Predicting Procedure Step Performance From Operator and Text Features: A Critical First Step Toward Machine Learning-Driven Procedure Design.
The goal of this study is to assess machine learning for predicting procedure performance from operator and procedure characteristics. Procedures are vital for the performance and safety of high-risk industries. Current procedure design guidelines are insufficient because they rely on subjective assessments and qualitative analyses that struggle to integrate and quantify the diversity of factors that influence procedure performance. We used data from a 25-participant study with four procedures, conducted on a high-fidelity oil extraction simulation to develop logistic regression (LR), random forest (RF), and decision tree (DT) algorithms that predict procedure step performance from operator, step, readability, and natural language processing-based features. Features were filtered using the Boruta approach. The algorithms were trained and optimized with a repeated 10-fold cross-validation. After training, inference was performed using variable importance and partial dependence plots. The RF, DT, and LR algorithms with all features had an area under the receiver operating characteristic curve (AUC) of 0.78, 0.77, and 0.75, respectively, and significantly outperformed the LR with only operator features (LROP), with an AUC of 0.61. The most important features were experience, familiarity, total words, and character-based metrics. The partial dependence plots showed that steps with fewer words, abbreviations, and characters were correlated with correct step performance. Machine learning algorithms are a promising approach for predicting step-level procedure performance, with acknowledged limitations on interpolating to nonobserved data, and may help guide procedure design after validation with additional data on further tasks. After validation, the inferences from these models can be used to generate procedure design alternatives.


[Intrinsic fluorescence of globular actin. Features of localization of tryptophan residues].
The contribution of individual Trp residues to alpha-actin fluorescence was evaluated by means of an analysis of their microenvironment, which was done on the basis of PIR-International protein sequence database information. The contribution of Trp79 and Trp86 was shown to be low due to an effective nonradiating energy transfer according to the inductive resonance mechanism between the Trp residues and the fluorescence quenching of Trp86 by S gamma of Cys10, an efficient fluorescence quencher. The intrinsic fluorescence of actin was found to be determined mainly by Trp340 and Trp356, which are internal, inaccessible to solvent, and have a high density microenvironment formed mainly by nonpolar groups of protein. It is possible that the side chain conformation of Trp340 (t-isomer; chi 1 190 degrees, chi 2 89 degrees), aromatic rings of Tyr and Phe residues, and Pro residues in the microenvironment of Trp340 and Trp356 substantially contribute to the short-wavelength fluorescence spectrum of actin.


Hematology and plasma biochemistry analytes in five age groups of immature, captive-reared loggerhead sea turtles (Caretta caretta).
Abstract: Blood samples of 85 immature, apparently healthy, captive-reared loggerhead sea turtles (Caretta caretta) were analyzed for 13 hematologic variables and total solids of 5 age groups (8, 20, 32, 44, and 56 mo old) and for 20 plasma biochemical analytes of 4 age groups (20 to 56 mo old). Each individual turtle was sampled under similar conditions during a blood collection period of 3 days. Hematologic analytes included packed cell volume, white blood cell (WBC) counts, WBC estimates, and leukocyte differentials. Biochemical analysis included albumin, alanine aminotransferase, alkaline phosphatase, amylase, aspartate aminotransferase, blood urea nitrogen, calcium, chloride, cholesterol, creatine kinase, creatinine, gamma glutamyltransferase, globulins, glucose, phosphorous, potassium, sodium, total bilirubin, total protein, total solids, and uric acid. In due consideration of small sample size in all five age groups, the results of hematologic and biochemical analysis were used to determine ranges for these analytes and to compare values among consecutive age groups. Several significant differences in some hematologic and biochemical variables were identified and need to be considered in the interpretation of blood work of immature, growing sea turtles in human care.


Status report on acid etching procedures. Council on Dental Materials and Devices.
The introduction of acid etching techniques into many dental disciplines has resulted in safe, simple, conservative, and sometimes more economic methods of treatment. Further, in some instances, it has extended greater opportunities for treating such groups as those physically and emotionally handicapped in whom preventive and restorative procedures are often difficult. It is a significant departure from conventional, established techniques and may supersede some and may share with other established techniques an adjunctive relationship. By many, acid etching techniques are viewed with cautious optimism. It is deceptively simple. Strict adherence to the basic principles of application is important to its success.


Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies before cardiac surgery.
Heparin-induced thrombocytopenia (HIT) is caused by anti-platelet factor 4/heparin (PF4/H) immunoglobulin (Ig) G antibodies, which activate platelets. In some patients, anti-PF4/H antibodies are already detectable before cardiac surgery. Whether preoperative presence of antibodies confers adverse prognosis and which particular antibody classes (IgG, IgA, IgM) might be implicated are unknown. We prospectively screened 591 patients undergoing cardiopulmonary bypass surgery for heparin-dependent antibodies by PF4/H immunoassay (separately for IgG, IgA, and IgM) and platelet activation test at preoperative baseline and at days 6 and 10. All patients received heparin or low-molecular-weight heparin postsurgery regardless of antibody status and were followed for postoperative complications, frequency of HIT, length of hospital stay, and 30-day mortality. Anti-PF4/H antibodies of any class were detected at preoperative baseline in 128 (21.7%) of 591 patients: IgG n = 44 (7.4%), IgA n = 36 (6.1%), and IgM n = 79 (13.4%); some patients had >1 antibody class. Neither IgG nor IgA was a risk factor for any adverse outcome parameter. However, preoperative presence of IgM antibodies was associated with an increased risk for nonthromboembolic complications (all complications combined: hazard ratio 1.73, 95% CI 1.15-2.61) and a longer in-hospital stay (P = .02), but without evidence for increased risk of thrombotic complications or subsequent HIT. Patients with preoperative anti-PF4/H antibodies of IgG and IgA class are not at increased risk for thrombotic or nonthrombotic adverse events, whereas those with baseline anti-PF4/H IgM had an increased risk of nonthrombotic adverse outcomes but not of subsequent HIT or thrombosis. Because IgM antibodies do not cause HIT, they could represent a surrogate marker for other heparin-independent risk factors.


Amphiregulin is not essential for induction of contact hypersensitivity.
Amphiregulin (AR) is expressed in Th2 cells, rather than Th1 cells, and plays an important role in Th2 cell/cytokine-mediated host defense against nematodes. We also found earlier that AR mRNA expression was strongly upregulated in inflamed tissue during Th2 cell/cytokine-mediated fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS), suggesting a contribution of AR to the induction of those responses. To elucidate the role of AR in the induction of FITC- or dinitrofluorobenzene (DNFB)-induced CHS, AR-deficient mice were sensitized and/or challenged with FITC or DNFB epicutaneously. The levels of FITC-mediated skin dendritic cell (DC) migration and FITC-specific lymph node cell proliferation and cytokine production were assessed by flow cytometry, [3H]-thymidine incorporation and ELISA, respectively, after FITC sensitization. The degree of ear swelling, the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in inflammatory sites and the levels of FITC-specific immunoglobulin (Ig) in sera were determined by histological analysis, colorimetric assay and ELISA, respectively, after FITC challenge. DC migration and FITC-specific lymph node cell proliferation and cytokine production were normal in the AR-deficient mice. Ear swelling, tissue MPO and EPO activities and FITC-specific serum Ig levels were also similar in AR-deficient and -sufficient mice. Amphiregulin is not essential for the induction of FITC- or DNFB-induced CHS responses in mice.


[Socioeconomic costs of food-borne disease using the cost-of-illness model: applying the QALY method].
This study estimated the annual socioeconomic costs of food-borne disease in 2008 from a societal perspective and using a cost-of-illness method. Our model employed a comprehensive set of diagnostic disease codes to define food-borne diseases with using the Korea National Health Insurance (KNHI) reimbursement data. This study classified the food borne illness as three types of symptoms according to the severity of the illness: mild, moderate, severe. In addition to the traditional method of assessing the cost-of-illness, the study included measures to account for the lost quality of life. We estimated the cost of the lost quality of life using quality-adjusted life years and a visual analog scale. The direct cost included medical and medication costs, and the non-medical costs included transportation costs, caregiver's cost and administration costs. The lost productivity costs included lost workdays due to illness and lost earnings due to premature death. The study found the estimated annual socioeconomic costs of food-borne disease in 2008 were 954.9 billion won (735.3 billion won-996.9 billion won). The medical cost was 73.4 - 76.8% of the cost, the lost productivity cost was 22.6% and the cost of the lost quality of life was 26.0%. Most of the cost-of-illness studies are known to have underestimated the actual socioeconomic costs of the subjects, and these studies excluded many important social costs, such as the value of pain, suffering and functional disability. The study addressed the uncertainty related to estimating the socioeconomic costs of food-borne disease as well as the updated cost estimates. Our estimates could contribute to develop and evaluate policies for food-borne disease.


Imaging and quantification of trans-membrane protein diffusion in living bacteria.
The cytoplasmic membrane forms the barrier between any cell's interior and the outside world. It contains many proteins that enable essential processes such as the transmission of signals, the uptake of nutrients, and cell division. In the case of prokaryotes, which do not contain intracellular membranes, the cytoplasmic membrane also contains proteins for respiration and protein folding. Mutual interactions and specific localization of these proteins depend on two-dimensional diffusion driven by thermal fluctuations. The experimental investigation of membrane-protein diffusion in bacteria is challenging due to their small size, only a few times larger than the resolution of an optical microscope. Here, we review fluorescence microscopy-based methods to study diffusion of membrane proteins in living bacteria. The main focus is on data-analysis tools to extract diffusion coefficients from single-particle tracking data obtained by single-molecule fluorescence microscopy. We introduce a novel approach, IPODD (inverse projection of displacement distributions), to obtain diffusion coefficients from the usually obtained 2-D projected diffusion trajectories of the highly 3-D curved bacterial membrane. This method provides, in contrast to traditional mean-squared-displacement methods, correct diffusion coefficients and allows unravelling of heterogeneously diffusing populations.


