E-cigarettes and smoking cessation: evidence from a systematic review and meta-analysis.
E-cigarettes are currently being debated regarding their possible role in smoking cessation and as they are becoming increasingly popular, the research to date requires investigation. To investigate whether the use of e-cigarettes is associated with smoking cessation or reduction, and whether there is any difference in efficacy of e-cigarettes with and without nicotine on smoking cessation. A systematic review of articles with no limit on publication date was conducted by searching PubMed, Web of Knowledge and Scopus databases. Published studies, those reported smoking abstinence or reduction in cigarette consumption after the use of e-cigarettes, were included. Studies were systematically reviewed, and meta-analyses were conducted using Mantel-Haenszel fixed-effect and random-effects models. Degree of heterogeneity among studies and quality of the selected studies were evaluated. Six studies were included involving 7,551 participants. Meta-analyses included 1,242 participants who had complete data on smoking cessation. Nicotine filled e-cigarettes were more effective for cessation than those without nicotine (pooled Risk Ratio 2.29, 95%CI 1.05-4.97). Amongst 1,242 smokers, 224 (18%) reported smoking cessation after using nicotine-enriched e-cigarettes for a minimum period of six months. Use of such e-cigarettes was positively associated with smoking cessation with a pooled Effect Size of 0.20 (95%CI 0.11-0.28). Use of e-cigarettes was also associated with a reduction in the number of cigarettes used. Included studies were heterogeneous, due to different study designs and gender variation. Whilst we were able to comment on the efficacy of nicotine vs. non-nicotine e-cigarettes for smoking cessation, we were unable to comment on the efficacy of e-cigarettes vs. other interventions for cessation, given the lack of comparator groups in the studies included in this meta-analysis. Use of e-cigarettes is associated with smoking cessation and reduction. More randomised controlled trials are needed to assess effectiveness against other cessation methods.


Exploring the Cause of Diarrhoea and Poor Growth in 8-11-Week-Old Pigs from an Australian Pig Herd Using Metagenomic Sequencing.
Diarrhoea and poor growth among growing pigs is responsible for significant economic losses in pig herds globally and can have a wide range of possible aetiologies. Next generation sequencing (NGS) technologies are useful for the detection and characterisation of diverse groups of viruses and bacteria and can thereby provide a better understanding of complex interactions among microorganisms potentially causing clinical disease. Here, we used a metagenomics approach to identify and characterise the possible pathogens in colon and lung samples from pigs with diarrhoea and poor growth in an Australian pig herd. We identified and characterized a wide diversity of porcine viruses including RNA viruses, in particular several picornaviruses-porcine sapelovirus (PSV), enterovirus G (EV-G), and porcine teschovirus (PTV), and a porcine astrovirus (PAstV). Single stranded DNA viruses were also detected and included parvoviruses like porcine bocavirus (PBoV) and porcine parvovirus 2 (PPV2), porcine parvovirus 7 (PPV7), porcine bufa virus (PBuV), and porcine adeno-associated virus (AAV). We also detected single stranded circular DNA viruses such as porcine circovirus type 2 (PCV2) at very low abundance and torque teno sus viruses (TTSuVk2a and TTSuVk2b). Some of the viruses detected here may have had an evolutionary past including recombination events, which may be of importance and potential involvement in clinical disease in the pigs. In addition, our metagenomics data found evidence of the presence of the bacteria Lawsonia intracellularis, Brachyspira spp., and Campylobacter spp. that may, together with these viruses, have contributed to the development of clinical disease and poor growth.


Is it possible to predict which patients with mild pneumonias will develop hypoxemia?
Usually, mortality due to mild community-acquired pneumonias (CAP) (Pneumonia severity index (PSI) classes I-III) is low (<3%), but the appearance of hypoxemia significantly increases mortality. Our aim was to determine the clinical parameters associated with risk factors of developing hypoxemia in subjects with mild CAP (PSI I-III) and the clinical outcomes of the hypoxemic group. We analyzed clinical characteristics and the outcomes of patients with mild CAP and hypoxemia (PaO2/FiO2<300), in a prospective, multicenter cohort study of 1195 patients. Mild pneumonias (PSI I-III) were found in 645 cases (53.9%), of which 217 (33.6%) presented hypoxemia according to a PaO2/FiO2<300. Patients with PaO2/FiO2<300 required more ICU admissions, mechanical ventilation, and developed septic shock than other PSI I-III patients. The clinical parameters associated with hypoxemia were: COPD, bilateral chest X-ray involvement, and hypoalbuminemia. We conclude that patients with COPD, those with bilateral chest X-ray involvement, or hypoalbuminemia were significantly more likely to have hypoxemia in mild CAP. Hypoxemic patients with low-risk pneumonia have worse clinical outcomes, including more ICU admission, need for mechanical ventilation and presence of septic shock than non-hypoxemic low-risk patients.


Biodegradable pH-responsive hydrogels for controlled dual-drug release.
Dual-drug loaded pH-responsive hydrogels were prepared as a delivery system carrying, as exemplars, both anti-cancer and anti-bacterial agents for pH controlled drug release. The hydrogels were composed of poly(l-lactide)-co-polyethyleneglycol-co-poly(l-lactide) dimethacrylates (with various molecular weights of l-lactide oligomers) as a macromolecular crosslinker and copolymerized with acrylic acid and N-isopropylacrylamide. The biodegradability, biocompatibility and mechanical properties of the hydrogels were characterized with the hydrogels being nontoxic to cells, while showing a reversible >80% reduction in volume at pH 1.2 compared to pH 7.4. Drug release profiles showed differential release of tetracycline over doxorubicin at pH 1.2, with both drugs being released equally at pH 7.4. Biodegradability was tunable by altering the crosslinking density and pH, with the total degradation of the best gels observed within 2 weeks at pH 7.4.


Alternative splicing-regulated protein of hepatitis B virus hacks the TNF-α-stimulated signaling pathways and limits the extent of liver inflammation.
Hepatitis B splicing-regulated protein (HBSP) of the hepatitis B virus (HBV) was uncovered a few years ago but its function remains unknown. HBSP expression occurs from a spliced viral transcript that increases during the course of liver disease. This study aimed at characterizing the impact of HBSP on cellular signaling pathways in vitro and on liver pathogenesis in transgenic (Tg) mice. By RT-qPCR array, NF-κB-inducible genes appeared modulated in HepG2 cells transduced with a HBSP-encoding lentivirus. Using luciferase and Western blot assays, we observed a decreased activation of the NF-κB pathway in HBSP-expressing cells following TNF-α treatment, as illustrated by lower levels of phosphorylated IκB-α. Meanwhile, the level of phosphorylated JNK increased together with the sensitivity to apoptosis. The contrasting effects on JNK and IκB-α activation upon TNF-α stimulation matched with a modulated maturation of TGF-β-activated kinase 1 (TAK1) kinase, assessed by 2-dimensional SDS-PAGE. Inhibition of the NF-κB pathway by HBSP was confirmed in the liver of HBSP Tg mice and associated with a significant decrease of chemically induced chronic liver inflammation, as assessed by immunohistochemistry. In conclusion, HBSP contributes to limit hepatic inflammation during chronic liver disease and may favor HBV persistence by evading immune response.


Carcinogen treatment in mouse selectively expressing activated N-Ras Q61K in melanocytes recapitulates metastatic cutaneous melanoma development.
The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.


A possible younger dryas record in southeastern alaska.
A stratigraphic record of climatic cooling equal in timing and severity to the Younger Dryas event of the North Atlantic region has been obtained from lacustrine sediments in the Glacier Bay area of southeastern Alaska. Fossil pollen show that a late Wisconsin pine parkland was replaced about 10,800 years ago by shrub- and herb-dominated tundra, which lasted until about 9,800 years ago. This vegetational change is matched by geochemical evidence for loss of organic matter from catchment soils and increased mineral erosion. If this event represents the Younger Dryas, then an explanation for a hemisphere-wide propagation of a North Atlantic climatic perturbation must be sought.


Effect of oxybenzone on PGE2-production in vitro and on plaque and gingivitis in vivo.
To study the effect of oxybenzone on prostaglandin E2 (PGE2) production in cell culture and to evaluate the effect of an oxybenzone-containing dentifrice on plaque and gingivitis in a 6-week clinical trial. Human embryo palatal mesenchyme (HEPM) cells were used for testing the inhibition of IL-1beta-stimulated PGE2-production in vitro by different concentrations of oxybenzone. For the in vivo study, a total of 66 individuals with a Quigley & Hein plaque index of at least 1.5 and an Ainamo & Bay gingival index of at least 0.2 were included in a double-blind clinical trial with two cells and a parallel design. Two compositions of fluoride dentifrice were used, one with the addition of 0.5% oxybenzone, and one without. Plaque and gingival index were obtained at three time points: (1) at baseline, (2) after 3 weeks, and (3) after 6 weeks. A dose-dependent inhibition of PGE2-production was found in the HEPM cell culture following oxybenzone exposure. In the clinical trial, a 25% reduction of gingival index was observed in the oxybenzone group (p<0.001) after 6 weeks as compared with 2% for the placebo group. These findings indicate that PGE2-production is reduced by oxybenzone in vitro and that the use of oxybenzone in a dentifrice reduces gingivitis in vivo.


