunction in diabetes are incompletely understood. Chronic treatment with triethylenetetramine (TETA), a Cu²⁺-selective chelator, improves cardiac function in diabetic patients, and in rats with heart disease; the latter displayed ∼3-fold elevations in free Cu²⁺ in the coronary effluent when TETA was infused into their coronary arteries. To further study the nature of defective cardiac Cu regulation in diabetes, we employed an isolated-perfused, working-heart model in which we infused micromolar doses of Cu²⁺ into the coronary arteries and measured acute effects on cardiac function in diabetic and non-diabetic-control rats. Infusion of CuCl₂ solutions caused acute dose-dependent cardiac dysfunction in normal hearts. Several measures of baseline cardiac function were impaired in diabetic hearts, and these defects were exacerbated by low-micromolar Cu²⁺ infusion. The response to infused Cu²⁺ was augmented in diabetic hearts, which became defective at lower infusion levels and underwent complete pump failure (cardiac output = 0 ml/min) more often (P < 0.0001) at concentrations that only moderately impaired function of control hearts. To our knowledge, this is the first report describing the acute effects on cardiac function of pathophysiological elevations in coronary Cu²⁺. The effects of Cu²⁺ infusion occur within minutes in both control and diabetic hearts, which suggests that they are not due to remodelling. Heightened sensitivity to the acute effects of small elevations in Cu²⁺ could contribute substantively to impaired cardiac function in patients with diabetes and is thus identified as a new mechanism of heart disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Few studies have investigated the relationship between sleep disorders (SD) and erectile dysfunction (ED). Therefore, this study explored whether patients with SD in an Asian population are at an increased risk of developing ED., Methods: This longitudinal nationwide population-based cohort study investigated the incidence and risk of developing ED in 34,548 men newly diagnosed with SD between 2002 and 2008 from the National Health Insurance Research Database. A total of 138,192 controls without SD were randomly recruited from the general population and frequency matched according to age and sex. The follow-up period began from the date of entering the study cohort until the date of an ED event, censoring, or 31 December 2010. We conducted Cox proportional hazard regression analyses to estimate the effects of SD on the risk of ED., Results: The SD cohort had a 2.11-fold adjusted hazard ratio (HR) of subsequent ED development compared with the non-SD cohort [95% confidence interval (CI) = 1.89-2.37]. The incidence of ED increased with age for both cohorts and was higher for the patients in the SD cohort. Compared with the participants without SD or comorbidities, the patients without SD with any comorbidity exhibited a 1.79-fold risk of developing ED (95% CI = 1.54-2.09); the highest risk was for those with both SD and any comorbidity (HR = 3.34, 95% CI = 2.82-3.95). Furthermore, SD patients who had a particular number of comorbidities showed the dose-response effect of developing ED., Conclusion: This nationwide cohort study determined that ED risk evidently increased in SD patients compared with the general population., (© 2015 John Wiley & Sons Ltd.)

Background: Pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB)] are associated with lung cancer mortality. However, the relationship between coexisting pulmonary diseases and survival in patients with lung squamous cell carcinoma (SqCC) has not been well defined., Methods: Patients newly diagnosed with SqCC between 2003 and 2008 were identified by linking the National Health Insurance Research Database and Taiwan Cancer Registry Database. Cases with SqCC were followed up until death, loss to follow-up, or study end in 2010. Information on health status, date of death and the main causes of death was ascertained from the National Death Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB., Results: During the study period, a total of 5406 cases with SqCC were enrolled. For all cause-mortality, HRs were 1.08 [95% confidence interval (CI), 0.99-1.18], 1.04 (95% CI, 0.97-1.12), and 1.14 (95% CI, 1.00-1.31) for individuals with asthma, COPD, and TB, respectively. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.56 (95% CI, 1.23-1.97) and 1.11 (95% CI, 1.00-1.24) for individuals with asthma+COPD+TB and asthma+COPD, respectively. Among male patients with stage III SqCC, HRs were 3.41 (95%CI, 1.27-9.17) and 1.65 (95%CI, 1.10-2.47) for individuals with asthma+TB and asthma+COPD+TB, respectively. Among male patients with stage IV SqCC, HRs were 1.40 (95%CI, 1.00-1.97) and 1.25 (95%CI, 1.03-1.52) for individuals with asthma+ COPD+TB and asthma. Among female patients with stage I and II, HR was 0.19 (95%CI, 005-0.77) for individuals with asthma., Conclusions: Coexisting pulmonary diseases increased the risk of mortality from SqCC in male patients. For female patients with early stage SqCC, pre-existing asthma decreased mortality. These patients deserve greater attention while undergoing cancer treatment.

In response to external stimuli, cells polarize morphologically into teardrop shapes prior to moving in the direction of their blunt leading edge through lamellipodia extension and retraction of the rear tip. This textbook description of cell migration implies that the initial polarization sets the direction of cell migration. Using microfabrication techniques to control cell morphologies and the direction of migration without gradients, we demonstrate that after polarization, lamelipodia extension and attachment can feedback to change and even reverse the initial morphological polarization. Cells do indeed migrate faster in the direction of their morphologically polarization. However, feedback from subsequent lamellipodia extension and attachment can be so powerful as to induce cells to reverse and migrate against their initial polarization, albeit at a slower speed. Constitutively active mutants of RhoA show that RhoA stimulates cell motility when cells are guided either along or against their initial polarization. Cdc42 activation and inhibition, which results in loss of directional motility during chemotaxis, only reduces the speed of migration without altering the directionality of migration on the micropatterns. These results reveal significant differences between substrate directed cell migration and that induced by chemotactic gradients.