Dendritic cell-lysosomal-associated membrane protein (LAMP) and LAMP-1-HIV-1 gag chimeras have distinct cellular trafficking pathways and prime T and B cell responses to a diverse repertoire of epitopes.
Ag processing is a critical step in defining the repertoire of epitope-specific immune responses. In the present study, HIV-1 p55Gag Ag was synthesized as a DNA plasmid with either lysosomal-associated membrane protein-1 (LAMP/gag) or human dendritic cell-LAMP (DC-LAMP/gag) and used to immunize mice. Analysis of the cellular trafficking of these two chimeras demonstrated that both molecules colocalized with MHC class II molecules but differed in their overall trafficking to endosomal/lysosomal compartments. Following DNA immunization, both chimeras elicited potent Gag-specific T and B cell immune responses in mice but differ markedly in their IL-4 and IgG1/IgG2a responses. The DC-LAMP chimera induced a stronger Th type 1 response. ELISPOT analysis of T cell responses to 122 individual peptides encompassing the entire p55gag sequence (15-aa peptides overlapping by 11 residues) showed that DNA immunization with native gag, LAMP/gag, or DC-LAMP/gag induced responses to identical immunodominant CD4+ and CD8+ peptides. However, LAMP/gag and DC-LAMP/gag plasmids also elicited significant responses to 23 additional cryptic epitopes that were not recognized after immunization with native gag DNA. The three plasmids induced T cell responses to a total of 39 distinct peptide sequences, 13 of which were induced by all three DNA constructs. Individually, DC-LAMP/gag elicited the most diverse response, with a specific T cell response against 35 peptides. In addition, immunization with LAMP/gag and DC-LAMP/gag chimeras also promoted Ab secretion to an increased number of epitopes. These data indicate that LAMP-1 and DC-LAMP Ag chimeras follow different trafficking pathways, induce distinct modulatory immune responses, and are able to present cryptic epitopes.


Anticonvulsant effect of hydroalcoholic seed extract of croton tiglium in rats and mice.
The study was aimed to evaluate the anticonvulsant effect of hydro-alcoholic seed extract of croton tiglium in rats and mice. Forty -eight each of rats and mice of either sex were randomised into four groups and subjected to seizures induced by electroconvulsiometer and pentylenetetrazole. The hydroalcoholic seed extract of croton tiglium (250 and 500mg/kg) was studied for its anticonvulsant effect using sodium valproate (200mg/kg) as standard and distilled water as control. The parameters observed were time for onset of HLE (Hind Limb Extension) and duration of HLE in electrically induced seizures, and time for onset of convulsions and duration of convulsions in chemically induced seizures. Mortality of the animals over 24 hours was observed in both the models. For testing statistical significance between various groups unpaired student t-test was used. In electrically induced seizures croton tiglium produced dose dependant prolongation of time for onset of HLE and a reduction in duration of HLE and in chemically induced convulsions, it prolonged time for onset of convulsions and reduced the duration of convulsions indicating its anticonvulsant effect in both models. However, anticonvulsant effect was less compared to sodium valproate. There was a higher percentage of mortality in croton tiglium group in chemically induced convulsions when compared to sodium valproate. Croton tiglium has dose dependant anticonvulsant effect in electrically induced seizures, while in pentylenetetrazole induced-seizures the protection is very minimal.


The statistical analysis of graft patency data in a clinical trial of antiplatelet agents following coronary artery bypass grafting.
Because most coronary artery bypass patients receive more than one graft at surgery, it is most important to determine whether statistical analysis of graft patency should be performed on the premise that the multiple grafts within patients are dependent or independent experimental units. Veterans Administration Cooperative Study No. 207 was a multicenter clinical trial comparing four different antiplatelet regimens to placebo in the prevention of graft occlusion following coronary artery bypass grafting. Using the results from the 1-week postoperative angiograms from the Veterans Administration Cooperative Study No. 207, in which there were 3.2 distal anastomoses per patient, we have tested the hypothesis that grafts within patients tend to act dependently with respect to patency or occlusion by comparing the graft patency data to a binomial distribution (i.e., that distribution that would have been manifest if grafts were independent). Because the graft patency results in Study No. 207 significantly deviated from the binomial distribution (p = 0.0003), a more appropriate analysis for graft patency data was applied using a ratio estimate as applied to cluster sampling. The statistical methods used in 11 previous clinical trials of antithrombotic therapy after coronary artery bypass grafting were examined. Only one of the previous studies used such an analysis, and three additional reports attempted to correct for dependency of grafts within patients in their analyses using other statistical methods. In seven of the studies the investigators did not address the potential problem of a dependent relationship between multiple grafts within patients. We conclude that grafts within patients act as dependent experimental units and that the ratio estimate as applied to cluster sampling may be appropriately applied to these data.


A prospective crossover comparison study of the single-needle and multiple-needle techniques for facet-joint medial branch block.
Medial branch blocks have been widely described in the literature as a diagnostic tool for facet joint pain. Recently, a new "single-needle' technique was described that is purported to be equally accurate, and in some respects, superior to the standard multiple-needle technique. To date, no studies have been performed that compared these 2 techniques. In a multicenter setting, 24 subjects underwent 2 separate diagnostic medial-branch blocks in a randomized, single-blind crossover comparison of the single-needle and multiple-needle techniques. Multiple variables were compared between the 2 techniques, including procedure-related discomfort, post-procedure pain relief, volume of local anesthetic required, accuracy as determined by final needle position and contrast-media spread, and time needed to perform the procedure. In this pilot study, the single-needle technique resulted in less procedure-related pain (P = .0003), required less superficial local anesthesia (P =.0006), and took less time to complete (P < .0001) than did the multiple-needle approach. With regard to final needle position, contrast spread, and post-procedure pain relief (P = .8), no differences were noted between the 2 techniques. Our results indicate that the single-needle technique takes less time to perform and causes less patient discomfort than does the standard technique but provides the same degree of accuracy. More studies with larger sample sizes are needed to corroborate these results and explore the effect the single-needle approach has on the rate of false-positive medial branch blocks.


Inclusion of People with Intellectual Disabilities in Health Literacy: Lessons Learned from Three Participative Projects for Future Initiatives.
Background: People with intellectual disabilities (IDs) constitute a high-risk group in relation to several diseases. Promoting their health literacy (HL) could be highly beneficial in the management of health information and making informed decisions. However, there are varying ranges of cognitive, communication and literacy levels in people with IDs. According to our literature review, a HL concept for this target group has not been adequately conceptualized. Methods: To increase knowledge about the target group, adapted HL results from three innovative (research) projects are presented. Results: The key factors are: a) target group orientation; b) social context and everyday life; c) individual resources, like communication and literacy levels; d) a multi-modal strategy to strengthen HL; and e) the self-determination and participation of people with IDs. Conclusions: The projects illustrate that the HL of people with IDs has been successfully addressed by taking these key factors into account. A target-group-orientated HL concept could affect more than positive health outcomes; it could also empower a high-risk group in relation to health problems. However, to develop successful action concepts and strategies, valid data are crucial. The heterogeneity of people with IDs is one of the biggest challenges in obtaining such data. Future studies will need to face these challenges.


Morphological plasticity in fungi.
Fungi grow for the most part as hyphae extending at their tips. Hyphae aggregate into mycelia, the form of which is dependent on many factors but often on the density of tips which is a function of such factors as the degree of hyphal branching, anastomoses and tip and hyphal death. Some possible mechanisms behind these processes are considered. A particularly important element in tip growth and branching is the movement of protons across the plasma membrane. Certain rhythmic growth phenomena are discussed in these terms. Another important element in morphological development is water flow bringing about a redistribution of solutes within a mycelium and probably influencing wall hydration and wall extensibility. Finally, special consideration is given to development of basidiomycete vegetative mycelium where there are indications that cytoplasmic factors can modulate the expressions of the nuclear genome.


Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons.
Lower muscle mass has been correlated with poor physical function; however, no studies have examined this relationship prospectively. This study aims to investigate whether low muscle mass, low muscle strength, and greater fat infiltration into the muscle predict incident mobility limitation. Our study cohort included 3075 well-functioning black and white men and women aged 70-79 years participating in the Health, Aging, and Body Composition study. Participants were followed for 2.5 years. Muscle cross-sectional area and muscle tissue attenuation (a measure of fat infiltration) were measured by computed tomography at the mid-thigh, and knee extensor strength by using a KinCom dynamometer. Incident mobility limitation was defined as two consecutive self-reports of any difficulty walking one-quarter mile or climbing 10 steps. Mobility limitations were developed by 22.3% of the men and by 31.8% of the women. Cox's proportional hazards models, adjusting for demographic, lifestyle, and health factors, showed a hazard ratio of 1.90 [95% confidence interval (CI), 1.27-2.84] in men and 1.68 (95% CI, 1.23-2.31) in women for the lowest compared to the highest quartile of muscle area (p <.01 for trend). Results for muscle strength were 2.02 (95% CI, 1.39-2.94) and 1.91 (95% CI, 1.41-2.58), p <.001 trend, and for muscle attenuation were 1.91 (95% CI, 1.31-2.83) and 1.68 (95% CI, 1.20-2.35), p <.01 for trend. When included in one model, only muscle attenuation and muscle strength independently predicted mobility limitation (p < .05). Among men and women, associations were similar for blacks and whites. Lower muscle mass (smaller cross-sectional thigh muscle area), greater fat infiltration into the muscle, and lower knee extensor muscle strength are associated with increased risk of mobility loss in older men and women. The association between low muscle mass and functional decline seems to be a function of underlying muscle strength.


[The effects of oxygen partial pressure changes on the osteometric markers of the bone tissue in rats].
Our purpose was to investigate the oxygen partial pressure changes on the osteometric and biochemical markers of bone tissue in rats. It was shown that breathing of altered gas mixture did not change the mass, general length, sagittal diameter and density thigh-bones in 12-month Wistar male-rats. The dosed normobaric hypoxia increased the activity of alkaline phosphatase and decreased the activity of tartrate-resistant acid phosphatase. At the same time normobaric hyperoxia with 40 and 90% oxygen conversely decreased the activity of alkaline phosphatase and increased the activity of tartrate-resistant acid phosphatase.