High-performance photodetectors based on Sb2S3 nanowires: wavelength dependence and wide temperature range utilization.
Photodetectors which can work at both low and high temperatures are very important for the development of practical optoelectronic devices. Many studies have shown that low-dimensional semiconductors have more advantages in optoelectronic applications than their bulk forms. Here, we report the preparation of high-quality Sb2S3 nanowires (NWs) by a sulphur-assisted vapour transport method. The corresponding individual Sb2S3 NW based photodetectors exhibit good photoresponse in a wide spectral range from about 300 to 800 nm. The optimal photoresponse values are measured under the illumination of a 638 nm laser at room temperature: a high current ON/OFF ratio of about 210, a spectral responsivity of 1152 A W-1, a detectivity of 2 × 1013 Jones, and rise and fall times of about 37 ms, respectively. More importantly, the temperature dependence of the electrical conductivity of Sb2S3 shows three variation regions which can be attributed to the interaction between the carrier mobility and carrier concentration. The temperature dependence of the photoresponse of the photodetectors shows that they have good adaptability to temperature, and they worked very well at a wide temperature range from 8 to 420 K. Our results indicate that low-dimensional Sb2S3 crystals are promising candidates for new multifunctional optoelectronic devices.


Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in middle-aged healthy men.
We aimed to determine the relationship between carotid intima-media thickness (IMT) and brachial artery flow-mediated dilation (FMD) in healthy middle-age men. Carotid IMT and brachial artery FMD are frequently used as surrogate measures of subclinical atherosclerosis. Whereas carotid IMT identifies early structural abnormalities, brachial artery FMD, considered a bioassay of endothelial function, measures functional vascular integrity. The relationship between carotid IMT and brachial artery FMD has not been well studied. We measured traditional risk factors, carotid IMT, and brachial artery FMD in 1,578 middle-aged men without known cardiovascular disease and analyzed the relationship between carotid IMT and brachial FMD. Carotid IMT correlated with age, systolic blood pressure, body mass index, fasting glucose, total and low-density lipoprotein (LDL) cholesterol, and with the overall Framingham risk score (p < 0.001 for all), whereas impaired brachial artery FMD correlated with systolic and diastolic blood pressure (p < 0.01). No relationship was observed between carotid IMT and brachial artery FMD for the entire cohort (r = -0.006, p = 0.82) and in subgroups defined by traditional risk factors or by quintiles of carotid IMT and brachial FMD. In middle-aged healthy men, there is no significant correlation between carotid IMT and brachial artery FMD. This finding suggests that these are unique, independent surrogates that measure different aspects and stages of early atherosclerosis. Further studies are needed to define their role in clinical research and in cardiovascular risk assessment.


Preparation and characterization of ZnO microcantilever for nanoactuation.
Zinc oxide [ZnO] thin films are deposited using a radiofrequency magnetron sputtering method under room temperature. Its crystalline quality, surface morphology, and composition purity are characterized by X-ray diffraction [XRD], atomic force microscopy [AFM], field-emission scanning electron microscopy [FE-SEM], and energy-dispersive X-ray spectroscopy [EDS]. XRD pattern of the ZnO thin film shows that it has a high c-axis-preferring orientation, which is confirmed by a FE-SEM cross-sectional image of the film. The EDS analysis indicates that only Zn and O elements are contained in the ZnO film. The AFM image shows that the film's surface is very smooth and dense, and the surface roughness is 5.899 nm. The microcantilever (Au/Ti/ZnO/Au/Ti/SiO2/Si) based on the ZnO thin film is fabricated by micromachining techniques. The dynamic characterizations of the cantilever using a laser Doppler vibrometer show that the amplitude of the cantilever tip is linear with the driving voltage, and the amplitude of this microcantilever's tip increased from 2.1 to 13.6 nm when the driving voltage increased from 0.05 to 0.3 Vrms. The calculated transverse piezoelectric constant d31 of the ZnO thin film is -3.27 pC/N. This d31 is high compared with other published results. This ZnO thin film will be used in smart slider in hard disk drives to do nanoactuation in the future.


Feature selection from a facial image for distinction of sasang constitution.
Recently, oriental medicine has received attention for providing personalized medicine through consideration of the unique nature and constitution of individual patients. With the eventual goal of globalization, the current trend in oriental medicine research is the standardization by adopting western scientific methods, which could represent a scientific revolution. The purpose of this study is to establish methods for finding statistically significant features in a facial image with respect to distinguishing constitution and to show the meaning of those features. From facial photo images, facial elements are analyzed in terms of the distance, angle and the distance ratios, for which there are 1225, 61 250 and 749 700 features, respectively. Due to the very large number of facial features, it is quite difficult to determine truly meaningful features. We suggest a process for the efficient analysis of facial features including the removal of outliers, control for missing data to guarantee data confidence and calculation of statistical significance by applying ANOVA. We show the statistical properties of selected features according to different constitutions using the nine distances, 10 angles and 10 rates of distance features that are finally established. Additionally, the Sasang constitutional meaning of the selected features is shown here.


Cyclin-specific control of ribosomal DNA segregation.
Following chromosome duplication in S phase of the cell cycle, the sister chromatids are linked by cohesin. At the onset of anaphase, separase cleaves cohesin and thereby initiates sister chromatid separation. Separase activation results from the destruction of its inhibitor, securin, which is triggered by a ubiquitin ligase called the anaphase-promoting complex (APC). Here, we show in budding yeast that securin destruction and, thus, separase activation are not sufficient for the efficient segregation of the repetitive ribosomal DNA (rDNA). We find that rDNA segregation also requires the APC-mediated destruction of the S-phase cyclin Clb5, an activator of the protein kinase Cdk1. Mutations that prevent Clb5 destruction are lethal and cause defects in rDNA segregation and DNA synthesis. These defects are distinct from the mitotic-exit defects caused by stabilization of the mitotic cyclin Clb2, emphasizing the importance of cyclin specificity in the regulation of late-mitotic events. Efficient rDNA segregation, both in mitosis and meiosis, also requires APC-dependent destruction of Dbf4, an activator of the protein kinase Cdc7. We speculate that the dephosphorylation of Clb5-specific Cdk1 substrates and Dbf4-Cdc7 substrates drives the resolution of rDNA in early anaphase. The coincident destruction of securin, Clb5, and Dbf4 coordinates bulk chromosome segregation with segregation of rDNA.


Early Improvement of Specific Symptoms Predicts Subsequent Recovery in Bipolar Depression: Reanalysis of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Data.
The aim of this post hoc analysis was to evaluate which specific depressive items could predict subsequent durable recovery in patients with bipolar depression. The study population was at least 18 years old and met DSM-IV criteria for a major depressive episode associated with either bipolar I or II disorder. The data were derived from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), in which patients with bipolar depression were randomly assigned to treatment for acute depression with a mood stabilizer plus an adjunctive antidepressant drug or placebo. The primary and secondary outcomes were durable recovery (ie, 8 consecutive weeks of euthymia) and treatment-emergent affective switch (ie, transition to mania or hypomania), respectively. Binary logistic regression analysis was performed to identify specific symptoms whose improvement during the first 2 weeks predicted those outcomes; the score change of each individual symptom in the continuous symptom subscales for depression (SUM-D) from week 0 to week 2 was used as an independent variable. In the evaluable 188 participants who took placebo and active drugs, the improvement in loss of self-esteem (P = .037) or loss of energy (P = .040) at week 2 was significantly associated with higher chances of subsequent durable recovery. For participants taking active drugs (n = 91), solely the improvement in loss of energy at week 2 was significantly associated with subsequent durable recovery (P = .027). There was a significant association between the improvement of psychomotor retardation at week 2 and subsequent affective switch (P = .008). These findings imply that focusing on individual symptoms is important in bipolar depression, rather than relying solely on a summed score in rating scales. The original STEP-BD dataset is registered on ClinicalTrials.gov (identifier: NCT00012558).


Contemporary national comparison of open, laparoscopic, and robotic-assisted laparoscopic pediatric pyeloplasty.
We sought to determine current and longitudinal trends in the usage of open (OP), laparoscopic (LP), and robotic pyeloplasties. (RALP) Furthermore, we aimed to describe patient and hospital level characteristics associated with the use of minimally invasive pyeloplasties (MIP) and to compare basic utilization metrics for each approach. The 2000, 2003, 2006, and 2009 Kid's Inpatient Databases (KID) were used to determine current and longitudinal trends. As a result of a specific billing code for robotic surgery introduced in 2008, the 2009 KID database was used for analysis of RALP. Patient and hospital characteristics examined included: age, gender, race, insurance status, hospital location, and academic status. Utilization metrics of length of stay (LOS) and cost were determined from each modality. In 2009, there were 3354 pediatric pyeloplasties performed in the USA (85% OP, 3% LP, 12% RP). Compared with 2000, this represents an 11.7% decrease in the overall number of pyeloplasties but a progressive increase in MIP from 0.34% in 2000 to 11.7%. Mean patient age was 3.7 years for OP, 9.3 years for LP and 9.9 years for RALP. MIP was more commonly performed in females, Caucasians, patients with private insurance, at urban hospitals and at teaching hospitals. Although length of stay (LOS) in days was statistically lower for MIP (3.46 OP, 2.86 LP, 1.96 RP, p < 0.001), total cost between the groups was not statistically different. On multivariable logistic regression analysis, age (OR 1.17, p < 0.001) increased the odds of MIP whereas lack of private insurance decreased the odds of MIP (OR 0.62, p = 0.002). Although utilization of MIP is increasing in the USA, especially in older children, OP remains predominant. MIP was associated with a decrease in LOS. The odds of MIP were higher in older children, whereas the lack of private insurance decreased the odds of MIP.