A facile approach is reported to process rod-coil block copolymers (BCPs) into highly ordered nanostructures in a rapid, low-energy process. By introducing a selective plasticizer into the rod-coil BCPs during annealing, both the annealing temperature and time to achieve thermodynamic equilibrium and highly ordered structures can be decreased. This process improvement is attributed to enhanced chain mobility, reduced rod-rod interaction, and decreased rod-coil interaction from the additive. The novel method is based on kinetically facilitating thermodynamic equilibrium. The process requires no modification of polymer structure, indicating that a wide variety of desired polymer functionalities can be designed into BCPs for specific applications., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Lasioseius phytoseioides species group was first characterised over 50 years ago. Two species of this group, Lasioseius chaudhrii (Wu & Wang) and Lasioseius parberlesei Bhattacharyya, have been considered potentially effective as biological control agents of pest mites of the family Tarsonemidae on rice (Oryza sativa L.) in Asia. A new characterisation of the species group is presented, taking into account a new species here described, Lasioseius piracicabensis Moraes & Pérez-Madruga n. sp., as well as other species mostly described since the first characterisation of the group. The main characteristics of the included species are the reduced number of dorsal idiosomal setae, including the absence of j1 and z1; antiaxial surface of fixed cheliceral digit with a subterminal pointed process; and males with broad lateral expansion of the peritrematic shield in the region between coxae II-III, bearing a pore and a lyrifissure. Complementary notes are presented for Lasioseius annandalei Bhattacharyya & Bhattacharyya, Lasioseius chaudhrii (Wu & Wang), Lasioseius parberlesei Bhattacharyya, L. phytoseioides Chant, Lasioseius punjabensis Bhattacharyya & Sanyal, Lasioseius terrestris Menon & Ghai and Lasioseius youcefi Athias-Henriot. New synonymies are proposed and possible misidentifications in the literature are discussed. A dichotomous key is presented to help the identification of the species of the group, and the distribution of the species is summarised.

This work both numerically and experimentally investigates the reflectance from the smooth side of a semi-transparent 508-µm-thick window with metallic gratings attached on the other side. The incident light is oblique and linearly polarized, and its wavelength ranges from 2.5 to 25 µm. Three gratings with various levels of profile complexity and periods are investigated. Influences from the intrinsic material absorption, light refraction, total internal reflection, interference, and diffraction on both the specular and hemispherical reflectance are studied. Moreover, the applicability of effective medium theory to our samples is verified.

Sepsis-related mortality has been found increased in RAG-1 knockout mice. However, in patients admitted to medical intensive care units, it is unknown whether severe lymphocyte depletion at admission is associated with increased interleukin (IL)-7 and IL-15 levels in circulation, and increased mortality. We prospectively enrolled 92 patients who were admitted to medical intensive care units for severe sepsis or septic shock. At admission, 24 patients (26.1%) had severe lymphopenia, defined as lymphocyte counts of less than 0.5 × 10(3)/μL. Severe lymphopenia was associated with significantly higher plasma levels of tumor necrosis factor α, IL-6, IL-8, and IL-10 and was also independently associated with 28-day mortality (adjusted hazard ratio, 3.532; 95% confidence interval, 1.482-8.416; P = 0.004). The levels of plasma IL-15, but not IL-7, were increased modestly in patients with severe lymphopenia compared with those without (median, 12.2 vs. 6.4 pg/mL; P = 0.005). The elevated plasma IL-15 levels were contrarily associated with significantly decreased B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells. In conclusion, severe lymphopenia was associated with increased mortality in patients with severe sepsis. We found that patients with sepsis with severe lymphopenia had down-regulated B-cell lymphoma 2 mRNA expression in peripheral blood mononuclear cells, despite increased plasma IL-15 concentrations. Whether IL-7 and IL-15 are insufficient in patients with severe lymphopenia during severe sepsis warrants further investigations.

Melioidosis is an emerging, potentially fatal disease caused by Burkholderia pseudomallei, which requires prolonged antibiotic treatment to prevent disease relapse. However, difficulties in laboratory diagnosis of melioidosis may delay treatment and affect disease outcomes. Isolation of B. pseudomallei from clinical specimens has been improved with the use of selective media. However, even with positive cultures, identification of B. pseudomallei can be difficult in clinical microbiology laboratories, especially in non-endemic areas where clinical suspicion is low. Commercial identification systems may fail to distinguish between B. pseudomallei and closely related species such as Burkholderia thailandensis. Genotypic identification of suspected isolates can be achieved by sequencing of gene targets such as groEL which offer higher discriminative power than 16S rRNA. Specific PCR-based identification of B. pseudomallei has also been developed using B. pseudomallei-specific gene targets such as Type III secretion system and Tat-domain protein. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, a revolutionary technique for pathogen identification, has been shown to be potentially useful for rapid identification of B. pseudomallei, although existing databases require optimization by adding reference spectra for B. pseudomallei. Despite these advances in bacterial identification, diagnostic problems encountered in culture-negative cases remain largely unresolved. Although various serological tests have been developed, they are generally unstandardized "in house" assays and have low sensitivities and specificities. Although specific PCR assays have been applied to direct clinical and environmental specimens, the sensitivities for diagnosis remain to be evaluated. Metabolomics is an uprising tool for studying infectious diseases and may offer a novel approach for exploring potential diagnostic biomarkers. The metabolomics profiles of B. pseudomallei culture supernatants can be potentially distinguished from those of related bacterial species including B. thailandensis . Further studies using bacterial cultures and direct patient samples are required to evaluate the potential of metabolomics for improving diagnosis of melioidosis., (© 2015 by the Society for Experimental Biology and Medicine.)