Inclusion and reactivity of main group radicals in the porous framework MIL-53(Al).
Inclusion of the dithiadiazolyl and diselenadiazolyl radicals PhCNEEN (E = S, Se) into the porous framework, Al(bdc)(OH) [MIL-53(Al); bdc = 1,4-benzenedicarboxylate] was achieved by vacuum sublimation. PXRD studies reveal the inclusion complexes adopt the orthorhombic space group Imma. Variable temperature PXRD studies coupled with thermal analysis reveal that for PhCNSSN@MIL-53(Al), radical elimination from the pores at elevated temperatures is accompanied by an opening of the pore channels. Radicals can also be extracted from the framework using an appropriate solvent. Oxidation of the radical guest within the host framework has been achieved with Cl2 or Br2 and led to complete radical oxidation (based on EPR studies) whereas the milder oxidant I2 leads to incomplete oxidation.


Cancer and Autism: How PTEN Mutations Degrade Function at the Membrane and Isoform Expression in the Human Brain.
Mutations causing loss of PTEN lipid phosphatase activity can promote cancer, benign tumors (PHTS), and neurodevelopmental disorders (NDDs). Exactly how they preferentially trigger distinct phenotypic outcomes has been puzzling. Here, we demonstrate that PTEN mutations differentially allosterically bias P loop dynamics and its connection to the catalytic site, affecting catalytic activity. NDD-related mutations are likely to sample conformations of the functional wild-type state, while sampled conformations for the strong, cancer-related driver mutation hotspots favor catalysis-primed conformations, suggesting that NDD mutations are likely to be weaker, and our large-scale simulations show why. Prenatal PTEN isoform expression data suggest exons 5 and 7, which harbor NDD mutations, as cancer-risk carriers. Since cancer requires more than a single mutation, our conformational and genomic analysis helps discover how same protein mutations can foster different clinical manifestations, articulates a role for co-occurring background latent driver mutations, and uncovers relationships of splicing isoform expression to life expectancy.


Complete genome sequence of Metallosphaera cuprina, a metal sulfide-oxidizing archaeon from a hot spring.
The genome of the metal sulfide-oxidizing, thermoacidophilic strain Metallosphaera cuprina Ar-4 has been completely sequenced and annotated. Originally isolated from a sulfuric hot spring, strain Ar-4 grows optimally at 65°C and a pH of 3.5. The M. cuprina genome has a 1,840,348-bp circular chromosome (2,029 open reading frames [ORFs]) and is 16% smaller than the previously sequenced Metallosphaera sedula genome. Compared to the M. sedula genome, there are no counterpart genes in the M. cuprina genome for about 480 ORFs in the M. sedula genome, of which 243 ORFs are annotated as hypothetical protein genes. Still, there are 233 ORFs uniquely occurring in M. cuprina. Genome annotation supports that M. cuprina lives a facultative life on CO(2) and organics and obtains energy from oxidation of sulfidic ores and reduced inorganic sulfuric compounds.


Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.
To evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania. Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone plus mood stabilizer or placebo plus mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (log-rank test). The study was conducted from December 2005 to May 2008. A total of 127 and 113 subjects were randomly assigned to ziprasidone and placebo, respectively. Intervention for a mood episode was required in 19.7% and 32.4% of ziprasidone and placebo subjects, respectively. The time to intervention for a mood episode was significantly longer for ziprasidone than placebo (P = .0104). The median time to intervention for a mood episode among those requiring such an intervention (n = 61) was 43.0 days for ziprasidone versus 26.5 days for placebo. The time to discontinuation for any reason was significantly longer for ziprasidone (P = .0047). Adjunctive ziprasidone treatment was well tolerated. Among treatment-emergent adverse events occurring in > or = 5% of subjects in either treatment group during period 2, only tremor occurred more frequently in the ziprasidone versus placebo group (6.3% vs 3.6%). Ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania. clinicaltrials.gov Identifier: NCT00280566.


The effects of chronic, low doses of Ra-226 on cultured fish and human cells.
To determine the chronic low-dose radiation effects caused by α-particle radiation from (226)Ra over multiple cell generations in CHSE/F fish cells and HaCaT human cells. CHSE/F cells and HaCaT cells were cultured in medium containing (226)Ra to deliver the chronic low-dose α-particle radiation. Clonogenic assay was used to test the clonogenic survival fractions of cells with or without being exposed to radiation from (226)Ra. The chronic low-dose radiation from (226)Ra does have effects on the clonogenic survival of CHSE/F cells and HaCaT cells. When CHSE/F cells were cultured in (226)Ra-medium over 9 passages for about 134 days, the clonogenic surviving fractions for cells irradiated at dose rates ranging from 0.00066 to 0.66mGy/d were significantly lower than that of cells sham irradiated. For HaCaT cells grown in medium containing the same range of (226)Ra activity, the clonogenic surviving fraction decreased at first and reached the lowest value at about 42 days (8 passages). After that, the clonogenic survival began to increase, and was significantly higher than that of control cells by the end of the experimental period. The chronic, low-dose high LET radiation from (226)Ra can influence the clonogenic survival of irradiated cells. CHSE/F cells were sensitized by the radiation, and HaCaT cells were initially sensitized but later appeared to be adapted. The results could have implications for determining risk from chronic versus acute exposures to radium.


Intercontinental dispersal of giant thermophilic ants across the Arctic during early Eocene hyperthermals.
Early Eocene land bridges allowed numerous plant and animal species to cross between Europe and North America via the Arctic. While many species suited to prevailing cool Arctic climates would have been able to cross throughout much of this period, others would have found dispersal opportunities only during limited intervals when their requirements for higher temperatures were met. Here, we present Titanomyrma lubei gen. et sp. nov. from Wyoming, USA, a new giant (greater than 5 cm long) formiciine ant from the early Eocene (approx. 49.5 Ma) Green River Formation. We show that the extinct ant subfamily Formiciinae is only known from localities with an estimated mean annual temperature of about 20°C or greater, consistent with the tropical ranges of almost all of the largest living ant species. This is, to our knowledge, the first known formiciine of gigantic size in the Western Hemisphere and the first reported cross-Arctic dispersal by a thermophilic insect group. This implies intercontinental migration during one or more brief high-temperature episodes (hyperthermals) sometime between the latest Palaeocene establishment of intercontinental land connections and the presence of giant formiciines in Europe and North America by the early middle Eocene.


Amino acid treatment enhances protein recovery from sediment and soils for metaproteomic studies.
Characterization of microbial protein expression provides information necessary to better understand the unique biological pathways that occur within soil microbial communities that contribute to atmospheric CO2 levels and the earth's changing climate. A significant challenge in studying the soil microbial community proteome is the initial dissociation of bacterial proteins from the complex mixture of particles found in natural soil. The differential extraction of intact bacterial cells limits the characterization of the complete representation of a microbial community. However, in situ lysis of bacterial cells in soil can lead to potentially high levels of protein adsorption to soil particles. Here, we investigated various amino acids for their ability to block soil protein adsorption sites prior to in situ lysis of bacterial cells, as well as their compatibility with both tryptic digestion and mass spectrometric analysis. The treatments were tested by adding proteins from lysed Escherichia coli cells to representative treated and untreated soil samples. The results show that it is possible to significantly increase protein identifications through blockage of binding sites on a variety of soil and sediment textures; use of an optimized desorption buffer further increases the number of identifications.


Endometrial stromal tumors: Diagnostic updates and challenges.
Endometrial stromal tumors are rare uterine mesenchymal tumors of endometrial stromal origin. They are classified into endometrial stromal nodule, low-grade endometrial stromal sarcoma, high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma by the current (2020) WHO classification. Correct diagnosis of endometrial stromal tumors is critical for proper patient management. However, due to infrequent encounters, overlapping morphological features and immunohistochemical profiles, the differential diagnoses among endometrial stromal lesions and their morphologic mimics are often challenging. Partially with our own experience, here we review and summarize the tumor morphology, immunohistochemical phenotype, as well as molecular feature of endometrial stromal tumors and key differential diagnoses, emphasizing the newest developments and their utilization in daily practice.


Graphonomy: Universal Image Parsing via Graph Reasoning and Transfer.
Prior highly-tuned image parsing models are usually studied in a certain domain with a specific set of semantic labels and can hardly be adapted into other scenarios (e.g.sharing discrepant label granularity) without extensive re-training. Learning a single universal parsing model by unifying label annotations from different domains or at various levels of granularity is a crucial but rarely addressed topic. This poses many fundamental learning challenges, e.g.discovering underlying semantic structures among different label granularity or mining label correlation across relevant tasks. To address these challenges, we propose a graph reasoning and transfer learning framework, named "Graphonomy," which incorporates human knowledge and label taxonomy into the intermediate graph representation learning beyond local convolutions. In particular, Graphonomy learns the global and structured semantic coherency in multiple domains via semantic-aware graph reasoning and transfer, enforcing the mutual benefits of the parsing across domains (e.g.different datasets or co-related tasks). The Graphonomy includes two iterated modules: Intra-Graph Reasoning and Inter-Graph Transfer modules. The former extracts the semantic graph in each domain to improve the feature representation learning by propagating information with the graph; the latter exploits the dependencies among the graphs from different domains for bidirectional knowledge transfer. We apply Graphonomy to two relevant but different image understanding research topics: human parsing and panoptic segmentation, and show Graphonomy can handle both of them well via a standard pipeline against current state-of-the-art approaches. Moreover, some extra benefit of our framework is demonstrated, e.g., generating the human parsing at various levels of granularity by unifying annotations across different datasets.