A case report of intraventricular gliofibroma.
Gliofibroma is a rare tumor with biphasic morphology. We report a case of a 3-month-old girl presenting with increasing head circumference. CT and MRI showed the presence of a large heterogeneous, nonenhancing tumor filling the atria and bodies of the lateral ventricles with caudal extension into the third ventricle. Hydrocephalus was noted. A biopsy was performed and pathology showed the presence of glial and collagenous tissue consistent with the diagnosis of gliofibroma. However, no mitosis or necrosis was seen. Immunohistochemistry was positive for glial fibrillary acid protein, Masson trichrome and reticulin. The patient was followed up for a period of 10 years. Recent MRI showed stable appearance of the tumor and clinically the patient is neurologically intact with normal cognitive development. Our case report has the longest follow-up so far reported in the literature, of 10 years. As evident from our case report, we recommend a conservative treatment approach for gliofibroma with benign histology.


Enrichment of deuterium oxide at hydrophilic interfaces in aqueous solutions.
The structure of water at aqueous interfaces is of the utmost importance in biology, chemistry, and geology. We use neutron reflectivity and quartz crystal microbalance to probe an interface between hydrophilic quartz and bulk liquid solutions of H2O/D2O mixtures. We find that near the interface the neutron scattering length density is larger than in the bulk solution and there is an excess adsorbed mass. We interpret this as showing that there is a region adjacent to the quartz that is enriched in D2O and extends 5-10 nm into the solution. This suggests caution when interpreting results where D2O is substituted for H2O in aqueous interfacial chemistry.


Prediction of Extensive Myocardial Fibrosis in Nonhigh Risk Patients With Hypertrophic Cardiomyopathy.
In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGEext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGEext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGEext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGEext, that is, LGE ≥15% of the left ventricular mass. LGEext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGEext, in addition to the improved clinical model of diagnostic accuracy (p = 0.04). A biomarker-only strategy allowed the exclusion of LGEext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L-sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGEext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables.


Spatial immobilization of endogenous growth factors to control vascularization in bone tissue engineering.
The intimate crosstalk between endothelial and bony cells is essential for the reconstruction of bone tissue defects. Indeed, a successful bone repair is greatly dependent on the formation of new blood vessels, to ensure the supply of nutrients and gases, as well as the removal of metabolites. Bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) are involved on cells differentiation and bone vascularization aiming to develop viable bone tissue. Herein it is hypothesized that endogenous BMP-2 and VEGF bound in a parallel arrangement over a single nanofibrous substrate (NFM) can lead to a successful osteogenic and angiogenic differentiation of mesenchymal stem cells. For that, an engineered biofunctional system was developed comprising anti-BMP-2 and anti-VEGF antibodies, immobilized over an electrospun NFMs in a parallel pattern design, with the attempt to recreate the vasculature of bone tissue. The osteogenic and angiogenic potential of this engineered biofunctional system was demonstrated by culturing human bone marrow-derived mesenchymal stem cells (hBM-MSCs) during 21 days without exogenous induction. A chick chorioallantoic membrane (CAM) assay showed that the engineered biofunctional system, comprising bound endogenous BMP-2 and VEGF, is able to induce an increased angiogenic response. The angiogenic ability of this system, together with the osteogenic inductor BMP-2, enable obtaining an effective vascularized bone tissue engineering approach.


A quality metric for homology modeling: the H-factor.
The analysis of protein structures provides fundamental insight into most biochemical functions and consequently into the cause and possible treatment of diseases. As the structures of most known proteins cannot be solved experimentally for technical or sometimes simply for time constraints, in silico protein structure prediction is expected to step in and generate a more complete picture of the protein structure universe. Molecular modeling of protein structures is a fast growing field and tremendous works have been done since the publication of the very first model. The growth of modeling techniques and more specifically of those that rely on the existing experimental knowledge of protein structures is intimately linked to the developments of high resolution, experimental techniques such as NMR, X-ray crystallography and electron microscopy. This strong connection between experimental and in silico methods is however not devoid of criticisms and concerns among modelers as well as among experimentalists. In this paper, we focus on homology-modeling and more specifically, we review how it is perceived by the structural biology community and what can be done to impress on the experimentalists that it can be a valuable resource to them. We review the common practices and provide a set of guidelines for building better models. For that purpose, we introduce the H-factor, a new indicator for assessing the quality of homology models, mimicking the R-factor in X-ray crystallography. The methods for computing the H-factor is fully described and validated on a series of test cases. We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor.


Effects of cortisol and oestradiol on hepatic 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor proteins in late-gestation sheep fetus.
In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).


Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile.
Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.


Fms-like tyrosine kinase-3 ligand alters antigen-specific responses to infections after severe burn injury.
Burn patients are susceptible to opportunistic infections partly because of decreased immune functions, especially TH1-driven antigen-specific responses, which are regulated by dendritic cells. The dendritic cell growth factor, fms-like tyrosine kinase-3 ligand (FL), has been shown to increase resistance to Pseudomonas aeruginosa, in a dendritic cell-dependent manner, in a mouse model of burn wound infection. The specific mechanisms of protection are not known. This study tested the hypothesis that FL can enhance production of P. aeruginosa-specific antibodies after burn wound infection. Mice that had been previously exposed to P. aeruginosa were infected after burn injury by wound inoculation or challenged by intraperitoneal injection of heat-killed P. aeruginosa. In response to wound infection, FL treatments enhanced bacterial clearance and induced a shift from immunoglobulin (Ig) M toward IgG and IgA. However, serum levels of neither P. aeruginosa-specific antibodies nor interferon gamma (IFN-gamma) were significantly increased by FL, possibly because of decreased systemic exposure to bacteria. After challenge with heat-killed bacteria, which ensured equal exposures, FL-treated mice produced significantly greater levels of P. aeruginosa-specific IgG2a, which correlated with an increase in serum levels of interferon gamma and enhanced opsonization capacity. IL-12, IL-10, and transforming growth factor beta were significantly increased in FL-treated mice, regardless of the type of challenge. These findings indicate that FL treatments after burn injury enhance cytokine responses to recall antigens and increase bacterial clearance. In addition, through its ability to promote TH1-associated antigen-specific responses, FL may have potential as an immunotherapy to enhance adaptive immunity after severe burn injury.


Survival after massive (>2000) Africanized honeybee stings.
We report the clinical case of a man who survived a massive attack of Africanized bees (>2000 bee stings). The man experienced anaphylactic shock and multisystem organ failure (neurologic, hepatic, renal, and hematologic failure). He was treated with administration of dopamine hydrochloride, antihistaminic agents, corticosteroids, fluid and electrolyte replenishment, peritoneal dialysis, and plasmapheresis. No sequelae have been observed during follow-up.


Attenuation of fibrosis in vitro and in vivo with SPARC siRNA.
SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs. In in vitro studies, skin fibroblasts obtained from a Tgfbr1 knock-in mouse (TBR1CA; Cre-ER) were transfected with SPARC siRNA. Gene and protein expressions of the Col1a2 and the Ctgf were examined by real-time RT-PCR and Western blotting, respectively. In in vivo studies, C57BL/6 mice were induced for skin and lung fibrosis by bleomycin and followed by SPARC siRNA treatment through subcutaneous injection and intratracheal instillation, respectively. The pathological changes of skin and lungs were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression changes of collagen in the tissues were assessed by real-time RT-PCR and non-crosslinked fibrillar collagen content assays. SPARC siRNA significantly reduced gene and protein expression of collagen type 1 in fibroblasts obtained from the TBR1CA; Cre-ER mouse that was induced for constitutively active TGF-beta receptor I. Skin and lung fibrosis induced by bleomycin was markedly reduced by treatment with SPARC siRNA. The anti-fibrotic effect of SPARC siRNA in vivo was accompanied by an inhibition of Ctgf expression in these same tissues. Specific inhibition of SPARC effectively reduced fibrotic changes in vitro and in vivo. SPARC inhibition may represent a potential therapeutic approach to fibrotic diseases.


