DNA dosimeter measurements of beam profile using a novel simultaneous processing technique.

A DNA dosimeter (DNAd) was previously developed that uses double-strand breaks (DSB) to measure dose. This dosimeter has been tested to measure dose in scenarios where transient-charged particle equilibrium (TCPE) has been established. The probability of double strand break (PDSBo), which is the ratio of broken double-stranded DNA (dsDNA) to the initial unbroken dsDNA in the dosimeter, was used to quantify DSBs and related to dose. The goal of this work is to produce a new technique to process and analyze the DNAd and quantify DNA-DSBs. This technique included simultaneously processing multiple DNAds and also establishing a new form to the probability of double strand break (PDSBn), which was then used to test the DNAd in a non-TCPE condition by taking beam penumbra measurements. The technique utilized a 384-well plate, and the measurements were made at the edge of a 10 × 10 cm field and compared to film measurements. During these penumbra measurements, while observing the positional differences in the higher gradient region at 4.1 and 4.55 cm from the center of the radiation field, the distance to agreement of PDSBo to film were 0.38 cm and 0.26 cm while the distance to agreement of PDSBn to film were 0.11 cm and 0.06 cm, respectively. Finally, the developed new separation technique reduced the time needed for the analysis of 25 samples from 200 min to 30 min.

Optimizing the response, precision, and cost of a DNA double-strand break dosimeter.

We developed a dosimeter that measures biological damage following delivery of therapeutic beams in the form of double-strand breaks (DSBs) to DNA. The dosimeter contains DNA strands that are labeled on one end with biotin and on the other with fluorescein and attached to magnetic microbeads. Following irradiation, a magnet is used to separate broken from unbroken DNA strands. Then, fluorescence is utilized to measure the relative amount of broken DNA and determine the probability for DSB. The long-term goal for this research is to evaluate whether this type of biologically based dosimeter holds any advantages over the conventional techniques. The purpose of this work was to optimize the dosimeter fabrication and usage to enable higher precision for the long-term research goal. More specifically, the goal was to optimize the DNA dosimeter using three metrics: the response, precision, and cost per dosimeter. Six aspects of the dosimeter fabrication and usage were varied and evaluated for their effect on the metrics: (1) the type of magnetic microbeads, (2) the microbead to DNA mass ratio at attachment, (3) the type of suspension buffer used during irradiation, (4) the concentration of the DNA dosimeter during irradiation, (5) the time waited between fabrication and irradiation of the dosimeter, and (6) the time waited between irradiation and read out of the response. In brief, the best results were achieved with the dosimeter when attaching 4.2 µg of DNA with 1 mg of MyOne T1 microbeads and by suspending the microbead-connected DNA strands with 200 µl of phosphate-buffered saline for irradiation. Also, better results were achieved when waiting a day after fabrication before irradiating the dosimeter and also waiting an hour after irradiation to measure the response. This manuscript is meant to serve as guide for others who would like to replicate this DNA dose measurement technique.

Direct thermo-optical tuning of silicon microresonators for the mid-infrared.

We use light from a visible laser diode to directly tune silicon-on-chip microresonators by thermo-optical effect. We show that this direct tuning is local, non invasive and has a much smaller time constant than global temperature tuning methods. Such an approach could prove to be highly effective for Kerr comb generation in microresonators pumped by quantum cascade lasers, which cannot be easily tuned to achieve comb generation and soliton-mode locked states.

Facet joint injection versus epidural steroid injection for lumbar spinal stenosis: intra-individual study.

AIM: To evaluate the efficacy of facet joint injection (FJI) for patients with lumbar central canal stenosis (LCS) in comparison with epidural steroid injection (ESI) in the same individuals. MATERIAL AND METHODS: Two hundred and fifty-two patients who underwent both FJI and ESI for LCS between January 2014 and December 2014 were considered for enrolment in the study. A radiologist retrospectively conducted a chart review and recorded which injection was chosen as the third injection after sequential injections of FJI and ESI, and why clinicians chose the particular injection method. The response was measured via the use of a five-point satisfaction scale. RESULTS: Among 252 patients, only 73 patients were included in the study (the remaining patients did not fulfil the inclusion criteria). Out of 73 patients (mean age, 69.7 years; range, 49∼87 years), 50 patients had received a third injection, 33 patients (66%) underwent FJIs as a third injection. Out of 19 patients who had experienced an ineffective first ESI, 13 (68.4%) patients reported the second FJI as effective. Out of six patients for whom the first FJI had been ineffective, three (50%) patients reported the second ESI as effective. CONCLUSION: FJIs can be administered as an alternative to ESIs in cases of LCS.