Enhancing Substance Abuse Treatment Engagement in Incarcerated Adolescents.
The purpose of this study was to determine whether motivational interviewing (MI), compared with an attention control condition (relaxation training [RT]) enhances substance abuse treatment engagement in incarcerated adolescents. At the start of incarceration, adolescents were randomly assigned to individually administered MI or RT. Subsequently, therapists and adolescents (N = 130) rated degree of adolescent participation in the facility's standard care group-based treatments targeting crime and substance use. All adolescents received the facility standard care treatment after their individual MI or RT session. MI statistically significantly mitigated negative substance abuse treatment engagement. Other indicators of treatment engagement were in the expected direction; however, effect sizes were small and nonsignificant. These findings are significant, given concerns regarding the deleterious effects of treating delinquent adolescents in groups and the potential for adolescents to reinforce each other's negative behavior, which in turn may lead to escalated substance use and other delinquent behaviors after release.


Constructing the "home-side" of a scientific legacy: Mary Everest Boole, pedagogy, and domesticity.
The Victorian writer Mary Everest Boole (1832-1916) developed an idiosyncratic pedagogical treatment of arithmetic, algebra, and logic. Her pedagogy favored active, child-directed learning, and is now generally admired as ahead of its time, though it must be deciphered through fairly eccentric delivery. A recurring theme in Mrs. Boole's prolific writing is the misunderstood legacy of her late husband, the renowned mathematician and logician George Boole (1815-1864). As existing literature has shown, she worked to promote a morally and religiously charged understanding of his work. More fundamentally, she presented an all-encompassing pedagogical perspective on Mr. Boole's life and work. Across her voluminous publications, Mrs. Boole filtered everything-mathematics, logic, religion, morality, and homelife-through the lens of pedagogy. She used this expansive conception of teaching to span the gulf between professional and domestic work, thereby claiming a privileged domestic perspective on her husband's intellectual output and enlisting his legacy as a resource for her own writing. The Booles' entangled careers show how particular ways of practicing domesticity could shape and be shaped by mathematical identities and ideas.


Dihydrotestosterone influenced numbers of healthy follicles and follicular amounts of LH receptor mRNA during the follicular phase of the estrous cycle in gilts.
The present experiments were conducted to determine androgenic effects on numbers, health, and amounts of gonadotropin receptor mRNA in late developing follicles of gilts. Gilts (n=5 per group) received daily injections of one of the following treatments on days 13-16 or days 13-18 of the estrous cycle: corn oil, 5alpha-dihydrotestosterone (DHT, 10 mg), flutamide (1.5 g, an androgen receptor inhibitor), DHT (10 mg) plus flutamide (1.5 g), testosterone (10 mg), and testosterone (10 mg) plus flutamide (1.5 g). Ovarian follicles > or =5 mm in diameter were evaluated on day 17 or 19, 24 h after receiving the last treatment dose. Follicles were classified as healthy (H), moderately atretic (MA), or very atretic (VA). Treatment with DHT increased (P<0.05) the numbers of H follicles relative to control gilts on days 17 and 19. DHT administration from days 13 to 16 diminished (P<0.05) the amounts of LH receptor (LHR) mRNA in H follicles from day 17 (relative amounts: 1.45+/-0.33 and 2.72+/-0.33 for DHT- and vehicle-treated gilts respectively). The effects of DHT on numbers of H follicles and LHR mRNA were not observed in gilts receiving DHT plus flutamide. Androgens did not influence numbers of MA, VA, and total follicles, or follicular estradiol-17beta concentrations and amounts of FSHR mRNA. Treating gilts with DHT during follicular recruitment and selection did not induce changes in the numbers of total follicles > or =5 mm, but rather increased the numbers of healthy follicles in this follicular population in association with decreased amounts of LHR mRNA.


Slow compressional wave propagation in wet human and bovine cortical bone.
Ultrasonic wave propagation in bovine plexiform and human Haversian bone was studied in the range 0.5 to 15 megahertz. A new longitudinal wave was observed which traveled more slowly than the ordinary longitudinal wave. The slow wave was associated with the dynamics of fluid motion in the pores of bone.


Soybean Roots and Soil From High- and Low-Yielding Field Sites Have Different Microbiome Composition.
The occurrence of high- (H) and low- (L) yielding field sites within a farm is a commonly observed phenomenon in soybean cultivation. Site topography, soil physical and chemical attributes, and soil/root-associated microbial composition can contribute to this phenomenon. In order to better understand the microbial dynamics associated with each site type (H/L), we collected bulk soil (BS), rhizosphere soil (RS), and soybean root (R) samples from historically high and low yield sites across eight Pennsylvania farms at V1 (first trifoliate) and R8 (maturity) soybean growth stages (SGS). We extracted DNA extracted from collected samples and performed high-throughput sequencing of PCR amplicons from both the fungal ITS and prokaryotic 16S rRNA gene regions. Sequences were then grouped into amplicon sequence variants (ASVs) and subjected to network analysis. Based on both ITS and 16S rRNA gene data, a greater network size and edges were observed for all sample types from H-sites compared to L-sites at both SGS. Network analysis suggested that the number of potential microbial interactions/associations were greater in samples from H-sites compared to L-sites. Diversity analyses indicated that site-type was not a main driver of alpha and beta diversity in soybean-associated microbial communities. L-sites contained a greater percentage of fungal phytopathogens (ex: Fusarium, Macrophomina, Septoria), while H-sites contained a greater percentage of mycoparasitic (ex: Trichoderma) and entomopathogenic (ex: Metarhizium) fungal genera. Furthermore, roots from H-sites possessed a greater percentage of Bradyrhizobium and genera known to contain plant growth promoting bacteria (ex: Flavobacterium, Duganella). Overall, our results revealed that there were differences in microbial composition in soil and roots from H- and L-sites across a variety of soybean farms. Based on our findings, we hypothesize that differences in microbial composition could have a causative relationship with observed within-farm variability in soybean yield.


Changing Perception: Outcomes from a Physical Medicine and Rehabilitation Medical Student Interest Fair.
Exposure to the field of Physical Medicine and Rehabilitation (PM&R) is limited in the curricula of many medical schools. As a result, many students lack awareness of the field and may therefore ultimately choose different careers. A medical student PM&R career fair was held on October 13th, 2015 at the University of Pittsburgh, and several local medical schools were invited to participate. Seven stations were deployed to highlight various aspects of PM&R careers. A total of 57 medical students attended, representing five different campuses across three states, with 29 of the reported medical students still within their first or second year of medical education. Self-reported interest and understanding of PM&R significantly increased in those attending the fair compared to baseline, with nearly half requesting further opportunities for faculty mentorship. These results indicate that PM&R interest fairs may be a means to further student understanding and awareness of PM&R while providing an opportunity to become more involved in the field.


Manual treatment for kidney mobility and symptoms in women with nonspecific low back pain and urinary infections.
Recent studies have suggested a connection between low back pain (LBP) and urinary tract infections (UTI). These disturbances could be triggered via visceral-somatic pathways, and there is evidence that kidney mobility is reduced in patients suffering from nonspecific LBP. Manual treatment of the perinephric fascia could improve both kidney mobility and LBP related symptoms. To assess whether manual treatment relieves UTI and reduces pain in patients with nonspecific LBP through improvement in kidney mobility. Records from all patients treated at a single physical therapy center in 2019 were retrospectively reviewed. Patients were included if they were 18 years of age or older, had nonspecific LBP, and experienced at least one UTI episode in the 3 months before presentation. Patients were excluded if they had undergone manipulative treatment in the 6 months before presentation, if they had one of several medical conditions, if they had a history of chronic pain medication use, and more. Patient records were divided into two groups for analysis: those who were treated with manipulative techniques of the fascia with thrust movement (Group A) vs those who were treated without thrust movement (Group B). Kidney Mobility Scores (KMS) were analyzed using high resolution ultrasound. Symptoms as reported at patients' 1 month follow up visits were also used to assess outcomes; these included UTI relapse, lumbar spine mobility assessed with a modified Schober test, and lumbar spine pain. Of 126 available records, 20 patients were included in this retrospective study (10 in Group A and 10 in Group B), all of whom who completed treatment and attended their 1 month follow up visit. Treatments took place in a single session for all patients and all underwent ultrasound of the right kidney before and after treatment. The mean (± standard deviation) KMS (1.9 ± 1.1), mobility when bending (22.7 ± 1.2), and LBP scores (1.2 ± 2.6) of the patients in Group A improved significantly in comparison with the patients in Group B (mean KMS, 1.1 ± 0.8; mobility when bending, 21.9 ± 1.1; and LBP, 3.9 ± 2.7) KMS, p<0.001; mobility when bending, p=0.003; and LBP, p=0.007). At the 1 month follow up visit, no significant statistical changes were observed in UTI recurrence (secondary outcome) in Group A (-16.5 ± 4.3) compared with Group B (-20.4 ± 7) (p=0.152). Manual treatments for nonspecific LBP associated with UTI resulted in improved mobility and symptoms for patients in this retrospective study, including a significant increase in kidney mobility.


Tortuosity entropy: a measure of spatial complexity of behavioral changes in animal movement.
The goal of animal movement analysis is to understand how organisms explore and exploit complex and varying environments. Animals usually exhibit varied and complicated movements, from apparently deterministic behaviours to highly random behaviours. It has been a common method to assess movement efficiency and foraging strategies by means of quantifying and analyzing movement trajectories. Here we introduce a tortuosity entropy (TorEn), a simple measure for quantifying the behavioral change in animal movement data. In our approach, the differences between pairwise successive track points are transformed into symbolic sequences, then we map these symbols into a group of pattern vectors and calculate the information entropy of pattern vectors. We test the algorithm on both simulated trajectories and real trajectories to show that it can accurately identify not only the mixed segments in simulated data, but also the different phases in real movement data. Tortuosity entropy can be easily applied to arbitrary real-world data, whether deterministic or stochastic, stationary or non-stationary. It could be a promising tool to reveal behavioral mechanism in movement data.