CD47 is a cell surface protein that transmits an anti-phagocytic signal, known as the "don't-eat-me" signal, to macrophages upon engaging its receptor signal regulatory protein α (SIRPα). Molecules that antagonize the CD47-SIRPα interaction by binding to CD47, such as anti-CD47 antibodies and the engineered SIRPα variant CV1, have been shown to facilitate macrophage-mediated anti-tumor responses. However, these strategies targeting CD47 are handicapped by large antigen sinks in vivo and indiscriminate cell binding due to ubiquitous expression of CD47. These factors reduce bioavailability and increase the risk of toxicity. Here, we present an alternative strategy to antagonize the CD47-SIRPα pathway by engineering high affinity CD47 variants that target SIRPα, which has restricted tissue expression. CD47 proved to be refractive to conventional affinity maturation techniques targeting its binding interface with SIRPα. Therefore, we developed a novel engineering approach, whereby we augmented the existing contact interface via N-terminal peptide extension, coined "Velcro" engineering. The high affinity variant (Velcro-CD47) bound to the two most prominent human SIRPα alleles with greatly increased affinity relative to wild-type CD47 and potently antagonized CD47 binding to SIRPα on human macrophages. Velcro-CD47 synergizes with tumor-specific monoclonal antibodies to enhance macrophage phagocytosis of tumor cells in vitro, with similar potency as CV1. Finally, Velcro-CD47 interacts specifically with a subset of myeloid-derived cells in human blood, whereas CV1 binds all myeloid, lymphoid, and erythroid populations interrogated. This is consistent with the restricted expression of SIRPα compared with CD47. Herein, we have demonstrated that "Velcro" engineering is a powerful protein-engineering tool with potential applications to other systems and that Velcro-CD47 could be an alternative adjuvant to CD47-targeting agents for cancer immunotherapy., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Idiopathic pulmonary fibrosis is a chronic pulmonary disease that is characterized by formation of scar tissue in lungs. Transforming growth factor-β (TGF-β) is considered an important cytokine in the pathogenesis of this disease. Hence, the antifibrotic effect of an inhibitor of the TGF-β type I receptor, namely, SB 431542, was investigated in our study. SB 431542 was used to treat TGF-β-treated IMR-90 cells; the expression of α-smooth muscle actin (α-SMA) was detected at the protein level by using an anti-α-SMA antibody, and at the gene level by reverse transcription-quantitative PCR. The effect of the inhibitor on cell proliferation was determined by a cell growth assay. The inhibitor was also administered into bleomycin-treated mice. Histopathological assessment and determination of total collagen levels were carried out to evaluate the severity of lung fibrosis in these mice. Our results demonstrated that treatment with SB 431542 inhibits TGF-β‑induced α-SMA expression in lung fibroblasts, at both the protein and the mRNA levels (P<0.05). However, the inhibitor did not significantly reduce lung fibroblast proliferation. In the bleomycin-induced pulmonary fibrosis mouse model, bleomycin treatment caused important morphological changes, accompanied by an increase in the collagen level of the lungs. Early treatment with SB 431542 prevented the manifestation of histopathological alterations, whereas delayed treatment significantly decreased the collagen level (P<0.05). These results suggest that inhibition of TGF-β signaling, via inhibition of the activin receptor-like kinase-5 (ALK-5) by SB 431542, may attenuate pulmonary fibrosis.

Purpose: Clinical care has become increasingly dependent on computerized physician order entry (CPOE) systems. No study has reported the adverse effect of CPOE on physicians' ability to handwrite prescriptions. This study took advantage of an extensive crash of the CPOE system at a large hospital to assess the completeness, legibility, and accuracy of physicians' handwritten prescriptions., Methods: The CPOE system had operated at the outpatient department of an academic medical center in Taiwan since 1993. During an unintentional shutdown that lasted 3.5 hours in 2010, physicians were forced to write prescriptions manually. These handwritten prescriptions, together with clinical medical records, were later audited by clinical pharmacists with respect to 16 fields of the patient's, prescriber's, and drug data., Findings: A total of 1418 prescriptions with 3805 drug items were handwritten by 114 to 1369 patients. Not a single prescription had all necessary fields filled in. Although the field of age was most frequently omitted (1282 [90.4%] of 1418 prescriptions) among the patient's data, the field of dosage form was most frequently omitted (3480 [91.5%] of 3805 items) among the drug data. In contrast, the scale of illegibility was rather small. The highest percentage reached only 1.5% (n = 57) in the field of drug frequency. Inaccuracies of strength, dose, and drug name were observed in 745 (19.6%), 517 (13.6%), and 435 (11.4%) prescribed drug items, respectively., Implications: The unintentional shutdown of a long-running CPOE system revealed that physicians fail to handwrite flawless prescriptions in the digital era. The contingency plans for computer disasters at health care facilities might include preparation of stand-alone e-prescribing software so that the service delay could be kept to the minimum. However, guidance on prescribing should remain an essential part of medical education., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