Isomerization of the osmium-tellurium cluster Os3(µ-TeR)2(CO)10: a kinetic and computational study.

The kinetics for the isomerization of the 50e cluster Os3(µ-TeTol-p)2(CO)10 (), where the tellurides bridge two different Os-Os edges, to one in which the tellurides bridge the same open OsOs edge () have been measured experimentally by (1)H NMR spectroscopy. The determined activation parameters are ΔH(‡) = 77 ± 9 kJ mol(-1) and ΔS(‡) = -12 ± 28 J mol(-1) K. The conversion of to has been computationally investigated by electronic structure calculations using the model compound Os3(µ-TeMe)2(CO)10. The computed isomerization pathway is consistent with the kinetic data and the thermodynamic preference for the product stereoisomer that possesses a slipped, eclipsed conformation for the two p-tolyl groups.

Accuracy of Xpert(®) MTB/RIF assay compared with AdvanSure™ TB/NTM real-time PCR using bronchoscopy specimens.

BACKGROUND: The performance of Xpert(®) MTB/RIF assay, an automated nucleic acid amplification test (NAAT) that was developed for the detection of tuberculosis (TB), has been evaluated in various clinical settings. However, few studies have compared Xpert with other NAATs, especially its performance using lower respiratory tract specimens (LRTS). OBJECTIVE: To compare the practical diagnostic performance of the Xpert assay with that of the AdvanSure™ TB/NTM RT-PCR kit in the detection of pulmonary TB (PTB), using LRTS obtained through bronchoscopy. RESULTS: Of 249 patients included, 105 had culture-confirmed PTB. Using culture as reference, the overall sensitivity of Xpert and AdvanSure was respectively 92.4% and 83.8%. When acid-fast bacilli smear results were taken into consideration, the sensitivity of Xpert for smear-positive and smear-negative LRTS was respectively 100% and 88.9%, while that of the AdvanSure was 100% and 76.4%. Xpert showed better results than AdvanSure in terms of sensitivity in smear-negative LRTS (P = 0.012), but no difference in smear-positive LRTS. CONCLUSIONS: Xpert may be advantageous in the detection of PTB using LRTS, particularly in low microbiological burden settings.

Changes in lung function according to disease extent before and after pulmonary tuberculosis.

OBJECTIVE: To evaluate changes in lung function in individuals before and after treatment for pulmonary tuberculosis (PTB) in relation to extent of disease. DESIGN: Using a retrospective cohort design, changes in and predictors of lung function were evaluated. RESULTS: A total of 41 patients were included in the final analysis. The median decline in annualised forced expiratory volume in 1 sec (FEV1) was 180.0 ml/year (95%CI 118.9-356.1) in advanced PTB and 94.7 ml/year (95%CI 33.4-147.3) in localised PTB (ΔFEV1% predicted/year 9.4%, 95%CI 4.4-14.0 vs. 3.8%, 95%CI 1.8-6.2). The median decline in annualised forced vital capacity (FVC) was 309.6 ml/year (95%CI 137.0-359.0) in advanced PTB and 101.1 ml/year (95%CI 30.3-219.6) in localised PTB (ΔFVC % predicted/year 7.3%, 95%CI 5.3-12.3 vs. 2.9%, 95%CI 0.9-6.5). CONCLUSIONS: As the sample size of our study was small, the conclusions could be biased. Nevertheless, our findings show that PTB causes a significant decline in lung function even in localised PTB, whereas advanced PTB was associated with excessive or even higher decline. This study suggests that early diagnosis and treatment of PTB is needed to preserve lung function.

Influence of Incorporated Pt-Fe2O3 Core-Shell Nanoparticles on the Resistive Switching Characteristics of ZnO Thin Film.