Penicillium subrubescens, a new species efficiently producing inulinase.
Inulin is a reserve carbohydrate in about 15 % of the flowering plants and is accumulated in underground tubers of e.g. chicory, dahlia and Jerusalem artichoke. This carbohydrate consists of linear chains of β-(2,1)-linked fructose attached to a sucrose molecule. Inulinases hydrolyse inulin into fructose and glucose. To find efficient inulin degrading fungi, 126 fungal strains from the Fungal Biotechnology Culture Collection (FBCC) at University of Helsinki and 74 freshly isolated strains from soil around Jerusalem artichoke tubers were screened in liquid cultures with inulin as a sole source of carbon or ground Jerusalem artichoke tubers, which contains up to 19 % (fresh weight) inulin. Inulinase and invertase activities were assayed by the dinitrosalicylic acid (DNS) method and a freshly isolated Penicillium strain originating from agricultural soil (FBCC 1632) was the most efficient inulinase producer. When it was cultivated at pH 6 and 28 °C in 2 litre bioreactors using inulin and Jerusalem artichoke as a carbon source, inulinase and invertase activities were on day 4 7.7 and 3.1 U mL(-1), respectively. The released sugars analysed by TLC and HPLC showed that considerable amounts of fructose were released while the levels of oligofructans were low, indicating an exoinulinase type of activity. Taxonomic study of the inulinase producing strain showed that this isolate represents a new species belonging in Penicillium section Lanata-divaricata. This new species produces a unique combination of extrolites and is phenotypically and phylogenetically closely related to Penicillium pulvillorum. We propose the name Penicillium subrubescens sp. nov. (CBS 132785(T) = FBCC 1632(T)) for this new species.


The relevance of non-human primate and rodent malaria models for humans.
At the 2010 Keystone Symposium on "Malaria: new approaches to understanding Host-Parasite interactions", an extra scientific session to discuss animal models in malaria research was convened at the request of participants. This was prompted by the concern of investigators that skepticism in the malaria community about the use and relevance of animal models, particularly rodent models of severe malaria, has impacted on funding decisions and publication of research using animal models. Several speakers took the opportunity to demonstrate the similarities between findings in rodent models and human severe disease, as well as points of difference. The variety of malaria presentations in the different experimental models parallels the wide diversity of human malaria disease and, therefore, might be viewed as a strength. Many of the key features of human malaria can be replicated in a variety of nonhuman primate models, which are very under-utilized. The importance of animal models in the discovery of new anti-malarial drugs was emphasized. The major conclusions of the session were that experimental and human studies should be more closely linked so that they inform each other, and that there should be wider access to relevant clinical material.


Spatially distributed successive approximation register (SDSAR) photonic ADCs based on phase-domain quantization.
We explore photonic ADC architectures based on encoding voltage-under-test into phase. The first step is to identify two basic optical building blocks: the optical phase comparator (1-bit ADC), based on interferometric comparison of phases in the well-known balanced photo-detection configuration, and the optical 1-bit DAC, namely electro-optic modulation with a bipolar electrical pulse. Equipped with these fundamental building blocks, we proceed to systematically port and adapt known ADC quantization architectures to photonic ADC, conceiving a hybrid between the Successive Approximation Register (SAR) and the Pipeline classic ADC architectures, referred to here as Spatially Distributed SAR (SDSAR). This novel photonic ADC, constructed out of B 1-bit ADCs and B-2 1-bit DACs, with B the number of bits, is not equivalent to any of the previous photonic ADCs in the literature, but appears superior to prior schemes in both optical power efficiency and electro-optic modulation complexity. We derive upper bounds on resolution, Effective Number of Bits (ENOB) performance as a function of average optical power for the new SDSAR device, developing analytic and numeric Monte-Carlo statistical models, comprising quantization, shot, thermal and DAC voltage noise sources. Our findings indicate that SDSAR is limited to ~11.5 ENOBs, assuming state-of-the-art mode-locked-lasers providing ~250 mW of average power (assuming ~7 dB excess losses). However, this upper bound is not tight, due to various physical impairments. In particular, the mode locked laser jitter is shown to have negligible impact on overall performance for RMS jitter < 20 fsec.


Propagating modes in gain-guided optical fibers.
Optical fibers in which gain-guiding effects are significant or even dominant compared with conventional index guiding may become of practical interest for future high-power single-mode fiber lasers. I derive the propagation characteristics of symmetrical slab waveguides and cylindrical optical fibers having arbitrary amounts of mixed gain and index guiding, assuming a single uniform transverse profile for both the gain and the refractive-index steps. Optical fibers of this type are best characterized by using a complex-valued v-squared parameter in place of the real-valued v parameter commonly used to describe conventional index-guided optical fibers.


Pharmacokinetics and tolerability of oseltamivir combined with probenecid.
Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 +/- 76 and 81 +/- 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 +/- 26 and 81 +/- 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.


Increasing the proportion of women in academic medicine: one institution's response.
To increase gender diversity among the physician consulting staff (PCS) at a major medical center. Because the proportion of female PCS at academic medical centers in the United States has not increased commensurately with increases in the proportion of female graduates from American medical schools, a modeling and graphing technique was developed to analyze this problem and recommend solutions for one large academic medical center. Personnel data, by gender and year from 1980 through 1994, were collected for all PCS at Mayo Clinic Rochester (MCR). These data were compared with similar data from other US academic medical centers and were used to develop models to predict the proportion of female PCS at MCR yearly until 2005, assuming various hiring and resignation patterns. Novel techniques were developed to illustrate and compare the models. Model-based predictions were compared with national projections, and a realistic target proportion of female PCS was defined on the basis of assumptions about the proportion of female graduates from medical school and internship programs during the next 10 years as well as probable hiring, retention, and resignation rates at MCR. To identify issues critical to recruitment, retention, and professional growth of female PCS at MCR, we used factor analysis to assess responses to a confidential questionnaire sent to all female faculty members. In 1994 and 1995, the proportion of female PCS was 25% at US academic medical centers but only 15% at MCR, and the rate at which this proportion increased from 1980 through 1994 at MCR was also lower than the national rate. Model-based predictions demonstrated that gradually (1.5% per year) increasing the female percentage of new recruits from 26% in 1995 to 40% in 2005 would achieve the targeted 25% female PCS in 13 years. Questionnaire responses from 119 (68%) of the 175 female PCS at MCR identified 6 important recommendations for recruitment and retention of female PCS: survey resignees and candidates who decline positions; appoint more qualified women to policy-making committees; require sensitivity and diversity training for all staff (especially leaders); develop explicit, gender-sensitive criteria for selecting department and division chairs; compare Mayo gender and diversity data with national data at the department or division level; and develop mechanisms for mentoring junior female staff members. We developed useful methods for analyzing the PCS gender distribution, defined feasible hiring strategies, and identified specific recommendations to enhance the professional experience of female PCS. These methods can provide a model for other institutions seeking to optimize gender diversity among their staff.


Comparison of single-use and reusable metal laryngoscope blades for orotracheal intubation during rapid sequence induction of anesthesia: a multicenter cluster randomized study.
Single-use metal laryngoscope blades are cheaper and carry a lower risk of infection than reusable metal blades. The authors compared single-use and reusable metal blades during rapid sequence induction of anesthesia in a multicenter cluster randomized trial. One thousand seventy-two adult patients undergoing general anesthesia under emergency conditions and requiring rapid sequence induction were randomly assigned on a weekly basis to either single-use or reusable metal blades (cluster randomization). After induction, a 60-s period was allowed to complete intubation. In the case of failed intubation, a second attempt was performed using the opposite type of blade. The primary endpoint was the rate of failed intubation, and the secondary endpoints were the incidence of complications (oxygen desaturation, lung aspiration, and/or oropharynx trauma) and the Cormack and Lehane score. Both groups were similar in their main characteristics, including the risk factors for difficult intubation. The rate of failed intubation was significantly decreased with single-use metal blades at the first attempt compared with reusable blades (2.8 vs. 5.4%, P < 0.05). In addition, the proportion of grades III and IV in Cormack and Lehane score were also significantly decreased with single-use metal blades (6 vs. 10%, P < 0.05). The global complication rate did not reach statistical significance, although the same trend was noted (6.8% vs. 11.5%, P = not significant). An investigator survey and a measure of illumination pointed that illumination might have been responsible for this result. The single-use metal blade was more efficient than a reusable metal blade in rapid sequence induction of anesthesia.


Cumulative radiation exposure in children with cystic fibrosis.
This retrospective study calculated the cumulative radiation dose for children with cystic fibrosis (CF) attending a tertiary CF centre. Information on 77 children with a mean age of 9.5 years, a follow up time of 658 person years and 1757 studies including 1485 chest radiographs, 215 abdominal radiographs and 57 computed tomography (CT) scans, of which 51 were thoracic CT scans, were analysed. The average cumulative radiation dose was 6.2 (0.04-25) mSv per CF patient. Cumulative radiation dose increased with increasing age and number of CT scans and was greater in children who presented with meconium ileus. No correlation was identified between cumulative radiation dose and either lung function or patient microbiology cultures. Radiation carries a risk of malignancy and children are particularly susceptible. Every effort must be made to avoid unnecessary radiation exposure in these patients whose life expectancy is increasing.


Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery.
Eighty patients with rheumatoid arthritis who had 129 surgical procedures on the hand and wrist over a 5-year period were reviewed. All patients continued with their usual medication throughout the perioperative period. There were 2 pin track infections and 1 wound infection in patients taking methotrexate alone (3 of 48), 1 wound dehiscence in a patient taking steroids without methotrexate (1 of 30), 1 wound infection in a patient taking both drugs (1 of 30), and 2 wound infections in patients taking neither of these drugs (2 of 21). There was no statistically significant risk of wound infection or breakdown in patients taking methotrexate or steroids or both. Rheumatoid patients with diabetes had an increased risk of wound infection (33%) compared with patients without (3.3%). No disease flare-ups occurred within 3 months of surgery. We recommend that these drugs be continued throughout the surgical and postoperative rehabilitation period.