In the past two decades, microfluidics has become of great value in precisely aligning cells or microparticles within fluids. Microfluidic techniques use either external forces or sheath flow to focus particulate samples, and face the challenges of complex instrumentation design and limited throughput. The burgeoning field of inertial microfluidics brings single-position focusing functionality at throughput orders of magnitude higher than previously available. However, most inertial microfluidic focusers rely on cross-sectional flow-induced drag force to achieve single-position focusing, which inevitably complicates the device design and operation. In this work, we present an inertial microfluidic focuser that uses inertial lift force as the only driving force to focus microparticles into a single position. We demonstrate single-position focusing of different sized microbeads and cells with 95-100% efficiency, without the need for secondary flow, sheath flow or external forces. We further integrate this device with a laser counting system to form a sheathless flow cytometer, and demonstrated counting of microbeads with 2200 beads s(-1) throughput and 7% coefficient of variation. Cells can be completely recovered and remain viable after passing our integrated cytometry system. Our approach offers a number of benefits, including simplicity in fundamental principle and geometry, convenience in design, modification and integration, flexibility in focusing of different samples, high compatibility with real-world cellular samples as well as high-precision and high-throughput single-position focusing.

Poor bonding between bone tissue and noble titanium (Ti) surfaces is one of the major problems that should be resolved. Given that SiO 2 is a documented differentiation promoter and polydopamine (PDA) is an adhesive molecule, it is worthwhile to investigate the synergetic performance of novel silica/polydopamine (SiO 2 /PDA) hybrid coatings on Ti substrates. The physicochemical properties of PDA, 2SiPDA, 10SiPDA, and 20SiPDA coatings including the microstructure, bond strength and corrosion resistance, and in vitro antibacterial activity against P. aeruginosa and S. aureus were examined. In addition, the osteogenesis level of MG63 human osteoblast-like cells on the coatings was detected. The experimental results indicated that the precipitated SiO 2 particles were within the PDA layer with sub-micro-scale thickness. The hybrid coating (20SiPDA) containing an appropriate amount of SiO 2 did not adversely affect shear bond strength compared with the Ti control and pure PDA coating. The SiO 2 /PDA coatings could effectively enhance the corrosion resistant ability of Ti implants. The 20SiPDA coatings elicited higher mortality rates of bacterial strains compared with the Ti control and pure PDA coating. More importantly, the incorporation of SiO 2 in the PDA coating layer could improve adhesion, proliferation, differentiation, and mineralization of MG63 osteoblasts. The new SiO 2 /PDA coating may be suitable for serving as a decorated layer to improve osteogenesis of Ti implants.

The multi-soil-layering (MSL) system primarily comprises two parts, specifically, the soil mixture layer (SML) and the permeable layer (PL). In Japan, zeolite is typically used as the permeable layer material. In the present study, zeolite was substituted with comparatively cheaper and more environmentally friendly materials, such as expanded clay aggregates, oyster shells, and already-used granular activated carbon collected from water purification plants. A series of indoor tests indicated that the suspended solid (SS) removal efficiency of granular activated carbon was between 76.2% and 94.6%; zeolite and expanded clay aggregates achieved similar efficiencies that were between 53.7% and 87.4%, and oyster shells presented the lowest efficiency that was between 29.8% and 61.8%. Further results show that the oyster shell system required an increase of wastewater retention time by 2 to 4 times that of the zeolite system to maintain similar chemical oxygen demand (COD) removal efficiency. Among the four MSL samples, the zeolite system and granular activated carbon system demonstrated a stable NH3-N removal performance at 92.3%-99.8%. The expanded clay aggregate system present lower removal performance because of its low adsorption capacity and excessively large pores, causing NO3--N to be leached away under high hydraulic loading rate conditions. The total phosphorous (TP) removal efficiency of the MSL systems demonstrated no direct correlation with the permeable layer material. Therefore, all MSL samples achieved a TP efficiency of between 92.1% and 99.2%.

Background: It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations., Methods: This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2)., Results: From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age., Conclusion: This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.

Objective: The present study assessed the effects of vegetarian and omnivorous diets on HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), TAG and the ratio of HDL-C to total cholesterol (TC) by gender., Design: HDL-C, LDL-C, TAG and HDL-C:TC were compared among three diet groups (vegan, ovo-lacto vegetarian and omnivorous). Multivariate linear regression analysis was performed to examine factors significantly and independently associated with vegetarian status and to estimate the β value of lipid profiles for the diet groups. Settings A cross-sectional study. Data were obtained from the Taiwanese Survey on the Prevalence of Hyperglycemia, Hyperlipidemia and Hypertension (TwSHHH)., Subjects: The study comprised included 3257 men and 3551 women., Results: After adjusting for confounders, vegan and ovo-lacto vegetarian diets lowered LDL-C levels (β=-10.98, P=0.005 and β=-7.12, P=0.025, respectively) in men compared with omnivorous diet. There was a significant association between HDL-C and vegan diet (β=-6.53, P=0.004). In females, the β values of HDL-C, TAG and HDL-C:TC were -5.72 (P<0.0001), 16.51 (P=0.011) and -0.02 (P=0.012) for vegan diet, and -4.86 (P=0.002), 15.09 (P=0.008) and -0.01 (P=0.026) for ovo-lacto vegetarian diet, when compared with omnivorous diet., Conclusions: Vegan diet was associated with lower HDL-C concentrations in both males and females. Because the ovo-lacto vegetarian diet was effective in lowering LDL-C, it may be more appropriate for males.