The resistance-switching characteristics of metal oxides have attracted great interest for the non-volatile memory applications such as resistive random access memory. A basic resistive random access memory device has a metal/insulator/metal structure, and its memory effect is achieved by applying voltage to change the resistance of the insulating layer. One of the promising candidates for explaining the resistance-switching mechanism is the formation and rupture of nanoscale conductive filaments. However, this model has an issue that needs to be addressed: the wide distribution of switching voltage due to randomly formed filaments. Therefore, some researchers have reported a decrease in switching voltage distribution and an increase in switching stability by incorporating nanoparticles into the insulating layer. In this study, we investigated influence of incorporated Pt-Fe2O3 core-shell nanoparticles on the resistive switching characteristics of ZnO thin films. Devices were fabricated on SiO2 wafers. A 100-nm-thick Cr layer was used as the bottom electrode. A 50-nm-thick ZnO layer was deposited using the sputtering method, and Pt-Fe2O3 nanoparticles were deposited on it by the dip coating method. A 50-nm-thick ZnO layer was then deposited again. A top Cr electrode (size: 100 µm x 100 µm) was deposited using a shadow mask and sputtering system. All the devices showed bipolar resistance-switching behavior that is observed in Cr/ZnO/Cr structures. However, the on/off voltage was dramatically lowered by incorporating nanoparticles into the insulating layer when compared with that of the devices without nanoparticles. In addition, the switching stability of the devices was improved upon the incorporation of nanoparticles. On the basis of these results, we can conclude that Pt-Fe2O3 nanoparticles may be used to enhance the resistance switching properties of ZnO thin films by incorporating them into the films.

Glycated albumin produced in diabetic hyperglycemia promotes monocyte secretion of inflammatory cytokines and bacterial adherence to epithelial cells.

BACKGROUND AND OBJECTIVE: The prevalence and severity of periodontal disease increase in patients with insulin-deficient or insulin-resistant forms of diabetes. A common characteristic of diabetes is the presence of hyperglycemia. A critical consequence of hyperglycemia is the nonenzymatic glycation and oxidation of proteins and lipids, resulting in the irreversible formation of advanced glycation end-products (AGEs). A central means by which AGEs are believed to impart their pathogenic effects is via interacting with specific cellular receptors; the best-characterized of these is receptor for AGE (RAGE). The major consequences of the AGE-RAGE interaction are the generation of enhanced cellular oxidant stress, hypersecretion of inflammatory mediators and altered subgingival flora. The aim of this study was to elucidate the influence of glycated albumin (G-alb), with or without lipopolysaccharide (LPS) isolated from periodontal pathogens, on the secretion of inflammatory cytokines by cultured monocytic cells and also to investigate the role of G-alb in adherence of bacteria to epithelial cells. MATERIAL AND METHODS: Activated THP-1 cells (1 × 10(6) cells) were incubated for 24 h with G-alb or normal albumin (N-alb), with or without LPS isolated from two periodontal pathogens. Supernatant fluids were collected and assayed for the cytokines interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by ELISA. For bacterial adhesion assays, S-G epithelial cells were grown on cover slips and incubated with G-alb (10 µg/mL) or N-alb (control) for 30 min. The cover slips were rinsed and then incubated with bacteria for 2 h. The number of adherent bacteria was determined by counting 20 epithelial cells chosen randomly under a light microscope. RESULTS: The secretion of IL-1ß, TNF-α and IL-6 by THP-1 cells was greater in the presence of G-alb than in the presence of N-alb. The amounts of cytokines secreted were even greater when THP-1 cells were incubated with G-alb and LPS of periodontal pathogens. The effect of G-alb and LPS was reduced when RAGE was blocked by its antibody. Coating the cultured epithelial cells with G-alb resulted in increased bacterial adherence. CONCLUSION: This study demonstrated the role of G-alb in stimulating cultured monocytic cells to secrete inflammatory cytokines. The stimulation was found to be greater when cells were incubated with LPS in addition to G-alb. The over-expression of inflammatory cytokines as a result of the combined effects of G-alb and bacterial LPS may contribute to the severity of periodontal disease in diabetic subjects.

S-1 plus irinotecan and oxaliplatin for the first-line treatment of patients with metastatic colorectal cancer: a prospective phase II study and pharmacogenetic analysis.