The international cancer expert corps: a unique approach for sustainable cancer care in low and lower-middle income countries.
The growing burden of non-communicable diseases including cancer in low- and lower-middle income countries (LMICs) and in geographic-access limited settings within resource-rich countries requires effective and sustainable solutions. The International Cancer Expert Corps (ICEC) is pioneering a novel global mentorship-partnership model to address workforce capability and capacity within cancer disparities regions built on the requirement for local investment in personnel and infrastructure. Radiation oncology will be a key component given its efficacy for cure even for the advanced stages of disease often encountered and for palliation. The goal for an ICEC Center within these health disparities settings is to develop and retain a high-quality sustainable workforce who can provide the best possible cancer care, conduct research, and become a regional center of excellence. The ICEC Center can also serve as a focal point for economic, social, and healthcare system improvement. ICEC is establishing teams of Experts with expertise to mentor in the broad range of subjects required to establish and sustain cancer care programs. The Hubs are cancer centers or other groups and professional societies in resource-rich settings that will comprise the global infrastructure coordinated by ICEC Central. A transformational tenet of ICEC is that altruistic, human-service activity should be an integral part of a healthcare career. To achieve a critical mass of mentors ICEC is working with three groups: academia, private practice, and senior mentors/retirees. While in-kind support will be important, ICEC seeks support for the career time dedicated to this activity through grants, government support, industry, and philanthropy. Providing care for people with cancer in LMICs has been a recalcitrant problem. The alarming increase in the global burden of cancer in LMICs underscores the urgency and makes this an opportune time fornovel and sustainable solutions to transform cancer care globally.


Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity.
CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor-dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.


Dopaminergic polymorphisms associated with time-on-task declines and fatigue in the Psychomotor Vigilance Test.
Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary.


Laboratory-based bidirectional reflectance distribution functions of radiometric tarps.
Laboratory-based bidirectional reflectance distribution functions (BRDFs) of radiometric tarp samples used in the vicarious calibration of Earth remote sensing satellite instruments are presented in this paper. The results illustrate the BRDF dependence on the orientation of the tarps' weft and warp threads. The study was performed using the GSFC scatterometer at incident zenith angles of 0 degrees, 10 degrees, and 30 degrees; scatter zenith angles from 0 degrees to 60 degrees; and scatter azimuth angles of 0 degrees, 45 degrees, 90 degrees, 135 degrees, and 180 degrees. The wavelengths were 485 nm, 550 nm, 633 nm, and 800 nm. The tarp's weft and warp dependence on BRDF is well defined at all measurement geometries and wavelengths. The BRDF difference can be as high as 8% at 0 degrees incident angle and 12% at 30 degrees incident angle. The fitted BRDF data show a very small discrepancy from the measured ones. New data on the forward and backscatter properties of radiometric tarps are reported. The backward scatter is well pronounced for the white samples. The black sample has well-pronounced forward scatter. The provided BRDF characterization of radiometric tarps is an excellent reference for anyone interested in using tarps for radiometric calibrations. The results are NIST traceable.


Just ask: a proposal to hone the indications for sophisticated radiology examinations.
AIthough MRI and CT have revolutionized healthcare, the growth in their utilization comes with a commensurate and unsustainable growth in spending. The cost of sophisticated radiology tests goes beyond the cost of the technology itself because the tests can be so sensitive, they can lead to excessive treatments when incidental findings are not labeled as such. Thus to improve utilization for its own sake, but more importantly to limit spending on unnecessary treatments, we propose that requests for MRI and CT studies must be accompanied by a clinical question, and all reports offering interpretations must include a direct answer. This approach should increase the effective specificity of the tests that are performed, and in turn decrease provocation for unnecessary treatments. This question/answer policy can be implemented by new Medicare payment guidelines that echo the Medicare reimbursement rules for standard medical consultations.


Anomalous reflection in a metallic plate with subwavelength grooves of circular cross section.
Resonant features in the response of finite arrays of rectangular grooves ruled on a metallic plate have been reported in connection with the excitation of phase resonances. These anomalies are generated by a particular arrangement of the magnetic field phases inside the subwavelength grooves when the structure is illuminated by a p-polarized electromagnetic wave. We show that this kind of resonance is also present for grooves of circular cross section and appear as sharp peaks in the specular response, the number of which increases with the number of grooves in the structure. A significant intensification of the field within the grooves is also found for these particular phase configurations. The dependence of the response on the geometrical parameters of the structure is analyzed in detail, in order to consider these structures for potential applications such as frequency selectors and polarizers.


A fast-response and highly specific Si-Rhodamine probe for endogenous peroxynitrite detection in living cells.
Peroxynitrite (ONOO-) is involved in a variety of physiological and pathological processes. We designed and synthesized a fluorescent probe SiNH based on Si-rhodamine. The nanoprobe SiNH encapsulated within the amphiphilic copolymer exhibited fast response within 10 s, and it was highly specific for ONOO- in aqueous solution. It is demonstrated that the nanoprobe SiNH is applicable for real-time tracing of endogenous ONOO- in living cells.


Purple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome.
Purple toes syndrome is an extremely uncommon, nonhemorrhagic, cutaneous complication associated with warfarin therapy. It is characterized by the sudden appearance of bilateral, painful, purple lesions on the toes and sides of the feet that blanch with pressure. The syndrome usually develops 3-8 weeks after the start of warfarin therapy. A 47-year-old man with a history of purple toes syndrome that resolved after discontinuing warfarin--prescribed for a deep vein thrombosis (DVT) in his right lower leg--experienced an acute, proximal DVT in his other leg. Warfarin again was prescribed; 1 week later, purple toes syndrome developed in that extremity. Warfarin therapy again was discontinued, and intravenous unfractionated heparin was started; the patient's clinical picture indicated a possible pulmonary embolism, and laboratory analysis suggested antiphospholipid syndrome. The patient's toe pain resolved, but the purple discoloration persisted. Follow-up laboratory analysis confirmed antiphospholipid syndrome, and warfarin was restarted with close monitoring. No further complications occurred with long-term therapy. Although a rare complication of therapy, clinicians should monitor for the development of purple toes syndrome in patients taking warfarin.


Optical coherence tomography for precision brain imaging, neurosurgical guidance and minimally invasive theranostics.
This review focuses on optical coherence tomography (OCT)-based neurosurgical application for imaging and treatment of brain tumors. OCT has emerged as one of the most innovative and successful translational biomedical-diagnostic techniques. It is a useful imaging tool for noninvasive, in vivo, in situ and real-time imaging in soft biological tissues, such as brain tumor imaging. OCT can detect the structure of biological tissue in a micrometer scale, and functional OCT has some clinical researches and applications, such as nerve fiber tracts and neurovascular imaging. OCT is able to identify tumor margins, and it gives intraoperative precision identification and resection guidance. OCT-based theranostics is introduced into preclinical neurosurgical resection, such as the integration of OCT and laser ablation. We discuss the challenges and opportunities of OCT-based system in the field of combination of intraoperative structural and functional imaging, neurosurgical guidance and minimally invasive theranostics. We point out that OCT and laser ablation-based theranostics can give more precision and intelligence for intraoperative diagnosis and therapeutics in clinical applications. The theranostics can precisely locate, or specifically target cancerous tissues, and then as much as possiblly eliminate them.


Ototoxicity risk assessment combining distortion product otoacoustic emissions with a cisplatin dose model.
An objective method for identifying ototoxic hearing loss among patients receiving cisplatin is necessary since the ability of patients to take a behavioral test may change over the course of treatment. Data from 56 monitoring visits by 19 Veterans taking cisplatin were used to identify combinations of distortion-product otoacoustic emission (DPOAE) metrics and ototoxicity risk factors that best identified ototoxic hearing loss. Models were tested that incorporated DPOAE metrics generated statistically using partial least-squares analysis. Models were also tested that incorporated a priori DPOAE change criteria, such as a minimum DPOAE level shift of 6 dB. Receiver Operating Characteristic analysis was used to compare the accuracy of these models. The best performing model incorporated weighted combinations of pre-treatment hearing, cumulative cisplatin dose and DPOAE metrics that were determined using partial least-squares and evaluated over a quarter octave range near each subjects' high frequency DPOAE limit. Using this model and the DPOAE recording methods described herein, the chance of ototoxic hearing change can be determined at any given observed change in DPOAE level. This approach appears to provide an accurate and rapid ototoxicity risk assessment (ORA) that once validated can be used clinically.