Surface properties play a critical role in influencing cell responses to a biomaterial. The objectives of this study were (1) to characterize changes in surface properties of zirconia (ZrO₂) ceramic after oxygen plasma treatment; and (2) to determine the effect of such changes on biological responses of human osteoblast-like cells (MG63). The results indicated that the surface morphology was not changed by oxygen plasma treatment. In contrast, oxygen plasma treatment to ZrO₂ not only resulted in an increase in hydrophilicity, but also it retained surface hydrophilicity after 5-min treatment time. More importantly, surface properties of ZrO₂ modified by oxygen plasma treatment were beneficial for cell growth, whereas the surface roughness of the materials did not have a significant efficacy. It is concluded that oxygen plasma treatment was certified to be effective in modifying the surface state of ZrO₂ and has the potential in the creation and maintenance of hydrophilic surfaces and the enhancement of cell proliferation and differentiation.

Inhalation of zinc oxide nanoparticles (ZnONP) has potential health impact. Because zinc ion may involve in the toxicity of ZnONP, we compared adverse effects of inhaled aerosolized ZnONP and zinc nitrate in mice. Aerosolized ZnONP and zinc nitrate were well-dispersed in the inhalation chamber. Inhalation of 0.86 mg/m(3) ZnONP or 1.98 mg/m(3) zinc nitrate for 5 h caused acute inflammation mainly at bronchioloalveolar junctions of lungs at 24-h post-exposure. Inhalation of ZnONP or zinc nitrate increased metallothionein expression in the epithelial cells of brochioloalveolar junction. While the effects on cytokines secretion in bronchoalveolar lavage were similar between ZnONP and zinc nitrate, only ZnONP increased lactate dehydrogenase activity. However, repeated exposure to 0.86 mg/m(3) ZnONP 5 h/day for 5 days failed to cause a similar adverse effect. Either single or repeated exposure to 0.86 mg/m(3) ZnONP increased activities of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and creatine phosphokinase in blood. In contrast, exposure to zinc nitrate had no similar systemic effects. In human bronchial epithelial cells, ZnONP-induced interleukin-8 secretion was partially prevented by co-treatment with the Toll-like receptor 4 (TLR4) inhibitor. Furthermore, ZnONP-induced pulmonary inflammation was greater in wild-type mice than in TLR4-deficent mice. It appears that ZnONP-induced acute pulmonary inflammation partially depended on TLR4. In summary, we demonstrated the dose-responsive effects for inhalation of ZnONP and zinc nitrate in mice. The threshold of cytokines induction for inhalation of ZnONP for 5 h was 0.43 mg/m(3). The particulate characters of ZnONP might contribute to the systemic adverse effects and shall be evaluated for assessing its health impact in humans.

We present an approach to fabricate a continuous and crystalline rubrene film using the melt-recrystallization process with the assistance of a silicon nanopillar template. Better film morphology, enhanced crystallinity, and mainly oriented crystallites with the c-axis of the orthorhombic rubrene aligning parallel to the nanopillars were obtained as compared to that on a planar substrate. The oriented crystal growth is further modulated by the surface modification. It is suggested that the sidewalls of nanopillars play a key role in mediating the switch of crystal orientation and crystal growth. The obtained nanopillar-templated rubrene film was used to fabricate a vertical field-effect transistor. The device gave a current density of 78 mA cm(-2), on-off ratio around 10(3-4), subthreshold swing of 89.1 mV per decade and transconductance of 154.9 mS cm(-2) on an ODTS-modified substrate surface.

Using the Serial Analysis of Gene Expression (SAGE) database from the Cancer Genome Anatomy Project, we identified heparin co-factor II (HCII), which is over-expressed in non-small cell lung cancer (NSCLC). Here, we investigated the clinical significance of HCII and provided molecular evidence to support the suggestion that HCII could enhance cancer metastasis in NSCLC. We found that high HCII expression in tumour tissue was associated with increased cancer recurrence and shorter overall survival times in 75 clinically operable NSCLC patients. High pretreatment plasma concentration of HCII was associated with reduced overall survival in 57 consecutive NSCLC patients. We over-expressed and knocked down HCII expression in lung cancer cell lines and confirmed that HCII could promote cell motility, invasion ability and filopodium dynamics in NSCLC cells in vitro and increased metastatic colonization in an in vivo mouse model. Exogenous treatment of HCII promoted cancer cell migration, and this promigratory effect of HCII was independent of thrombin. We further showed that HCII could up-regulate cancer cell migration through the activation of PI3K, which acts upstream of Rac1 and Cdc42, and this effect could be blocked by heparin. We suggest that HCII is a novel metastasis enhancer and may be used as a prognostic predictor for heparin treatment in NSCLC., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The association between tuberculosis (TB) and lung cancer is well known. However, carcinogenesis of TB and its connection with epidermal growth factor receptor (EGFR) mutation remains unclear. This study aimed to determine this connection to see if TB can affect the outcome of patients with lung cancer. This is a retrospective cohort study of patients with lung cancer receiving EGFR-tyrosine kinase inhibitors (TKIs) between 1996 and 2010 using the National Health Insurance Research Database of Taiwan. Because therapeutic response was required to apply EGFR-TKIs for >90 days, only patients with a follow-up of >120 days were studied and a responder was defined as intake of EGFR-TKIs >90 days. Predictors of EGFR-TKI response and survival were identified using logistic and Cox regression analyses, respectively. There were 8265 patients analyzed, including 6073 (73.5%) EGFR-TKI responder and 2192 (26.5%) nonresponder. A history of TB was found in 1.2% and 1.8% of the 2 groups, respectively. Comparing to male with pulmonary TB history, female with or without pulmonary TB history and male without pulmonary TB history all had a better EGFR-TKI response and 1-year progression-free survival (PFS). Gender and TB history were not independent prognostic factors of 2-year overall survival. The findings were similar in the subpopulation without chronic obstructive pulmonary disease, malignancies other than lung cancer, and low-income status. TB has a gender-dependent impact, with better EGFR-TKI response and 1-year PFS in female patients with lung cancer. The carcinogenesis and inflammation of TB may be different between genders.