BACKGROUND: S-1 is an oral fluoropyrimidine that mimics infusional 5-fluorouracil. The aim of this phase II trial was to explore the clinical efficacy of the triplet regimen TIROX, which consists of S-1, irinotecan and oxaliplatin. METHODS: Forty-two chemo-naive patients with metastatic colorectal cancer (mCRC) were planned to be enrolled and be treated with irinotecan 150 mg m(-2) followed by oxaliplatin 85 mg m(-2) on day 1 and S-1 80 mg m(-2) per day from day 1 to 14 every 3 weeks. Polymorphisms in the UGT1A1, UGT1A6, UGT1A7 and CYP2A6 genes were analysed. RESULTS: Between July 2007 and February 2008, 43 patients were enrolled. An objective response was noted in 29 patients (67.4%, 95% confidence interval: 53.4-81.4), of which 2 achieved durable complete responses. The median progression-free survival was 10.0 months and the median overall survival was 19.2 months. Significant grade 3 or 4 adverse events were neutropenia (45.2%), febrile neutropenia (9.5%), diarrhoea (7.1%) and vomiting (9.5%). Increased gastrointestinal toxicities were associated with the presence of UGT1A6*2 or UGT1A7*3 and an improved tumour response was noted in those without variant alleles of CYP2A6 or UGT1A1*60. CONCLUSION: The combination of S-1, irinotecan and oxaliplatin showed favourable efficacy and tolerability in untreated patients with mCRC.

Pharmacokinetics and bioequivalence evaluation of leflunomide tablets in Korean healthy volunteers.

Leflunomide is a disease-modifying antirheumatic drug. The purpose of this study was to evaluate the bioequivalence of a test drug (CJ leflunomide) and a commercially available reference drug (Arava®) at 2 doses (10 and 20 mg) in healthy Korean volunteers. This was a single-dose (28 individuals enrolled at each dose group), randomized, open-label, 2-way crossover study. The 2 treatment periods were separated by a 56-day wash-out interval. Blood sampling was conducted until 672 h after drug administration. Plasma teriflunomide (active metabolite of leflunomide) concentrations were determined, and pharmacokinetic parameters were calculated. Bioequivalence was evaluated using an ANOVA model, based on the AUCt and the Cmax after administration of leflunomide tablets. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUCt and Cmax for the test and reference drugs being within the range of 0.80-1.25. The GMRs (90% CI) for AUCt and Cmax were 0.9506 (0.9091-0.9941) and 0.9861 (0.9360-1.0389), respectively, in the 10 mg study, and 0.9524 (0.9101-0.9968) and 0.9740 (0.9314-1.0186), respectively, in the 20 mg study. The 90% CIs of AUCt and Cmax at each dose were within the accepted range for bioequivalence. Based on the results, the test drug (CJ leflunomide) was bioequivalent to the commercially available reference drug (Arava®) at both doses.

Systemic modelling of human bioenergetics and blood circulation.

This work reviews the main aspects of human bioenergetics and the dynamics of the cardiovascular system, with emphasis on modelling their physiological characteristics. The methods used to study human bioenergetics and circulation dynamics, including the use of mathematical models, are summarised. The main characteristics of human bioenergetics, including mitochondrial metabolism and global energy balance, are first described, and the systemic aspects of blood circulation and related physiological issues are introduced. The authors also discuss the present status of studies of human bioenergetics and blood circulation. Then, the limitations of the existing studies are described in an effort to identify directions for future research towards integrated and comprehensive modelling. This review emphasises that a multi-scale and multi-physical approach to bioenergetics and blood circulation that considers multiple scales and physiological factors are necessary for the appropriate clinical application of computational models.

The role of high-mobility group box-1 (HMGB1) in the pathogenesis of asthma.

BACKGROUND: High-mobility group box 1 protein (HMGB1) belonging to endogenous danger signals prolongs eosinophil survival and acts as a chemoattractant. OBJECTIVE: The authors evaluated the role of HMGB1 in the pathogenesis of asthma characterized by eosinophilic airway inflammation. METHODS: Firstly, HMGB1 expressions in induced sputum obtained from human asthmatics were determined. This was followed by an evaluation of the role of HMGB1 in a murine model of asthma using anti-HMGB1 antibodies. Then the effect of HMGB1 on the receptor of advanced glycation end products (RAGE) expressions on CD11b-CD11c(+) cells isolated from a murine model of asthma were measured to elucidate the mechanisms involved. RESULTS: Sputum HMGB1 expressions were markedly higher in asthmatics than in normal controls, and were positively correlated with sputum eosinophilia and sputum TNF-α, IL-5 and IL-13 expressions. In a murine model of asthma, HMGB1 expressions in lung tissue and HMGB1 levels in bronchoalveolar lavage fluid were significantly elevated and eosinophilic airway inflammation, non-specific airway hyperresponsiveness, and pathological changes were attenuated by blocking HMGB1 activity. Furthermore, we found that enhanced RAGE expressions on CD11b-CD11c(+) also significantly decreased when HMGB1 activity was blocked. CONCLUSION AND CLINICAL RELEVANCE: Our findings suggest that HMGB1 plays a key role in the pathogenesis of clinical and experimental asthma characterized by eosinophilic airway inflammation.