[Comparison of learning and concentration effects of "knowledge of results (KR)" in alpha-wave feedback training].
Effects of KR on biofeedback have conventionally been limited by learning factor. The effects of feedback on an increase in EEG alpha have been believed to be so limited as well. However, the effects of KR are also believed to include factors such as motivation and concentration. In this study, the tendencies for alpha rhythm to change were analysed and compared under 3 different KR conditions in order to demonstrate the existence of the later factors. Effects of two parameters, alpha index and microvolt integral value, were also compared. The KR conditions consisted of three types with regard to an increase in alpha rhythm: true-KR, false-KR, and mixed-KR. Ten female college students underwent the feedback task for 10 minutes under each condition. It was shown that (1) the degree of achievement and temporal profile under three KR conditions demonstrated the involvement of learning factor as well as motivation and concentration factors, and (2) alpha index showed the effects of learning, motivation and concentration in KR more distinctly than the microvolt integral value.


Neoadjuvant versus adjuvant chemotherapy for upper tract urothelial carcinoma.
Presently, no level I evidence is available to support the use of neoadjuvant chemotherapy (N)(AC) in patients diagnosed with high-grade upper tract urothelial carcinoma (UTUC). We aimed to compare outcomes of patients treated with radical nephroureterectomy (RNU) who received NAC vs. those who received AC. The National Cancer Database was queried for UTUC patients with cT2-4N0M0 disease treated with RNU and NAC or AC. The role of NAC or AC on overall survival (OS) was evaluated by means of a multivariable Cox regression. Time to death was evaluated from diagnosis. Overall, 936 patients were identified, 128 (14%) received NAC whereas 808 (86%) received AC. No difference was observed between NAC vs. AC in terms of OS (P = 0.9). When sub-stratifying patients who received NAC in responders (cT>pT, given pN0; n = 46 [36%]) vs. nonresponders (n = 82 [64%]), we found that, relatively to AC, the subgroup of patients who did not respond to NAC had higher risk of dying from any cause (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.03,1.91; P = 0.03), whereas the sub-group who responded to NAC had better OS (HR: 0.45; 95% CI: 0.24,0.85; P = 0.01). The 5-year OS rates for responders to NAC vs. nonresponders vs. AC were: 71% vs. 26% vs. 43%, respectively. A landmark analysis fitted at 6 months after diagnosis, including 903 patients (NAC: 126 vs. AC: 777) confirmed our findings. while we found no difference in outcomes between NAC vs. AC in high-grade UTUC, we found a hypothesis-generating association between survival and response to NAC. Further studies aimed at identifying potential responders to NAC are warranted.


Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection.
The rising incidence of Clostridium difficile infection (CDI) could be reduced by lowering exposure to high-risk antibiotics. The objective of this study was to determine the association between antibiotic class and the risk of CDI in the community setting. The EMBASE and PubMed databases were queried without restriction to time period or language. Comparative observational studies and randomized controlled trials (RCTs) considering the impact of exposure to antibiotics on CDI risk among nonhospitalized populations were considered. We estimated pooled odds ratios (OR) for antibiotic classes using random-effect meta-analysis. Our search criteria identified 465 articles, of which 7 met inclusion criteria; all were observational studies. Five studies considered antibiotic risk relative to no antibiotic exposure: clindamycin (OR = 16.80; 95% confidence interval [95% CI], 7.48 to 37.76), fluoroquinolones (OR = 5.50; 95% CI, 4.26 to 7.11), and cephalosporins, monobactams, and carbapenems (CMCs) (OR = 5.68; 95% CI, 2.12 to 15.23) had the largest effects, while macrolides (OR = 2.65; 95% CI, 1.92 to 3.64), sulfonamides and trimethoprim (OR = 1.81; 95% CI, 1.34 to 2.43), and penicillins (OR = 2.71; 95% CI, 1.75 to 4.21) had lower associations with CDI. We noted no effect of tetracyclines on CDI risk (OR = 0.92; 95% CI, 0.61 to 1.40). In the community setting, there is substantial variation in the risk of CDI associated with different antimicrobial classes. Avoidance of high-risk antibiotics (such as clindamycin, CMCs, and fluoroquinolones) in favor of lower-risk antibiotics (such as penicillins, macrolides, and tetracyclines) may help reduce the incidence of CDI.


A case of ulcerative colitis with digital arterial thrombosis.
Thromboembolic events are rare in the course of ulcerative colitis and related with the activity of the disease. These complications are especially seen in young patients and cause high mortality and morbidity. Arterial thrombotic complications are less frequent and are usually seen after a surgical procedure. Here, we present a 36-year-old man with active ulcerative colitis presenting via digital arterial thrombosis and digital necrosis that was not associated with a surgical procedure.


Performance analysis of triple asymmetrical optical multiple ring resonator with a 1 × 3 input-output waveguide for application as an optical filter.
Modelling of a triple asymmetrical optical multiple ring resonator (TAOMRR) with a 1×3 input-output waveguide has been carried out in the present paper, and its performance as an optical filter is analyzed. The mathematical modelling of the proposed configuration is carried out in the z domain using a delay line signal processing technique. Free spectral range (FSR), group delay, and dispersion characteristics of the proposed TAOMRR are evaluated from the frequency response plot obtained in MATLAB from all the possible input-output port configurations. The field analysis of the proposed configuration is realized using the finite difference time domain (FDTD) method. The optimal coupling coefficient obtained from the MATLAB simulation is used to design the various optical couplers in FDTD analysis. The proposed configuration offers three outputs with different FSRs for a single input port, which greatly enhances the data handling capabilities in communication networks.


Verteporfin Inhibits PD-L1 through Autophagy and the STAT1-IRF1-TRIM28 Signaling Axis, Exerting Antitumor Efficacy.
Programmed cell death 1 ligand 1 (PD-L1) is a key driver of tumor-mediated immune suppression, and targeting it with antibodies can induce therapeutic responses. Given the costs and associated toxicity of PD-L1 blockade, alternative therapeutic strategies are needed. Using reverse-phase protein arrays to assess drugs in use or likely to enter trials, we performed a candidate drug screen for inhibitors of PD-L1 expression and identified verteporfin as a possible small-molecule inhibitor. Verteporfin suppressed basal and IFN-induced PD-L1 expression in vitro and in vivo through Golgi-related autophagy and disruption of the STAT1-IRF1-TRIM28 signaling cascade, but did not affect the proinflammatory CIITA-MHC II cascade. Within the tumor microenvironment, verteporfin inhibited PD-L1 expression, which associated with enhanced T-lymphocyte infiltration. Inhibition of chromatin-associated enzyme PARP1 induced PD-L1 expression in high endothelial venules (HEV) in tumors and, when combined with verteporfin, enhanced therapeutic efficacy. Thus, verteporfin effectively targets PD-L1 through transcriptional and posttranslational mechanisms, representing an alternative therapeutic strategy for targeting PD-L1.


Preparation of photolithographically patterned inverse opal hydrogel microstructures and its application to protein patterning.
Protein pattern has played an important role in biosensors, bioMEMS, tissue engineering, fundamental studies of cell biology, and basic proteomics research. Here, we developed a straightforward and effective protein patterning technique using macroporous poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel micropatterns as a three-dimensional (3D) template for protein immobilization. Micropatterns of macroporous hydrogels with inverse opal structures were prepared on poly(ethylene glycol) (PEG)-coated silicon substrates by combining a colloidal crystal templating method with photopatterning. The resultant inverse opal hydrogel (IOH) micropatterns were modified with 3-aminopropyltriethoxysilane using the hydroxyl groups in PHEMA for the covalent immobilization of proteins. Proteins were selectively immobilized only on the hydrogel micropatterns, while the PEG regions served as an effective barrier to protein adsorption. Because of their highly ordered and interconnected 3D macroporous structures and large internal surface areas, protein loading in the IOH micropattern was about six times greater than that on a non-porous hydrogel micropattern, which consequently improved the protein activity. The porosity of the hydrogel micropatterns could be controlled using different sizes of colloidal nanoparticles, and using smaller nanoparticles produced hydrogel micropatterns with higher protein loading capacities and activities. To demonstrate the potential use of IOH micropatterns in biosensor systems, biotin was micropatterned on the hydrogels and the specific binding of streptavidin was successfully assayed using IOH micropatterns with better fluorescence signals and sensitivity than that of the corresponding non-porous hydrogel micropatterns.


[Identification of Biomarkers for Tubular Injury and Interstitial Fibrosis in Chronic Kidney Disease].
In chronic kidney disease (CKD), progressive nephron loss causes tubulointerstitial fibrosis and progressive tubular injury. Recent identification of the major cell populations of myofibroblast precursors in the kidney has enabled us to dissect the fibrogenic process after tubular injury. Kidney pericytes are a possible precursor of myofibroblasts, and may be promising targets for treating fibrogenesis. Our recent studies have shown that pericytes activate Toll-like receptor (TLR) 2/4- and myeloid differentiation primary response 88 (MyD88)-dependent proinflammatory signaling in response to renal tubular injury. We also found active roles of inflammasomes in kidney pericytes, leading to interleukin (IL)-1β and IL-18 secretion. Genetic ablation of MyD88 in pericytes, or pharmacological inhibition of MyD88 signaling by an IL-1 receptor-associated kinase 4 (IRAK4) inhibitor, halted interstitial fibrosis after renal tubular injury. Our data indicate that pericytes not only contribute to interstitial fibrosis by aberrant wound-healing responses, but also serve as innate immune surveillance cells that regulate the inflammatory process, exacerbating tubular injury by the release of cytokines and chemokines. On the other hand, our recent study using a microarray analysis aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage in patients with CKD. The results indicated that 5 genes were up-regulated in the kidney of CKD patients, and that their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury. These findings provide important information for the development of diagnostic tools and therapeutic agents for predicting and preventing progressive renal disease.