Effect of Glyphosate Application on Foliar Diseases in Glyphosate-Tolerant Alfalfa.
Glyphosate, the active ingredient in Roundup herbicide, inhibits 5-enol-pyruvyl shikimate 3-phophate synthase (EPSPS), an enzyme found in plants, fungi, and bacteria. Plants engineered for glyphosate tolerance with a glyphosate-insensitive EPSPS take up and translocate the herbicide throughout the plant. In greenhouse experiments, we found that application of glyphosate at the recommended field application rate completely controlled alfalfa rust (Uromyces striatus) on 4-week-old plants inoculated with the fungus 3 days after glyphosate treatment. Control was effective in all seven cultivars tested. The level of protection declined with time after application, indicating that control transitory and protection declined with time after inoculation, suggesting that protective treatments have fungistatic activity. Complete control of rust was obtained when glyphosate was applied up to 10 days after inoculation with rust spores, indicating that the herbicide also has curative activity. Treatment increased protection from anthracnose, caused by Colletotrichum trifolii, a hemibiotrophic pathogen, and reduced symptom severity for spring black stem and leaf spot, caused by Phoma medicaginis, a necrotrophic pathogen. These results indicate that glyphosate could be used to help manage foliar diseases in glyphosate-tolerant alfalfa.


Picture This: Management of Canine Pyotraumatic Dermatitis (a.k.a., Hot Spot).
Pyotraumatic dermatitis (a.k.a., hot spot) is a rapidly developing, superficial, moist, exudative dermatitis commonly induced by self-inflicted trauma. Although not acutely life threatening, these lesions are extremely pruritic and distracting and significantly interfere with the canine's operational effectiveness and ability to stay on task. The review discusses a case, including clinical presentation, diagnosis, treatment, and prognosis.


Inter-population comparisons of copper resistance and accumulation in the red seaweed, Gracilariopsis longissima.
Copper (Cu) resistance and accumulation of five populations of the red seaweed Gracilariopsis longissima collected from sites in south west England (Fal Estuary, Helford Estuary and Chesil Fleet) that differ in their degree of Cu contamination was assessed under controlled laboratory conditions, on two separate occasions (April and October). The effects of a range of Cu concentrations (0-250 μg l(-1)) on relative growth rates was the same for all populations with reductions observable at concentrations as low as 12 μg l(-1) and cessation of growth at 250 μg l(-1). There was no significant difference in the calculated EC(50) values for the April and October samples, with means of 31.1 and 25.8 μg l(-1), respectively. Over the range of concentrations used in this study, copper content increased linearly and the pattern of accumulation was the same for all populations at both time periods. From the linear regressions of the pooled data a concentration factor of 2.25 × 10(3) was calculated. These results imply that G. longissima has an innate tolerance to Cu and that populations have not evolved copper-tolerant ecotypes. In laboratory studies, accumulated Cu was released when transferred to 'clean' seawater with approximately 80% being lost after 8 days, with no significant difference between populations in their response. The results from a 30 days in situ transplantation experiment using two populations from the Fal Estuary provided further evidence for dynamic changes in Cu content in response to changes in Cu bioavailability. The findings in this study are discussed in the context of implications for seaweed biomonitoring.


Transitions in living arrangements of Canadian seniors: findings from the NPHS longitudinal data.
This paper examines transitions in living arrangement decisions of the seniors using the first six cycles of the Canadian longitudinal National Population Health Survey microdata. Transitions from independent to intergenerational and institutional living arrangements are uniquely analyzed using a discrete-time hazard rate multinomial logit modelling framework and accounted for unobserved individual heterogeneity in the data. Our results show: a) provision of publicly-provided homecare reduces the likelihood of institutionalization, but it has no effect on intergenerational living arrangements; b) access to social support services reduces the probability of both institutional and intergenerational living arrangements; c) higher levels of functional health status, measured by Health Utility Index, reduce the probability of transitions from independent to intergenerational and institutional living arrangements; d) a decline in self-reported health status increases the probability of institutionalization, but its effect on intergenerational living arrangements is statistically insignificant; e) higher levels of household income tend to decrease the probability of institutionalization; and f) the likelihood of transitioning to both intergenerational and institutional living arrangements increases with the duration of survival. Our findings suggest that access to and availability of publicly-provided homecare, social support services and other programs designed to foster better functional health status would contribute positively towards independent or intergenerational living arrangements and reduce the probability of institutionalization.


Denunciation and the construction of norms in group conflict: examples from an Al-Qaeda-supporting group.
In situations of violent group conflict, group members often argue about how to deal with the outgroup. While some argue for aggression, force, and separation, others argue for negotiation and cooperation. Each side attempts to persuade the group that their own position is normative and is most in line with the interests and essence of the group. These arguments often involve denunciations of opponents as disloyal or deviant. In such situations, definitions of group identities and norms, and what counts as loyalty and deviance, are therefore disputed. This article analyses how a UK-based Al-Qaeda-supporting organization denounces 'moderate' Muslims in the United Kingdom who engage with secular institutions and who ally themselves with non-Muslims in political disputes. Drawing on theological, historical, and political arguments, a prescriptive norm is constructed whereby the correct behaviour of Muslims in the West is to avoid participation in secular political systems and to avoid political cooperation with non-Muslims. Muslims who are seen as breaking these norms are denounced and denigrated in a variety of ways by assigning them a range of deviant identity positions. Denunciations involve explanatory accounts which construct opponents as unworthy representatives of the group based on their deviation from Islam, or from ignorance, cowardice, mental weakness, or self-interest. This article illustrates that the practice of denunciation is an important aspect of the organization of group conflict. Finally, it argues that it is dangerous for social psychologists to treat group norms and prototypes as consensual.


Assisted reproduction in polycystic ovarian disease: A multicentric trial in India.
The aim of this study is to compare ovarian response, oocyte, embryo quality, ovarian hyperstimulation syndrome incidence, and pregnancy rates in polycystic ovary syndrome (PCOS) and non-PCOS group. This was a prospective observational study on PCOS carried out in seven assisted reproduction centers in India between August 2008 and July 2010, as part of trial under the Indian Society of Assisted Reproduction. A total of 192 women (77 in the PCOS group and 115 in the non- PCOS group) undergoing in vitro fertilization/intracytoplasmic sperm injection were included. All women had long protocol and recombinant follicle-stimulating hormone stimulation. The mean number of follicles and oocytes was higher in PCOS group compared with non-PCOS, being 27.2 (±8.8) and 13.6 (±5.3); 15.9 (±6.3) and 10.9 (±6.2), respectively. The recovery rates of oocytes and mature oocytes per follicle were less in the PCOS group which was 64% and 61.1%, respectively as opposed to 80.3% and 74.5%, respectively in non-PCOS group. The total numbers of top-quality embryos were less in the PCOS group. In PCOS women though the number of follicles was more, recovery of mature oocytes, top-quality embryos was less. Pregnancy rates were comparable in both groups.


HTLV-3/4 and simian foamy retroviruses in humans: discovery, epidemiology, cross-species transmission and molecular virology.
Non-human primates are considered to be likely sources of viruses that can infect humans and thus pose a significant threat to human population. This is well illustrated by some retroviruses, as the simian immunodeficiency viruses and the simian T lymphotropic viruses, which have the ability to cross-species, adapt to a new host and sometimes spread. This leads to a pandemic situation for HIV-1 or an endemic one for HTLV-1. Here, we present the available data on the discovery, epidemiology, cross-species transmission and molecular virology of the recently discovered HTLV-3 and HTLV-4 deltaretroviruses, as well as the simian foamy retroviruses present in different human populations at risk, especially in central African hunters. We discuss also the natural history in humans of these retroviruses of zoonotic origin (magnitude and geographical distribution, possible inter-human transmission). In Central Africa, the increase of the bushmeat trade during the last decades has opened new possibilities for retroviral emergence in humans, especially in immuno-compromised persons.


Optimization of steady-state ¹³C-labeling experiments for metabolic flux analysis.
While steady-state (13)C metabolic flux analysis is a powerful method for deducing multiple fluxes in the central metabolic network of heterotrophic and mixotrophic plant tissues, it is also time-consuming and technically challenging. Key steps in the design and interpretation of steady-state (13)C labeling experiments are illustrated with a generic protocol based on applications to plant cell suspension cultures.


Adhesion and proliferation of skeletal muscle cells on single layer poly(lactic acid) ultra-thin films.
An increasing interest in bio-hybrid systems and cell-material interactions is evident in the last years. This leads towards the development of new nano-structured devices and the assessment of their biocompatibility. In the present study, the development of free-standing single layer poly(lactic acid) (PLA) ultra-thin films is described, together with the analysis of topography and roughness properties. The biocompatibility of the PLA films has been tested in vitro, by seeding C2C12 skeletal muscle cells, and thus assessing cells shape, density and viability after 24, 48 and 72 h. The results show that free-standing flexible PLA nanofilms represent a good matrix for C2C12 cells adhesion, spreading and proliferation. Early differentiation into myotubes is also allowed. The biocompatibility of the novel ultra-thin films as substrates for cell growth promotes their application in the fields of regenerative medicine, muscle tissue engineering, drug delivery, and-in general-in the field of bio-hybrid devices.