Purpose: Urinary calculi is a familiar disease. A well-known complication of endourological treatment for impacted ureteral stones is the formation of ureteral strictures, which has been reported to occur in 14.2% to 24% of cases., Materials and Methods: This was a prospective study. Ureterotripsy treatment was used on patients with impacted ureteral stones. Then, after 3 months and 6 months, the condition of these patients was assessed by means of a kidney-ureter-bladder (KUB) ultrasound. If the KUB ultrasound indicated moderate to serious hydronephrosis, the patient was further assessed by means of a computed tomography intravenous urogram or retrograde pyelogram to confirm the occurrence of ureteral strictures., Results: Of the 77 patients who participated in the study, 5 developed ureteral strictures. Thus, the stricture rate was 7.8%. An analysis of the intraoperative risk factors including perforation of the ureter, damage to the mucous membrane, and residual stone impacted within the ureter mucosa revealed that none of these factors contributed significantly to the formation of the ureteric strictures. The stone-related risk factors that were taken into consideration were stone size, stone impaction site, and duration of impaction. These stone factors also did not contribute significantly to the formation of the ureteral strictures., Conclusions: This prospective study failed to identify any predictable factors for ureteral stricture formation. It is proposed that all patients undergo a simple postoperative KUB ultrasound screening 3 months after undergoing endoscopic treatment for impacted ureteral stones.

Objective: There is currently no documentation on the availability and implementation of policies related to men's health in Asia. This Delphi study aimed to achieve an Asian consensus on men's health policy based on the opinions and recommendations from men's health key opinion leaders., Study Design: A two-phase Delphi online survey was used to gather information from men's health stakeholders across Asian countries., Methods: All stakeholders were invited to participate in the survey through men's health conferences, personal contacts, recommendations from international men's health organizations and snowballing method. Stakeholders were asked about their concerns on 17 men's health key issues as well as their opinion on the availability and recommendations on men's health policies and programmes in their countries., Results: There were a total of 128 stakeholders (policy makers, clinicians, researchers and consumers), from 28 Asian countries, who responded in the survey. Up to 85% of stakeholders were concerned about various men's health issues in Asia and in their respective country, particularly in smoking, ischaemic heart disease and high blood pressure. There is a lack of men's health policies and programmes in Asia (availability = 11.6-43.5%) and up to 92.9% of stakeholders recommended that these should be developed., Conclusions: These findings call for policy change and development, and more importantly a concerted effort to elevate men's health status in Asia., (Copyright © 2014 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common pulmonary diseases associated with lung cancer. Besides, smoking is more prevalent in Taiwanese men. This study evaluated gender disparities in coexisting pulmonary diseases on survival of patients with lung adenocarcinoma. Patients newly diagnosed with lung cancer between 2003 and 2008 were identified from Taiwan National Health Insurance Research Database. Cases with lung adenocarcinoma were further confirmed using the Cancer Registry Database and followed up until the end of 2010. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD, and/or TB to estimate all-cause mortality risk. During the study period, 13,399 cases of lung adenocarcinoma were identified. The HRs of adenocarcinoma in men and women were 1.20 (95% confidence interval [CI], 1.10-1.30) and 1.05 (95% CI, 0.95-1.16), respectively, for individuals with asthma, 1.32 (95% CI, 1.16-1.51) and 0.97 (95% CI, 0.89-1.05), respectively, for COPD, and 0.99 (95% CI, 0.93-1.06) and 1.06 (95% CI, 0.86-1.32), respectively, for individuals with TB. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.63 (95% CI, 1.25-2.13), 1.31 (95% CI, 1.08-1.59), and 1.23 (95% CI, 1.11-1.36) for individuals with asthma + COPD + TB, asthma + COPD, and COPD + TB, respectively. However, there was no increase risk of mortality among women with coexisting pulmonary diseases. Coexisting pulmonary diseases are at an elevated risk of mortality among male patients with lung adenocarcinoma. Such patients deserve greater attention while undergoing cancer treatment.

Background: Prescribing inappropriate pill splitting is not rare in clinical practice. To reduce inappropriate pill splitting, we developed an automatic warning system linked to a computerized physician order entry (CPOE) system for special oral formulation drugs in outpatient settings. We examined the impact of the warning system on inappropriate prescribing of pill splitting and assess prescribers' responses to the warnings., Methods: Drugs with extended-release or enteric-coated formulations that were not originally intended to be split were recognized as "special oral formulations". A hard-stop system which could examine non-integer doses of drugs with special oral formulations, provide warnings to interrupt inappropriate prescriptions was integrated in CPOE in a medical center since June 2010. We designed an intervention study to compare the inappropriate splitting before and after the implementation of the warning system (baseline period 2010 January to May vs. intervention period 2010 June to 2011 August). During the intervention period, prescription changes in response to a warning were logged and analyzed., Results: A total of 470,611 prescribed drug items with 34 different drugs with special oral formulations were prescribed in the study period. During the 15-month intervention period, 909 warnings for 26 different drugs were triggered among 354,523 prescribed drug items with special oral formulations. The warning rate of inappropriate splitting in the late intervention period was lower than those in baseline period (0.16% vs. 0.61%, incidence rate ratio 0.27, 95% CI 0.23-0.31, P<0.001). In respond to warnings, physicians had to make adjustments, of which the majority was changing to an unsplit pill (72.9%)., Conclusions: The interruptive warning system could avoid the prescriptions with inappropriate pill splitting. Accordingly, physicians changed their behavior of prescribing special oral formulations regarding inappropriate pill splitting. We suggest the establishment of such system to target special oral formulations with warnings to prevent inappropriate pill splitting.