Dynamics of ATP-dependent and ATP-independent steppings of myosin-V on actin: catch-bond characteristics.
An analytical theory is presented for the dynamics of myosin-V molecular motor, where both ATP-dependent and ATP-independent steppings are taken into account. Specifically, the dependences of velocity, run length and unbinding rate upon both forward and backward loads and ATP concentration are studied, explaining quantitatively the diverse available single-molecule data and providing predicted results. The results show that the unbinding rate increases with the increase of ATP concentration and levels off at both low and high ATP concentrations. More interestingly, at an ATP concentration that is not very low, the unbinding rate exhibits characteristics of a catch-slip bond under backward load, with the unbinding rate decreasing rapidly with the increase of the backward load in the range smaller than about 2.5 pN and then increasing slowly with the further increase of the backward load. By contrast, under forward load the unbinding rate exhibits a slip-bond characteristic.


Optimal and maximin sample sizes for multicentre cost-effectiveness trials.
This paper deals with the optimal sample sizes for a multicentre trial in which the cost-effectiveness of two treatments in terms of net monetary benefit is studied. A bivariate random-effects model, with the treatment-by-centre interaction effect being random and the main effect of centres fixed or random, is assumed to describe both costs and effects. The optimal sample sizes concern the number of centres and the number of individuals per centre in each of the treatment conditions. These numbers maximize the efficiency or power for given research costs or minimize the research costs at a desired level of efficiency or power. Information on model parameters and sampling costs are required to calculate these optimal sample sizes. In case of limited information on relevant model parameters, sample size formulas are derived for so-called maximin sample sizes which guarantee a power level at the lowest study costs. Four different maximin sample sizes are derived based on the signs of the lower bounds of two model parameters, with one case being worst compared to others. We numerically evaluate the efficiency of the worst case instead of using others. Finally, an expression is derived for calculating optimal and maximin sample sizes that yield sufficient power to test the cost-effectiveness of two treatments.


Proangiogenic function of CD40 ligand-CD40 interactions.
Angiogenesis is a characteristic component of cell-mediated immune inflammation. However, little is known of the immunologic mediators of angiogenesis factor production. Interactions between CD40 ligand (CD40L) and CD40 have been shown to have pluripotent functions in inflammation, including the production of cytokines, chemokines, as well as the angiogenesis factor, vascular endothelial growth factor (VEGF), by endothelial cells. In this study we found that treatment of cultured human endothelial cells with an anti-CD40 Ab (to ligate CD40) resulted in the expression of several other angiogenesis factors, including fibroblast growth factor-2 and the receptors Flt-1 and Flt-4. To determine the proangiogenic effect of CD40L in vivo, human skin was allowed to engraft on SCID mice for 6 wk. These healed human skins express CD40 on resident endothelial cells and monocyte/macrophages, but not on CD20-expressing B cells. Skins were injected with saline, untransfected murine fibroblasts, or murine fibroblasts stably transfected with human CD40L. We found that the injection of CD40L-expressing cells, but not control cells, resulted in the in vivo expression of several angiogenesis factors (including VEGF and fibroblast growth factor) and a marked angiogenesis reaction. Mice treated with anti-VEGF failed to elicit an angiogenesis reaction in response to injection of CD40L-expressing cells, suggesting that the proangiogenic effect of CD40L in vivo is VEGF dependent. These observations imply that ligation of CD40 at a peripheral inflammatory site is of pathophysiological importance as a mediator of both angiogenesis and inflammation.


Effects of diesel exhaust particles on left ventricular function in isoproterenol-induced myocardial injury and healthy rats.
The associations between ambient particulate matter with an aerodiameter less than 2.5 mu m (PM(2.5)) and congestive heart failure (CHF) have been reported. However, the underlying mechanisms remain unclear. We investigated the effect of diesel exhaust particles (DEPs) on left ventricular function in isoproterenol (ISO)-induced myocardial injury and healthy rats. Male Sprague-Dawley (SD) rats were injected with ISO or normal saline. Seven days later, both groups were further assigned to receive either DEPs or normal saline by intratracheal instillation (IT). Echocardiography was used to measure fractional shortening (FS) and left ventricular end-diastolic diameter (LVDd) 24 h before and after IT in each rat. Fractional shortening (FS) was significantly decreased in SD rats treated with ISO as compared to those treated with normal saline (p < .05, t-test). When FS and LVDd before and after treatment were compared in each rat, there was no difference for normal saline treatment in healthy or ISO groups. However, there was significantly lower FS before and after DEPs exposure in both groups (p < .05, paired t-test). When using SD rats treated with normal saline as a reference group, both SD rats treated with DEPs and ISO rats treated with normal saline had lower FS (p < .05 and .0001, respectively, t-test), while ISO rats treated with DEPs had the lowest FS (p < .0001, t-test). Echocardiographic assessment revealed that left ventricular function was impaired by acute DEPs exposure, and this LV function was further compromised in rats with preexisting ISO-induced myocardial injury.


Involving patients and the public In sTatistIcal Analysis pLans (INITIAL): A delphi survey.
Patient and public involvement (PPI) in trials aims to enhance research by improving its relevance and transparency. Planning for statistical analysis begins at the design stage of a trial within the protocol and is refined and detailed in a Statistical Analysis Plan (SAP). While PPI is common in design and protocol development it is less common within SAPs. This study aimed to reach consensus on the most important and relevant statistical analysis items within an SAP to involve patients and the public. We developed a UK-based, two-round Delphi survey through an iterative consultation with public partners, statisticians, and trialists. The consultation process started with 55 items from international guidance for statistical analysis plans. We aimed to recruit at least 20 participants per key stakeholder group for inclusion in the final analysis of the Delphi survey. Participants were asked to vote on each item using a Likert scale from 1 to 9, where a rating of 1 to 3 was labelled as having 'limited importance'; 4 to 6 as 'important but not critical' and 7 to 9 as 'critical' to involve patients and the public. Results from the second round determined consensus on critical items for PPI. The consultation exercise led to the inclusion of 15 statistical items in the Delphi survey. We recruited 179 participants, of whom 72% (129: 36 statisticians, 29 patients or public partners, 25 clinical researchers or methodologists, 27 trial managers, and 12 PPI coordinators) completed both rounds. Participants were on average 48 years old, 60% were female, 84% were White, 64% were based in England and 84% had at least five years' experience in trials. Four items reached consensus regarding critical importance for patient and public involvement: presentation of results to trial participants; summary and presentation of harms; interpretation and presentation of findings in an academic setting; factors impacting how well a treatment works. No consensus was reached for the remaining 11 items. In general, the results were consistent across stakeholder groups. We identified four critical items to involve patients and the public in statistical analysis plans. The remaining 11 items did not reach consensus and need to be considered in a case-by-case basis with most responders considering patient and public involvement important (but not critical). Our research provides a platform to enable focused future efforts to improve patient and public involvement in trials and enhance the relevance of statistical analyses to patients and the public.


The effects of ceruletide in schizophrenia.
Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide diethylamine, a cholecystokininlike peptide, in a placebo-controlled, double-blind, cross-over study. Ceruletide or placebo was administered intramuscularly twice a day for four consecutive days while patients received a constant dose of fluphenazine hydrochloride. Cholecystokinin octapeptide was also administered to four different schizophrenic patients in a double-blind, cross-over study. Cholecystokinin or placebo was administered as a slow intravenous infusion daily for four days. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo, ceruletide, or cholecystokinin administration. Furthermore, there was no tendency for the patients' conditions to either improve or worsen during the course of ceruletide or cholecystokinin treatment. In contrast to previous reports from uncontrolled studies, cholecystokininlike peptides appear to be devoid of antipsychotic properties when administered parenterally.


Differential Expression Profiles and Function Predictions for tRFs & tiRNAs in Skin Injury Induced by Ultraviolet Irradiation.
Ultraviolet (UV) radiation is a major environmental factor contributing skin damage. As UV exposure is inevitable, it is necessary to pay attention to the underlying molecular mechanisms of UV-induced skin damage to develop effective therapies. tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs) are tRNA-derived small RNAs (tsRNAs) that are a novel class of short, non-coding RNAs. However, the functions behind tRFs & tiRNAs in UV-induced skin injury are not yet clear. Firstly, the animal model of ultraviolet irradiation induced skin damage was established. Then the skin samples were preserved for the follow-up experiment. Sequencing was used to screen expression profiles and predict target genes. Compared with normal skin, a total of 31 differentially expressed tRFs & tiRNAs were screened. Among these, 10 tRFs & tiRNAs were shown to be significantly different in expression levels, where there were 4 up-regulated and 6 down-regulated target genes. Bioinformatics analyses revealed potential up-regulated tsRNAs (tRF-Val-AAC-012, tRF-Pro-AGG-012, tRF-Val-CAC-018, tRF-Val-AAC-031) and down-regulated tsRNAs (tRF-Arg-CCT-002, tRF-Trp-TCA-001, tiRNA-Ser-GCT-001, tRF-Gly-CCC-019, tRF-Ala-TGC-001, tRF-Ala-TGC-002). In summary, it was speculated that tRF-Gly-CCC-019 plays an important role in acute skin injury induced by UVB radiation by regulating the ras-related C3 botulinum toxin substrate 1 (Rac1) gene in the WNT signaling pathway. This study provides new insights into the mechanisms and therapeutic targets of UV-induced skin injury.


A prediction nomogram for hepatitis B virus-associated hepatocellular carcinoma.
Background: The present study aimed to develop and validate a new nomogram for predicting the incidence of hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients receiving antiviral therapy from real-world data. Methods: The nomogram was established based on a real-world retrospective study of 764 patients with HBV from October 2008 to July 2020. A predictive model for the incidence of HCC was developed by multivariable Cox regression, and a nomogram was constructed. The predictive accuracy and discriminative ability of the nomogram were assessed by the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Risk group stratification was performed to assess the predictive capacity of the nomogram. The nomogram was compared to three current commonly used predictive models. Results: A total of 764 patients with HBV were recruited for this study. Age, family history of HCC, alcohol consumption, and Aspartate aminotransferase-to-Platelet Ratio Index (APRI) were all independent risk predictors of HCC in CHB patients. The constructed nomogram had good discrimination with a C-index of 0.811. The calibration curve and DCA also proved the reliability and accuracy of the nomogram. Three risk groups (low, moderate, and high) with significantly different prognoses were identified (p < 0.001). The model's performance was significantly better than that of other risk models. Conclusions: The nomogram was superior in predicting HCC risk among CHB patients who received antiviral treatment. The model can be utilized in clinical practice to aid decision-making on the strategy of long-term HCC surveillance, especially for moderate- and high-risk patients.