HL-T, a new cell line derived from HL-60 promyelocytic leukemia cell cultures expressing terminal transferase and secreting suppressor activity.
A cell line with immature blast cell morphology was isolated from HL-60 promyelocytic leukemia cell cultures and designated HL-T. This new cell type is biphenotypic, expressing terminal transferase (TdT) together with myelomonocytoid immunologic features. TdT enzymatic activity, undetectable in HL-60, was determined to be 140 to 180 units/10(8) HL-T cells by the dGTP-assay, approximately 20% of the activity found in lymphoblastoid cell lines. HL-T predominantly synthesize the known 58-kDa TdT-protein plus a minor 54/56-kDa doublet. The 58-kDa steady state form is nonglycosylated and is phosphorylated. Precursor antigens S3.13 and MY-10, absent on HL-60, are expressed by HL-T; however, the cells are negative for HLA-Dr. Southern blot analysis by hybridization with immunoglobulin heavy chain (JH) and T cell-receptor chain gene (T beta) probes shows JH to be in the germ-line configuration in both cell lines and the T beta gene to be in germ-line in HL-60 but to be rearranged in HL-T. Truncation of the gene encoding the granulocyte-macrophage-colony-stimulating factor (GM-CSF), as found in HL-60, is not observed in HL-T. HL-T are resistant to differentiation-induction by retinoic acid and 1,25-dihydroxyvitamin D3. Cytogenetically HL-T share with HL-60 a deletion of the short arm of chromosome 9 at breakpoint p13, an aberration frequently found in patients with T cell leukemia. In addition, HL-T display t(8;9)(p11;p24) and trisomy 20. Tetraploidy is observed in 80% of HL-T metaphases with aberrations identical to those in the diploid karyotype. Like HL-60, the new line shows some surface-antigenic-T cell characteristics. Despite an antigenic pattern most consistent with that of helper-inducer T cells (T4+, D44+/-, 4B4+, 2H4-, TQ1+/-), HL-T cells and their conditioned culture medium suppress antigen, mitogen, and mixed-leukocyte-culture-mediated lymphocyte proliferation.


Stressful life events are associated with a poor in-vitro fertilization (IVF) outcome: a prospective study.
There is preliminary evidence to suggest an impact of stress on chances of achieving a pregnancy with in-vitro fertilization (IVF). The majority of the available research has focused on stress related to infertility and going through IVF-treatment, and it is still unclear whether non-fertility-related, naturally occurring stressors may influence IVF pregnancy chances. Our aim was to explore the association between IVF-outcome and negative, i.e. stressful, life-events during the previous 12 months. Prior to IVF, 809 women (mean age: 31.2 years) completed the List of Recent Events (LRE) and questionnaires measuring perceived stress and depressive symptoms. Women who became pregnant reported fewer non-fertility-related negative life-events prior to IVF (Mean: 2.5; SD: 2.5) than women who did not obtain a pregnancy (Mean: 3.0; SD: 3.0) (t(465.28) = 2.390, P = 0.017). Logistic regression analyses revealed that the number of negative life-events remained a significant predictor of pregnancy (OR: 0.889; P = 0.02), when controlling for age, total number of life-events, perceived stress within the previous month, depressive symptoms, and relevant medical factors related to the patient or treatment procedure, including duration of infertility, number of oocytes retrieved and infertility etiology. Mediation analyses indicated that the association between negative life events and IVF pregnancy was partly mediated by the number of oocytes harvested during oocyte retrieval. A large number of life-events perceived as having a negative impact on quality of life may indicate chronic stress, and the results of our study indicate that stress may reduce the chances of a successful outcome following IVF, possibly through psychobiological mechanisms affecting medical end-points such as oocyte retrieval outcome.


Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux.
Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity. ApoA-I also stimulates secretion of apolipoprotein E (apoE) from macrophage foam cells, although the mechanism of this process is not understood. In this study, we demonstrate that apoA-I stimulates secretion of apoE independently of both ABCA1-mediated cholesterol efflux and of lipid binding by its C terminus. Pulse-chase experiments using (35)S-labeled cellular apoE demonstrate that macrophage apoE exists in both relatively mobile (E(m)) and stable (E(s)) pools, that apoA-I diverts apoE from degradation to secretion, and that only a small proportion of apoA-I-mobilized apoE is derived from the cell surface. The structural requirements for induction of apoE secretion and cholesterol efflux are clearly dissociated, as C-terminal deletions in recombinant apoA-I reduce cholesterol efflux but increase apoE secretion, and deletion of central helices 5 and 6 decreases apoE secretion without perturbing cholesterol efflux. Moreover, a range of 11- and 22-mer alpha-helical peptides representing amphipathic alpha-helical segments of apoA-I stimulate apoE secretion whereas only the C-terminal alpha-helix (domains 220-241) stimulates cholesterol efflux. Other alpha-helix-containing apolipoproteins (apoA-II, apoA-IV, apoE2, apoE3, apoE4) also stimulate apoE secretion, implying a positive feedback autocrine loop for apoE secretion, although apoE4 is less effective. Finally, apoA-I stimulates apoE secretion normally from macrophages of two unrelated subjects with genetically confirmed Tangier Disease (mutations C733R and c.5220-5222delTCT; and mutations A1046D and c.4629-4630insA), despite severely inhibited cholesterol efflux. We conclude that apoA-I stimulates secretion of apoE independently of cholesterol efflux, and that this represents a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE.


NRPS-PKS: a knowledge-based resource for analysis of NRPS/PKS megasynthases.
NRPS-PKS is web-based software for analysing large multi-enzymatic, multi-domain megasynthases that are involved in the biosynthesis of pharmaceutically important natural products such as cyclosporin, rifamycin and erythromycin. NRPS-PKS has been developed based on a comprehensive analysis of the sequence and structural features of several experimentally characterized biosynthetic gene clusters. The results of these analyses have been organized as four integrated searchable databases for elucidating domain organization and substrate specificity of nonribosomal peptide synthetases and three types of polyketide synthases. These databases work as the backend of NRPS-PKS and provide the knowledge base for predicting domain organization and substrate specificity of uncharacterized NRPS/PKS clusters. Benchmarking on a large set of biosynthetic gene clusters has demonstrated that, apart from correct identification of NRPS and PKS domains, NRPS-PKS can also predict specificities of adenylation and acyltransferase domains with reasonably high accuracy. These features of NRPS-PKS make it a valuable resource for identification of natural products biosynthesized by NRPS/PKS gene clusters found in newly sequenced genomes. The training and test sets of gene clusters included in NRPS-PKS correlate information on 307 open reading frames, 2223 functional protein domains, 68 starter/extender precursors and their specific recognition motifs, and also the chemical structure of 101 natural products from four different families. NRPS-PKS is a unique resource which provides a user-friendly interface for correlating chemical structures of natural products with the domains and modules in the corresponding nonribosomal peptide synthetases or polyketide synthases. It also provides guidelines for domain/module swapping as well as site-directed mutagenesis experiments to engineer biosynthesis of novel natural products. NRPS-PKS can be accessed at http://www.nii.res.in/nrps-pks.html.


Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain-Barrier Disruption Results in Radiographic Response.
High-dose bevacizumab delivered via super selective intra-arterial cerebral infusion (SIACI) is one promising clinical trial combination for patients with glioblastoma (GBM). Although both continuous intravenous and intra-arterial administration of bevacizumab, and rechallenge with intravenous bevacizumab, have demonstrated improved survival, this is the first description of rechallenging GBM with SIACI of bevacizumab. We report a case of a 43-year-old woman with recurrent GBM who had received treatment from 3 clinical trials, including a rechallenge with SIACI of bevacizumab. First, she enrolled into a phase I/II trial for patients newly diagnosed with GBM (NCT01811498) and received 3 doses of SIACI bevacizumab over 180 days in addition to standard of care chemotherapy and radiation. Following progression, as indicated on her magnetic resonance imaging scan, she consented for a separate clinical trial for her disease and received 2 cycles of temozolomide with an investigational agent. The patient was removed from the study on tumor progression. Subsequently, she was rechallenged with SIACI of bevacizumab via a third clinical trial (NCT01269853) and then completed 3 intravenous infusions. After completing the third trial, her magnetic resonance imaging scan demonstrated improvement based on Response Assessment In Neuro-Oncology criteria. This is the first report to highlight the effect of rechallenging a patient with SIACI of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus intravenous bevacizumab for GBM and further explore theories of bevacizumab resistance.


Two randomized studies to evaluate the cooling sensation, consumer liking, and tolerability of a skin disinfectant spray.
The aim of these two clinical studies was to evaluate the sensory characteristics and irritation potential of a prototype disinfectant spray (containing 0.13% w/v benzalkonium chloride and a cooling agent) in subjects with experimental wounds. The pilot study was a single center, "replicated latinClinicalTrials.ClinicalTrials. square design," randomized and double-blinded study. The pivotal study was a single center, randomized, controlled, crossover, double-blinded study, following a direct comparison test design of the study products. The experimental wounds were generated using sequential tape strippings of the forearm skin before product application. The test product was compared with the currently marketed BACTROBAN® disinfectant spray, negative control (0.9% w/v saline), and positive control (70% w/v isopropyl alcohol, pilot study only). The pilot study was intended to inform the study design and sample size for the pivotal study. The pilot study demonstrated that the positive control product delivered significantly more irritancy (stinging /burning sensory) than the negative control product on the experimental wound, which verified the integrity of the wound model. The results of the pivotal study suggested that the prototype formulation delivered significantly more cooling sensation than both BACTROBAN® disinfectant spray and negative control at 3 and 5 min after product application, and overall for a 15-min period after application. No statistically significant differences in product liking were observed between the prototype disinfectant spray and the BACTROBAN® disinfectant spray or negative control. The prototype disinfectant spray, BACTROBAN® disinfectant spray, and control products were well-tolerated in these studies.