Effects of pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and lung tuberculosis (TB)] on subsequent lung cancer development have been reported. However, whether patients with coexisting pulmonary diseases are at greater risk of developing various histologic types of lung cancer remains elusive. Patients newly diagnosed with lung cancer between 2004 and 2008 were identified from National Health Insurance Research Database (Taiwan). The histologic types of lung cancer were further confirmed using Taiwan Cancer Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB to estimate lung cancer risk by histologic type. During the study period, 32,759 cases of lung cancer were identified from 15,219,024 residents age 20 years and older, who were free from the disease before 2003. Coexisting pulmonary diseases showed stronger association with lung cancer than specific lung disorders. Specifically, among men, the HRs for squamous cell carcinoma (SqCC) were 3.98 (95% CI, 3.22-4.93), 2.68 (95% CI, 2.45-2.93), and 2.57 (95% CI, 2.10-3.13) for individuals with asthma+COPD+TB, asthma+COPD, and COPD+TB, respectively. Among women, the HRs for SqCC were 3.64 (95% CI, 1.88-7.05), 3.35 (95% CI, 1.59-7.07), and 2.21 (95% CI, 1.66-2.94) for individuals with TB, COPD+TB, and asthma+COPD, respectively. Adenocarcinoma HRs for men and women were 2.00 (95% CI, 1.54-2.60) and 2.82 (95% CI, 1.97-4.04) for individuals with asthma+COPD+TB, 2.28 (95% CI, 1.91-2.73) and 2.16 (95% CI, 1.57-2.95) for COPD+TB, and 1.76 (95% CI, 1.04-2.97) and 2.04 (95% CI, 1.02-4.09) for individuals with asthma+TB. Specifically, small cell carcinoma (SmCC) HRs among men were 3.65 (95% CI, 1.97-6.80), 2.20 (95% CI, 1.45-3.36), and 2.14 (95% CI, 1.86-2.47) for those with asthma+TB, asthma+COPD+TB, and asthma+ COPD, respectively. Among women, the HRs of SmCC were 8.97 (95% CI, 3.31-24.28), 3.94 (95% CI, 1.25-12.35) and 3.33 (95% CI, 2.23-4.97) for those with asthma+COPD+TB, COPD+TB, and asthma+COPD, respectively. Patients with coexistence of pulmonary diseases were more susceptible to lung cancer. Affected persons deserve greater attention while undergoing cancer screening.

Purpose: The proposed Men's Health Index (MHI) aims to provide a practical and systematic framework for comprehensively assessing and stratifying older men with the intention of optimising their health and functional status., Materials and Methods: A literature search was conducted using PubMed from 1980 to 2012. We specifically looked for instruments which: assess men's health, frailty and fitness; predict life expectancy, mortality and morbidities. The instruments were assessed by the researchers who then agreed on the tools to be included in the MHI. When there was disagreements, the researchers discussed and reached a consensus guided by the principle that the MHI could be used in the primary care setting targetting men aged 55-65 years., Results: The instruments chosen include the Charlson's Combined Comorbidity-Age Index; the International Index of Erectile Function-5; the International Prostate Symptom Score; the Androgen Deficiency in Aging Male; the Survey of Health, Ageing and Retirement in Europe Frailty Instrument; the Sitting-Rising Test; the Senior Fitness Test; the Fitness Assessment Score; and the Depression Anxiety Stress Scale-21. A pilot test on eight men was carried out and showed that the men's health index is viable., Conclusions: The concept of assessing, stratifying, and optimizing men's health should be incorporated into routine health care, and this can be implemented by using the MHI. This index is particularly useful to primary care physicians who are in a strategic position to engage men at the peri-retirement age in a conversation about their life goals based on their current and predicted health status.

To investigate the effects of ellagic acid on the growth inhibition of TSGH8301 human bladder cancer cells in vitro, cells were incubated with various doses of ellagic acid for different time periods. The phase-contrast microscope was used for examining and photographing the morphological changes in TSGH8301 cells. Flow cytometric assay was used to measure the percentage of viable cells, cell cycle distribution, apoptotic cells, ROS, mitochondrial membrane potential (ΔΨm), Ca(2+) , caspase-9 and -3 activities in TSGH8301 cells after exposure to ellagic acid. Western blotting was used to examine the changes of cell cycle and apoptosis associated proteins levels. Results indicated that ellagic acid induced morphological changes, decreased the percentage of viable cells through the induction of G0/G1 phase arrest and apoptosis, and also showed that ellagic acid promoted ROS and Ca(2+) productions and decreased the level of ΔΨm and promoted activities of caspase-9 and -3. The induction of apoptosis also confirmed by annexin V staining, comet assay, DAPI staining and DNA gel electrophoresis showed that ellagic acid induced apoptosis and DNA damage in TSGH8301 cells. Western blotting assay showed that ellagic acid promoted p21, p53 and decreased CDC2 and WEE1 for leading to G0/G1 phase arrest and promoting BAD expression, AIF and Endo G, cytochrome c, caspase-9 and -3 for leading to apoptosis in TSGH8301 cells. On the basis of these observations, we suggest that ellagic acid induced cytotoxic effects for causing a decrease in the percentage of viable cells via G0/G1 phase arrest and induction of apoptosis in TSGH8301 cells., (Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.)

Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20-25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants.

Objectives: This study aims to compare health status and its risk factors between men and women who are from countries of different income status in Asia., Method: We have included 47 Asian countries and 2 regions in this study. Life expectancy, mortality rate from communicable disease, non-communicable disease and injuries, the prevalence of non-communicable diseases risk factors and their trends were extracted from the WHO and respective governmental database. Subgroup analysis was performed based on country income groups., Results: Overall, men have shorter life expectancy and higher mortality rates compared to women. Men from higher-income countries lived longer compared to men from lower-income countries. There is a wide variation of male life expectancy in upper and lower middle income countries. The mean systolic blood pressure, fasting blood glucose and body mass index in Asia have also increased over the years., Conclusion: This study confirms that Asian men have poorer health compared to women besides the growing concerns on NCD risk factors. The findings from this study calls for a concerted effort to find solutions in addressing men's health problems in Asia., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mussel-inspired polydopamine (PDA) has emerged as a promising molecule used for anchoring synthetic and biological substances or forming an adhesive layer onto various substrates for biomedical and nanotechnology applications because of its outstanding properties. This review article provides an overview of the recent progress in the PDA-based materials, including synthesis of nanoparticles, capsules, structure-mechanism, physicochemical and biological properties, and medical applications. Frist, to understand how PDA nanoparticles, capsules and films produce the unique properties is insight on the processing parameters. Next, we highlight what is known regarding the mechanism of self-polymerization and the structure features of dopamine (DA), which is based on the formation of covalent bond or through a combination mode between monomers. The inherent hydrophilicity and adhesive property of PDA with the coexistence of catechol and amine functionalities provide desirable surface characteristics without the need for further modification. Finally, successful applications, such as grafting substances, biomineralization, antifouling and antibacterial coatings, drug/gene delivery, and tissue engineering, reported to date involving PDA will be focused. The future study of PDA to develop novel materials with unique properties is emerging for specific nanomedicine applications.

Melioidosis, caused by Burkholderia pseudomallei, is an emerging infectious disease with an expanding geographical distribution. Although assessment of the environmental load of B. pseudomallei is important for risk assessment in humans or animals in endemic areas, traditional methods of bacterial culture for isolation have low sensitivities and are labor-intensive. Using a specific polymerase chain reaction (PCR) assay targeting a Tat domain protein in comparison with a bacterial culture method, we examined the prevalence of B. pseudomallei in soil samples from an oceanarium in Hong Kong where captive marine mammals and birds have contracted melioidosis. Among 1420 soil samples collected from various sites in the oceanarium over a 15-month period, B. pseudomallei was detected in nine (0.6%) soil samples using bacterial culture, whereas it was detected in 96 (6.8%) soil samples using the specific PCR assay confirmed by sequencing. The PCR-positive samples were detected during various months, with higher detection rates observed during summer months. Positive PCR detection was significantly correlated with ambient temperature (P<0.0001) and relative humidity (P=0.011) but not with daily rainfall (P=0.241) or a recent typhoon (P=0.787). PCR-positive samples were obtained from all sampling locations, with the highest detection rate in the valley. Our results suggest that B. pseudomallei is prevalent and endemic in the oceanarium. The present PCR assay is more sensitive than the bacterial culture method, and it may be used to help better assess the transmission of melioidosis and to design infection control measures for captive animals in this unique and understudied environment.

Introduction: Germline Bcl-2-like protein 11 (BIM) deletion polymorphism in Asian is a poor predictive factor for treatment outcomes to tyrosine kinase inhibitors (TKIs) in malignancies. We explored the impact of BIM deletion polymorphism on treatment outcome of advanced non-small-cell lung cancer (NSCLC)., Methods: We prospectively collected tissue samples, blood, and clinical data from two cohorts of advanced NSCLC patients. BIM deletion polymorphism was correlated with overall survival (OS) and progression-free survival (PFS) to epidermal growth factor receptor (EGFR) TKIs and chemotherapy treatment., Results: BIM deletion polymorphism was detected in blood of 16.2% (33 of 204) patients. The PFS to first-line EGFR-TKIs in 153 patients were 8.6 and 4.6 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.004). Among 120 patients who received chemotherapies, the PFS to chemotherapies were 5.6 and 3.5 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.050). The OS of all 204 patients was 24.8 and 16.8 months for patients with wild-type BIM and BIM deletion polymorphism, respectively (p = 0.005). Multivariate analyses suggested that BIM deletion polymorphism was an independent predictor for shorter PFS to EGFR-TKIs (hazard ratio [HR] 2.15, p = 0.002), PFS to chemotherapy (HR 2.40, p = 0.016), and OS (HR 1.65, p = 0.039)., Conclusions: BIM deletion polymorphism predicts shorter PFS to EGFR-TKIs and OS in advanced NSCLC.

We report a patient with non-small cell lung cancer (NSCLC) developed leptomeningeal carcinomatosis (LMC) after 4 years of multiple treatments. High-dose tyrosine kinase inhibitor (TKI) was given for LMC at first but was not effective. She then received dual therapy combining of afatinib and cetuximab. Brain magnetic resonance imaging (MRI) showed a partial response of disease and the patient experienced a clinical benefit. Our case suggests that dual targeting of epidermal growth factor receptor (EGFR) by a combination of afatinib and cetuximab can be a potential novel treatment option in treating LMC when high-dose TKI failed., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)