DNA mimics of red fluorescent proteins (RFP) based on G-quadruplex-confined synthetic RFP chromophores.
Red fluorescent proteins (RFPs) have emerged as valuable biological markers for biomolecule imaging in living systems. Developing artificial fluorogenic systems that mimic RFPs remains an unmet challenge. Here, we describe the design and synthesis of six new chromophores analogous to the chromophores in RFPs. We demonstrate, for the first time, that encapsulating RFP chromophore analogues in canonical DNA G-quadruplexes (G4) can activate bright fluorescence spanning red and far-red spectral regions (Em = 583-668 nm) that nearly match the entire RFP palette. Theoretical calculations and molecular dynamics simulations reveal that DNA G4 greatly restricts radiationless deactivation of chromophores induced by a twisted intramolecular charge transfer (TICT). These DNA mimics of RFP exhibit attractive photophysical properties comparable or superior to natural RFPs, including high quantum yield, large Stokes shifts, excellent anti-photobleaching properties, and two-photon fluorescence. Moreover, these RFP chromophore analogues are a novel and distinctive type of topology-selective G4 probe specific to parallel G4 conformation. The DNA mimics of RFP have been further exploited for imaging of target proteins. Using cancer-specific cell membrane biomarkers as targets, long-term real-time monitoring in single live cell and two-photon fluorescence imaging in tissue sections have been achieved without the need for genetic coding.


Reading microdots of a molecularly imprinted polymer by surface-enhanced Raman spectroscopy.
Writing a molecularly imprinted polymer (MIP) by nano-fountain pen on surface-enhanced Raman scattering (SERS)-active surfaces resulted in site-controlled arrays of microdots of approximately 6-12μm in diameter. The monitoring of SERS spectra with a micro-Raman system enabled examining the uptake and release of the S-propranolol imprinting template and allowed imaging individual dots as well as multiple dots in an array, revealing the distribution of the imprinted polymer. This distribution was confirmed by atomic force microscopy, showing that even in dots of <300nm thickness, corresponding to MIP volumes of 0.5fl, significantly less than previously reported, the target analyte could be detected and identified. This study shows that nanolithography techniques combined with SERS might open the possibility of miniaturized arrayed MIP sensors with label-free, specific and quantitative detection.


Oxcarbazepine treatment of bipolar disorder.
To assess the effectiveness and safety of oxcarbazepine in bipolar disorder. A chart review of naturalistic treatment with oxcarbazepine in 42 outpatients with DSM-IV bipolar disorder (10 males, 32 females; mean +/- SD age = 33.3 +/- 12.4 years; 25 with bipolar disorder type I, 4 with bipolar disorder type II, and 13 with bipolar disorder not otherwise specified) was conducted. Patients had received oxcarbazepine monotherapy or adjunctive therapy between April 2000 and April 2002. Treatment response was defined as a Clinical Global Impressions-Improvement scale score of 1 (marked improvement) or 2 (moderate improvement). Oxcarbazepine was moderately to markedly effective in 24 subjects (57%). Mixed symptoms were the most common indication (52% [22/42]). The mean oxcarbazepine dose was 1056.6 mg/day, and mean treatment duration was 16.2 weeks. Sedation (17/42, 40%) was the most common side effect, but 16 patients (38%) had no side effects. Twenty-two patients (52%) stopped treatment, mostly due to side effects (12/22). Males were more likely to respond than females (10/10 vs. 14/32, p =.006). Dose, bipolar subtype, indication, past nonresponse to mood stabilizers, concurrent mood stabilizer use, and monotherapy use of oxcarbazepine did not differentially predict response. Oxcarbazepine appeared effective in about one half of patients with bipolar disorder and was well tolerated.


Spatial Transcriptomics Reveals Signatures of Histopathological Changes in Muscular Sarcoidosis.
Sarcoidosis is a multisystemic disease characterized by non-caseating granuloma infiltrating various organs. The form with symptomatic muscular involvement is called muscular sarcoidosis. The impact of immune cells composing the granuloma on the skeletal muscle is misunderstood. Here, we investigated the granuloma-skeletal muscle interactions through spatial transcriptomics on two patients affected by muscular sarcoidosis. Five major transcriptomic clusters corresponding to perigranuloma, granuloma, and three successive muscle tissue areas (proximal, intermediate, and distal) around the granuloma were identified. Analyses revealed upregulated pathways in the granuloma corresponding to the activation of T-lymphocytes and monocytes/macrophages cytokines, the upregulation of extracellular matrix signatures, and the induction of the TGF-β signaling in the perigranuloma. A comparison between the proximal and distal muscles to the granuloma revealed an inverse correlation between the distance to the granuloma and the upregulation of cellular response to interferon-γ/α, TNF-α, IL-1,4,6, fibroblast proliferation, epithelial to mesenchymal cell transition, and the downregulation of muscle gene expression. These data shed light on the intercommunications between granulomas and the muscle tissue and provide pathophysiological mechanisms by showing that granuloma immune cells have a direct impact on proximal muscle tissue by promoting its progressive replacement by fibrosis via the expression of pro-inflammatory and profibrosing signatures. These data could possibly explain the evolution towards a state of disability for some patients.


Improving documentation within the acute stroke unit: Introducing a stroke specific clerking proforma.
The Royal College of Physicians outline the guidelines for acute stroke management, they highlight the importance of early identification to enable prompt and effective treatment. The first contact that a clinician has with a patient is usually at the point of clerking. The information obtained and impression formed are the key factors which determine the management plan. The documentation of the information gleaned is subsequently used by all of the medical team to determine the sequence of events from admission. It is crucial in determining any progression of symptoms, of particular importance in this group of patients in whom this can signify potentially fatal consequences. The quality of clerkings of patients admitted to the acute stroke unit in the Royal Devon and Exeter hospital was analysed and subjective data was obtained from the junior doctors involved in this process to determine how well these were being completed. Baseline measurements showed that junior doctors lacked confidence in this process and the initial audit demonstrated that only half of the recommended categories were being completed. To address this issue a stroke specific admission proforma was made and piloted on the ward. Following this, a re-audit was completed which showed a significant improvement in the quality of clerkings produced.


[Development of the Brazilian version of the Multiple Sclerosis Functional Composite Measure (MSFC-BCTRIMS): pilot study].
Initial efforts are reported to develop and validate a Brazilian version of the Multiple Sclerosis Functional Composite Measure (MSFC-BCTRIMS). MSFC is an outcome measure in multiple sclerosis (MS) which assesses motor functions of legs and arms/hands besides cognitive function. MSFC was designed to have better sensitivity and sounder psychometric foundations than traditional measures in detecting therapeutic benefits of disease-modifying agents. Results from the pilot study indicate that the MSFC-BCTRIMS discriminates between MS individuals and a control group. An initial approach to construct validation, intercorrelating the MSFC-BCTRIMS scores with several other measures, suggests speed of information processing is important for both arm/hand and cognitive function.


Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays.
A growing body of evidence indicates that P2X receptors (P2XRs), a family of ligand-gated cation channels activated by extracellular ATP, play an important role in pain signaling. In contrast to the role of the P2X3R subtype that has been extensively studied, the precise roles of others among the seven P2XR subtypes (P2X1R-P2X7R) remain to be determined because of a lack of sufficiently powerful tools to specifically block P2XR signaling in vivo. In the present study, we investigated the behavioral phenotypes of a line of mice in which the p2rx4 gene was disrupted in a series of acute and chronic pain assays. While p2rx4(-/-) mice showed no major defects in pain responses evoked by acute noxious stimuli and local tissue damage or in motor function as compared with wild-type mice, these mice displayed reduced pain responses in two models of chronic pain (inflammatory and neuropathic pain). In a model of chronic inflammatory pain developed by intraplantar injection of complete Freund's adjuvant (CFA), p2rx4(-/-) mice exhibited attenuations of pain hypersensitivity to innocuous mechanical stimuli (tactile allodynia) and also of the CFA-induced swelling of the hindpaw. A most striking phenotype was observed in a test of neuropathic pain: tactile allodynia caused by an injury to spinal nerve was markedly blunted in p2rx4(-/-) mice. By contrast, pain hypersensitivity to a cold stimulus (cold allodynia) after the injury was comparable in wild-type and p2rx4(-/-) mice. Together, these findings reveal a predominant contribution of P2X4R to nerve injury-induced tactile allodynia and, to the lesser extent, peripheral inflammation. Loss of P2X4R produced no defects in acute physiological pain or tissue damaged-induced pain, highlighting the possibility of a therapeutic benefit of blocking P2X4R in the treatment of chronic pain, especially tactile allodynia after nerve injury.


Regulated nuclear targeting of cauliflower mosaic virus.
The mature cauliflower mosaic virus (CaMV) capsid protein (CP), if expressed in the absence of other viral proteins, is transported into the plant cell nucleus by the action of a nuclear localization signal (NLS) close to the N terminus. In contrast, virus particles do not enter the nucleus, but dock at the nuclear membrane, a process inhibited by anti-NLS antibodies or by GTP gamma S, and apparently mediated by interaction of CP with host importin alpha. The very acidic N-terminal extension of the viral CP precursor inhibits nuclear targeting of the protein and hence the precursor is localized in the cytoplasm. We hypothesize that this provides a control mechanism which ensures that the CP precursor is used for virus assembly in the cytoplasm and that only mature virus particles reach the nuclear pore.