A supertree of early tetrapods.
A genus-level supertree for early tetrapods is built using a matrix representation of 50 source trees. The analysis of all combined trees delivers a long-stemmed topology in which most taxonomic groups are assigned to the tetrapod stem. A second analysis, which excludes source trees superseded by more comprehensive studies, supports a deep phylogenetic split between lissamphibian and amniote total groups. Instances of spurious groups are rare in both analyses. The results of the pruned second analysis are mostly comparable with those of a recent, character-based and large-scale phylogeny of Palaeozoic tetrapods. Outstanding areas of disagreement include the branching sequence of lepospondyls and the content of the amniote crown group, in particular the placement of diadectomorphs as stem diapsids. Supertrees are unsurpassed in their ability to summarize relationship patterns from multiple independent topologies. Therefore, they might be used as a simple test of the degree of corroboration of nodes in the contributory analyses. However, we urge caution in using them as a replacement for character-based cladograms and for inferring macroevolutionary patterns.


Punctate hyperfluorescent spots associated with polypoidal choroidal vasculopathy on indocyanine green angiography.
To evaluate punctate hyperfluorescent spots on indocyanine green angiography (ICGA) in eyes with polypoidal choroidal vasculopathy (PCV). Retrospective observation case series of 88 eyes of 81 patients (63 men and 18 women) analyzing fundus photography, fluorescein angiography, ICGA, and spectral-domain optical coherence tomography (OCT) findings at baseline. Seven patients (9%) had bilateral PCV lesions. Mean age was 68.44 ± 5.94 years (range: 45 to 86 years). Macular-type PCV was found in 72 eyes (81.8%), peripapillary-type PCV in 12 eyes (13.6%), and combined-type PCV in four eyes (4.5%). Choroidal vascular hyperpermeability was observed in 38 eyes (43.2%), and punctate hyperfluorescent spots on ICGA in 47 eyes (53.4%). ICGA of unaffected fellow eyes of 74 patients with unilateral PCV revealed choroidal hyperpermeability in 23 eyes (31.1%) and punctate hyperfluorescent spots in 38 eyes (51.4%). Presence of punctate hyperfluorescent spots was significantly associated with choroidal vascular hyperpermeability (P < .001). Punctate hyperfluorescent spots were frequently observed in eyes with PCV in late-phase ICGA, as previously described in eyes with central serous chorioretinopathy, which may represent leakage from punctate hyperpermeable inner choroid spots or late staining of forme fruste drusen or drusen-like subretinal pigment epithelium deposits associated with choroidal hyperpermeability.


Parental experiences of providing skin-to-skin care to their newborn infant--part 2: a qualitative meta-synthesis.
To synthesize and interpret qualitative research findings focusing on parental experiences of skin-to-skin care (SSC) for newborn infants. SSC induces many benefits for newborn infants and their parents. Three meta-analyses have been conducted on physiological outcomes, but no previous qualitative meta-synthesis on parental experiences of SSC has been identified. The present meta-synthesis was guided by the methodology described by Paterson and co-workers. Four databases were searched, without year or language limitations, up until December 2013. Manual searches were also performed. The searches and subsequent quality appraisal resulted in the inclusion of 29 original qualitative papers from 9 countries, reporting experiences from 401 mothers and 94 fathers. The meta-synthesis entails a meta-data analysis, analysis of meta-method, and meta-theory in the included primary studies. Based on the three analyses, the meta-synthesis represents a new interpretation of a phenomenon. The results of the meta-data analysis have been presented as a qualitative systematic review in a separate paper. When synthesizing and interpreting the findings from the included analyses, a theoretical model of Becoming a parent under unfamiliar circumstances emerged. Providing SSC seems to be a restorative as well as an energy-draining experience. A supportive environment has been described as facilitating the restorative experience, whereas obstacles in the environment seem to make the provision of SSC energy-draining for parents. When the process is experienced as positive, it facilitates the growth of parental self-esteem and makes the parents ready to assume full responsibility for their child. The results show that SSC can be interpreted not only as a family-including and important health care intervention but also in terms of actually becoming a parent. The process of becoming a parent in this specific situation is influenced by external factors in three different levels; family and friends, community, and society at large. The descriptions of providing SSC are similar to what has previously been described as the natural process of becoming a mother or a father.


Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth.
Geranylgeranyltransferase I inhibitors (GGTIs) are presently undergoing advanced preclinical studies and have been shown to disrupt oncogenic and tumor survival pathways, to inhibit anchorage-dependent and -independent growth, and to induce apoptosis. However, the geranylgeranylated proteins that are targeted by GGTIs to induce these effects are not known. Here we provide evidence that the Ras-like small GTPases RalA and RalB are exclusively geranylgeranylated and that inhibition of their geranylgeranylation mediates, at least in part, the effects of GGTIs on anchorage-dependent and -independent growth and tumor apoptosis. To this end, we have created the corresponding carboxyl-terminal mutants that are exclusively farnesylated and verified that they retain the subcellular localization and signaling activities of the wild-type geranylgeranylated proteins and that Ral GTPases do not undergo alternative prenylation in response to GGTI treatment. By expressing farnesylated, GGTI-resistant RalA and RalB in Cos7 cells and human pancreatic MiaPaCa2 cancer cells followed by GGTI-2417 treatment, we demonstrated that farnesylated RalB, but not RalA, confers resistance to the proapoptotic and anti-anchorage-dependent growth effects of GGTI-2417. Conversely, farnesylated RalA but not RalB expression renders MiaPaCa2 cells less sensitive to inhibition of anchorage-independent growth. Furthermore, farnesylated RalB, but not RalA, inhibits the ability of GGTI-2417 to suppress survivin and induce p27(Kip1) protein levels. We conclude that RalA and RalB are important, functionally distinct targets for GGTI-mediated tumor apoptosis and growth inhibition.


The role of the bone morphogenetic proteins in leukaemic stem cell persistence.
CML (chronic myeloid leukaemia) is characterized by the presence of the oncogenic tyrosine kinase fusion protein BCR (breakpoint cluster region)-Abl, responsible for driving the disease. Current TKI (tyrosine kinase inhibitor) therapies effectively inhibit BCR-Abl to control CML in the majority of patients, but do not eliminate the LSC (leukaemic stem cell) population, which becomes quiescent following treatment. Patients require long-term treatment to sustain remission; alternative strategies are therefore required, either alone or in combination with TKIs to eliminate the LSCs and provide a cure. The embryonic morphogenetic pathways play a key role in haemopoiesis with recent evidence suggesting LSCs are more dependent on these signals following chemotherapy than normal HSCs (haemopoietic stem cells). Recent evidence in the literature and from our group has revealed that the BMP (bone morphogenetic protein) pathway is differentially expressed in CML patients compared with normal donors. In the present review, we explore the role that BMP signalling plays in oesteoblast differentiation, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM (bone marrow) niche. Overall, we highlight the BMP pathway as a potential target for developing LSC-directed therapies in CML in the future.


The role of agricultural use of insecticides in resistance to pyrethroids in Anopheles gambiae s.l. in Burkina Faso.
Agricultural use of insecticides is involved in the selection of resistance to these compounds in field populations of mosquitoes in Burkina Faso. Anopheles gambiae s.l. was resistant to permethrin and DDT in cotton-growing and urban areas, but susceptible in areas with limited insecticide selection pressure (rice fields and control areas). Nevertheless, resistance to these insecticides was observed in a village on the outskirts of the rice fields at the end of the rainy season, suggesting that the latter population of mosquitoes had migrated from the surrounding cotton villages into the rice fields. A seasonal variation of resistance observed in the cotton-growing area is related to the distribution of the molecular M and S forms of An. gambiae, since resistance to pyrethroids has so far only been reported in the S form. Pyrethroid resistance in west African An. gambiae was conferred by target site insensitivity through a knockdown resistance (kdr)-like mutation, which was present at high frequencies in mosquitoes in the cotton-growing and urban areas.


Efficacy of korean red ginseng in the treatment of atopic dermatitis.
In order to determine the efficacy of functional foods, objective measurement of the severity of atopic dermatitis (AD) after taking foods is important. The aim of this study was to conduct an objective evaluation of whether Korean red ginseng (KRG) might be helpful for improvement of skin condition and serum IgE in patients with AD. Thirty atopic patients (18 females and 12 males) participated in this study. Patients took KRG for 16 weeks. Bioengineering methods, including the corneometer and evaporimeter, were used at the start of the study and after 8 weeks and 16 weeks. In addition, we assessed serum IgE levels and the severity scoring of the atopic dermatitis (SCORAD) index. Transepidermal water loss and skin hydration showed significant improvement after 16 weeks. A significant decrease in the SCORAD index, as well as in serum IgE level, was observed after 16 weeks. Our results demonstrated that KRG may be helpful as a functional food for patients with AD.