New index for categorising cardiac reentrant wave: in silico evaluation.

Based on the similarity between a reentrant wave in cardiac tissue and a vortex in fluid dynamics, the authors hypothesised that a new non-dimensional index, like the Reynolds number in fluid dynamics, may play a critical role in categorising reentrant wave dynamics. Therefore the goal of the present study is to devise a new index to characterise electric wave conduction in cardiac tissue and examined whether this index can be used as a biomarker for categorising the reentrant wave pattern in cardiac tissue. Similar to the procedure used to derive the Reynolds number in fluid dynamics, the authors used a non-dimensionalisation technique to obtain the new index. Its usefulness was verified using a two-dimensional simulation model of electrical wave propagation in cardiac tissue. The simulation results showed that electrical waves in cardiac tissue move into an unstable region when the index exceeds a threshold value.

Anxiety, helplessness/hopelessness and 'desire for hastened death' in Korean cancer patients.

Despite a relatively high rate of suicide associated with cancer, this issue has not been explored in Korean patients. This study investigates the prevalence and factors related to 'the desire for hastened death' (DHD) in Korean cancer patients. A cross-sectional survey using standardised measures, including the Schedule of Attitudes toward Hastened Death and the Hospital Anxiety and Depression Scale, was performed with 131 patients with different types of cancer. 13.7% of the participants experienced moderate DHD (Schedule of Attitudes toward Hastened Death scores 5-9) and 1.7% experienced high DHD (≥10). Socio-demographic and disease-associated factors of the DHD included age, overall health and shortness of breath. The majority of psychosocial variables such as sadness, distress, 'helplessness/hopelessness' and 'anxious preoccupation' had a moderate association with DHD. Patients with a clinically significant level of anxiety or depression reported higher levels of DHD. Other significant correlates included 'meaning/peace', a sense of burdening family, dignity impairment and suicidal thoughts after diagnosis. Helplessness/hopelessness and anxiety were the strongest predictors of DHD in multivariate analysis. In view of significant role of helplessness/hopelessness and anxiety in the DHD of cancer patients, careful monitoring and management of these factors should be an integral part of cancer care to reduce the occurrence of DHD.

Cartilage oligomeric matrix protein-angiopoientin-1 enhances angiogenesis of isolated islet and maintains normoglycemia following transplantation.

Islet transplantation (ITx) has potential as a therapy for patients with type 1 diabetes. For successful engraftment and insulin independence, the transplanted islets must establish an adequate, stable blood supply. Angiopoientin-1 (Ang1) is a specific growth factor that induces vascularization via the Tie2 or Tie1 receptor. In this study, we used an in vitro angiogenesis assay to evaluate islet function following transplantation and the effect of the Ang1 variant cartilage oligomeric matrix protein (COMP) Ang1 on isolated islets. The enhanced function of islets transduced with COMP-Ang1 was also confirmed in a streptozotocin (STZ)-induced diabetic mice model. In a three-dimensional collagen-based culture system, the transduction of COMP-Ang1 into islets significantly increased angiogenesis compared with the bacterial-ß-galactosidase (LacZ)-transduced controls and an intact, nontransduced islet negative control group. COMP-Ang1 transduced islets also attenuated hyperglycemia in syngeneic diabetic C57BL/6 mice and enhanced glucose tolerance by areas under the curves of intraperitoneal glucose tolerance tests. These findings demonstrated the capacity of COMP-Ang1 to promote revascularization in cultured islets, which may contribute to successful transplantation in vivo.

Genetic variants of the organic cation transporter 2 influence the disposition of metformin.

Genetic variants of the organic cation transporter 2 (protein, OCT2; gene, SLC22A2) were evaluated for their contribution to the variations in the pharmacokinetics of metformin, especially to its renal elimination. Genetic variants of SLC22A2 (c.596C>T, c.602C>T, and c.808G>T) showed significant differences in metformin pharmacokinetics when compared with the reference genotype, with higher peak plasma concentration (C(max)) and area under the curve (AUC) and lower renal clearance (Cl(renal)), thereby suggesting that a decrease in transport function associated with the SLC22A2 variants results in reduced Cl(renal) of metformin and consequently leads to increased plasma concentrations.