Photoredox catalysis using infrared light via triplet fusion upconversion.
Recent advances in photoredox catalysis have made it possible to achieve various challenging synthetic transformations, polymerizations and surface modifications1-3. All of these reactions require ultraviolet- or visible-light stimuli; however, the use of visible-light irradiation has intrinsic challenges. For example, the penetration of visible light through most reaction media is very low, leading to problems in large-scale reactions. Moreover, reactants can compete with photocatalysts for the absorption of incident light, limiting the scope of the reactions. These problems can be overcome by the use of near-infrared light, which has a much higher penetration depth through various media, notably biological tissue4. Here we demonstrate various photoredox transformations under infrared radiation by utilizing the photophysical process of triplet fusion upconversion, a mechanism by which two low-energy photons are converted into a higher-energy photon. We show that this is a general strategy applicable to a wide range of photoredox reactions. We tune the upconversion components to adjust the output light, accessing both orange light and blue light from low-energy infrared light, by pairwise manipulation of the sensitizer and annihilator. We further demonstrate that the annihilator itself can be used as a photocatalyst, thus simplifying the reaction. This approach enables catalysis of high-energy transformations through several opaque barriers using low-energy infrared light.


Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome.
Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.


Integrated cervical smear screening using liquid based cytology and bioimpedance analysis.
To minimize the false negativity in cervical cancer screening with Papanicolaou (Pap) test, there is a need to explore novel cytological technique and identification of unique and important cellular features from the perspectives of morphological as well as biophysical properties. The present study explores the feasibility of low-cost cervical monolayer techniques in extracting cyto-pathological features to classify normal and abnormal conditions. The cervical cells were also analyzed in respect to their electrical bioimpedance. The results show that newly developed monolayer technique for cervical smears is cost effective, capable of cyto-pathological evaluation. Electrical bioimpedance study evidenced distinction between abnormal and normal cell population at more than two order of magnitude difference. The integration of bioimpedance observation along with the proposed low-cost monolayer technology could increase the efficiency of the cervical screening to a greater extent thereby reducing the rates of faulty diagnosis.


Airway inflammatory response to ozone in subjects with different asthma severity.
The aim of this study was to evaluate whether ozone exposure induces a similar airway inflammatory response in subjects with different degrees of asthma severity. Two groups of asthmatic subjects were studied: seven with intermittent mild asthma not requiring regular treatment (group A); and seven with persistent mild asthma requiring regular treatment with inhaled corticosteroids and long-acting beta2-agonists (group B). All subjects were exposed, in a randomized cross-over design, to air or O3 (0.26 parts per million (ppm) for 2 h with intermittent exercise); subjects in group B withdrew from regular treatment 72 h before each exposure. Before the exposure, and 1 and 2 h after the beginning of the exposure they performed a pulmonary function test, and a questionnaire was completed to obtain a total symptom score (TSS). Six hours after the end of the exposure, hypertonic saline (HS) sputum induction was conducted. Sputum cell percentages, eosinophil cationic protein (ECP) and interleukin (IL)-8 concentrations in the sputum supernatant were measured. TSS significantly increased and forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) significantly decreased after O3 exposure in comparison with air exposure in group A, whereas no changes were observed in group B except for a significant decrement of FEV1 2 h after the beginning of O3 exposure. Sputum neutrophil percentage was significantly higher after O3 exposure than after air exposure in both groups (Group A: 70.2% (28-87) versus 26.6% (8.6-73.2); Group B: 62.1% (25-82.4) versus 27.9% (14.4-54)). IL-8 was higher in sputum supernatant collected 6 h after O3 exposure than after air, only in group A. No change due to O3 has been found in sputum eosinophil percentage and ECP concentration in both groups. In conclusion, the degree of airway response to a short-term exposure to ozone is different in subjects with asthma of different severity. The available data do not allow elucidation of whether this difference depends on the severity of the disease or on the regular anti-inflammatory treatment.


Compensating lipid fluxes generated by the aminophospholipid translocase.
By a combined kinetic and thermodynamic model on the transbilayer dynamics and asymmetric distribution of lipids in the red blood cell, compensating lipid fluxes to the exoplasmic leaflet have been analysed, counterbalancing the active transport of aminophospholipids to the cytoplasmic monolayer by the aminophospholipid translocase. The compensating fluxes are assumed to be of passive nature generated by forces of lateral mechanical stress and of lipid concentration differences between the two monolayers. These forces are shown to be caused and maintained by the operation of the aminophospholipid translocase. Simulations reveal that a reduction of the compensating fluxes upon ATP-depletion can be attributed to the inhibition of the aminophospholipid translocase. Thus, a Mg(2+)- and ATP-dependence of the outward movement of phospholipid analogues in the plasma membrane of red blood cells can be expected independent of the existence and operation of an ATP-dependent 'floppase' activity.


Maternal and cord blood homocysteine and folic acid levels in smoking and nonsmoking pregnant women.
The homocysteine level in blood is affected by gender, diet, smoking, folic acid and B-complex vitamins. It is known that higher than normal homocysteine levels in plasma may cause vascular endothelium dysfunction, resulting in the promotion of thrombus formation. In our study, we aimed to assess the effects of smoking during pregnancy on the homocysteine and folic acid levels of the mother and baby. The study included 58 pregnant women who had completed their 37th week of gestation: 30 women were nonsmokers (NONSM) and 28 were smokers (SM). The measurement of homocysteine and folic acid levels in all samples were performed with an Immulite 2000 analyzer, using the chemiluminescence method. Maternal blood folic acid levels were significantly lower in SM (p = 0.041) than in NONSM. In SM, homocysteine levels in the umbilical cord blood were found to be significantly higher than those in NONSM (p = 0.006). High homocysteine levels in umbilical cord blood of smoking mothers, and the probable continuation of passive smoking for the babies after birth, make us think that the baby may have a predisposition towards vascular diseases at later periods in life.


Nasalance statistics for two Mexican populations.
This study was undertaken (1) to obtain nasalance statistics for 152 Spanish-speaking normal males and females in three age groups (young children, older children, and adults) from two cities in central Mexico, (2) to determine the reliability of nasalance statistics, and (3) to test whether cities, age group, and/or gender significantly affected nasalance scores. Randomly selected volunteers, screened for normal speech and hearing, in two middle-class neighborhoods in each city participated. Measures were made in private homes. Eight nasalance measures were obtained: means, "deviations," maxima, and minima for two sets of sentences; one set that contained no nasals (NN); and another set that included sentences containing several words with nasal sounds (N). Reliability (Cronbach's alpha) of the measures was demonstrated to be very high (0.87 to 0.95). Eight multivariate analyses of variance, one for each type of measure, were performed. Significant differences among subgroups were limited to four: (1) cities differed in their NN means, (2) age groups differed in their NN minima, (3) cities differed in their N minima, and (4) genders differed in their N minima. (Bonferroni adjusted alphas = 0.05).


Lower pain and faster treatment with mechanico-chemical endovenous ablation using ClariVein®.
To assess the efficacy of the ClariVein(®) system of mechanico-chemical ablation of superficial vein incompetence. ClariVein(®) treatment uses a micropuncture technique and a 4-Fr sheath to allow a catheter to be placed 1.5 cm from the saphenofemoral junction. Unlike laser (endovenous laser treatment (EVLT)) or radiofrequency ablation (RFA), no tumescence is required. The technique depends on a wire rotating at 3500 r/min causing endothelial damage whilst liquid sclerosant (1.5% sodium tetradecyl sulphate) is infused. The wire is pulled back whilst continuously infusing sclerosant along the target vessel's length. Initially, 8 mL of dilute sclerosant was used, but this was subsequently increased to 12 mL. No routine post-op analgesia was prescribed and specifically no non-steroidal anti-inflammatory drugs. Procedure times and pain scores (visual analogue scale) were recorded and compared to EVLT and RFA. All patients were invited for duplex post-procedure. Fifty-one great saphenous veins and six short saphenous veins were treated and followed up with duplex in the 10 months from July 2011. No major complications or deep vein thrombosis were reported. Duplex showed patency of three treated veins with two more veins having only a short length of occlusion, giving a technical success rate of 91%. Comparison with 50 RFA and 40 EVLT showed procedure times were significantly less for ClariVein(®) (23.0 ± 8.3 min) than for either RFA (37.9 ± 8.3 min) or EVLT (44.1 ± 11.4 min). Median pain scores were significantly lower for ClariVein(®) than RFA and EVLT (1 vs. 5 vs. 6, p < 0.01). Mechanochemical ablation with the ClariVein(®) system is safe and effective. After some initial failures, the use of 12 mL of dilute sclerosant results in a very high technical success rate >90% which accords with the limited published literature. Procedure times and pain scores are significantly better than for RFA and EVLT. We await the long-term clinical outcomes.


Observation and analysis of the Coulter effect through carbon nanotube and graphene nanopores.
Carbon nanotubes (CNTs) and graphene are the rolled and flat analogues of graphitic carbon, respectively, with hexagonal crystalline lattices, and show exceptional molecular transport properties. The empirical study of a single isolated nanopore requires, as evidence, the observation of stochastic, telegraphic noise from a blocking molecule commensurate in size with the pore. This standard is used ubiquitously in patch clamp studies of single, isolated biological ion channels and a wide range of inorganic, synthetic nanopores. In this work, we show that observation and study of stochastic fluctuations for carbon nanopores, both CNTs and graphene-based, enable precision characterization of pore properties that is otherwise unattainable. In the case of voltage clamp measurements of long (0.5-1 mm) CNTs between 0.9 and 2.2 nm in diameter, Coulter blocking of cationic species reveals the complex structuring of the fluid phase for confined water in this diameter range. In the case of graphene, we have pioneered the study and the analysis of stochastic fluctuations in gas transport from a pressurized, graphene-covered micro-well compartment that reveal switching between different values of the membrane permeance attributed to chemical rearrangements of individual graphene pores. This analysis remains the only way to study such single isolated graphene nanopores under these realistic transport conditions of pore rearrangements, in keeping with the thesis of this work. In summary, observation and analysis of Coulter blocking or stochastic fluctuations of permeating flux is an invaluable tool to understand graphene and graphitic nanopores including CNTs.