REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia.
This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2) d 1, 8, 15; B: 72 mg/m(2) d 1, 8; C: 72 mg/m(2) or 90 mg/m(2) d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2) d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.


Differential expression of platelet-derived growth factor receptors in porcine fibroblasts cultured from skin and granulation tissue.
This study investigated the biological response of fibroblasts cultured from uninjured skin and granulation tissue from different stages of healing wounds to the three isoforms of platelet-derived growth factor. Fibroblasts were derived by explant culture from the skin or the granulation tissue that formed within open mesh nylon Schilling-Hunt chambers (postoperative days 10, 20, 30, and 50) which had been implanted subcutaneously in the backs of domestic pigs. Cells were cultured under identical conditions in Dulbecco's modified Eagle's medium containing 10% fetal calf serum. Mitogenic activity was measured with (3)H-thymidine incorporation into DNA. Fibroblasts from normal skin responded equally well to all of the platelet-derived growth factor isoforms in the mitogenic assays. All of the wound fibroblasts exhibited a decreased response to platelet-derived growth factor compared with those from skin. Granulation tissue fibroblasts responded to platelet-derived growth factor BB, less to platelet-derived growth factor AB, and poorly to platelet-derived growth factor AA. These results correlated with a significantly decreased growth rate of fibroblasts in culture from both 30- and 50-day postsurgical wound tissue compared with normal skin. Western blot studies of cell membrane extracts showed that wound fibroblasts contained less than 20% as many platelet-derived growth factor-alpha receptors as found in fibroblasts cultured from normal skin. No significant difference in the amount of platelet-derived growth factor-beta receptor was detected. The decreases in platelet-derived growth factor-alpha receptors are sufficient to account for the diminished response of the wound fibroblasts to all platelet-derived growth factor isoforms and the differential loss of responsiveness to platelet-derived growth factor AA. These results show that fibroblasts derived from granulation tissue of pig skin wounds exhibit a decreased growth response to platelet-derived growth factor and a decreased growth rate in culture media as compared with fibroblasts derived from uninjured skin. How these differences may relate to the physiologic characteristics of normal and healing-impaired wounds is considered.


Structural effect of association on protein molecules in partially folded intermediates.
Fluorescence and circular dichroism spectroscopy, small angle X-ray scattering and high performance liquid gel filtration have shown that oligomerization considerably affects the structural properties and conformational stability of partially folded intermediates of staphylococcal nuclease. Conformational transitions induced by different anions and association in the acid-unfolded protein are described. It is shown that association of non-native conformations of the protein molecule can be an additional structuring factor. The corresponding folding schemes and phase diagrams are suggested.


Conformational Selection of a Polyproline Peptide by Ebola Virus VP30.
An adaptive temperature-based replica-exchange simulation of a peptide extracted from the Ebola virus nucleoprotein containing a polyproline sequence motif is reported. The simulation results of applying the CHARMM36m force field with a generalized Born solvent model is presented. Conformational heterogeneity is described by potentials of mean force (PMFs) for a set of reaction coordinates that define the topological fold space. Starting from an extended backbone conformation of the peptide observed in an X-ray crystallographic assembly with the Ebola virus protein VP30, the PMFs report a conformational landscape populated by chain excursions to collapsed states with limited transitions to either an extended fold or a canonical polyproline type II helix. Clustering of the conformations and applying an elastic network interpolation model yield a multistep pathway of conformational selection that minimizes the net transition-state cost from the population hub to the bound state. Related difference between the pathway endpoints taken from the PMFs reveal a significant free-energy penalty in reaching a population shift. To evaluate sequence fitness of the Ebola virus peptide in generating probability distributions, two human sequence variants are modeled and are found to produce profiles that show extensive deviations, thus suggesting either dissimilar binding mechanisms or the lack of recognition by VP30.


Effect of high-frequency bio-oxidative ozone therapy for masticatory muscle pain: a double-blind randomised clinical trial.
To evaluate the effect of bio-oxidative ozone application at the points of greatest pain in patients with chronic masticatory muscle pain. A total number of 40 (40 women, with a mean age of 31·7) were selected after the diagnosis of myofacial pain dysfunction syndrome according to the Research Diagnostic Criteria for temporomandibular disorder (RDC/TMD). The patients were randomly divided into two groups: patients received the ozone therapy at the point of greatest pain, ozone group (OG; n = 20); patients received the sham ozone therapy at the point of greatest pain, placebo group (PG; n = 20). Ozone and placebo were applied three times per week, for a total of six sessions. Mandibular movements were examined, masticator muscles tenderness were assessed and pressure pain threshold (PPT) values were obtained. Subjective pain levels were evaluated using visual analogue sale (VAS). These assessments were performed at baseline, 1 month and 3 months. Ozono therapy decreased pain intensity and increased PPT values significantly from baseline to 1 month and 3 months in OG compared with PG. PPTs of the temporal (OG = 24·85 ± 6·65, PG = 20·65 ± 5·43, P = 0.035) and masseter (OG = 19·03 ± 6·42, PG = 14·23 ± 2·95, P = 0.007) muscles at 3 months of control (T2) were significantly higher in the OG group. PPT value of the lateral pole was also significantly higher at T2 in the OG group (OG = 21·25 ± 8·43, PG = 15·35 ± 4·18, P = 0.012). Mandibular movements did not show significant differences between treatment groups except right lateral excursion values at T2 (OG = 8·90 ± 1·77, PG = 6·85 ± 2·41, P = 0.003); however, OG demonstrated significantly better results over time. Overall improvements in VAS scores from baseline to 3 months were OG 67·7%; PG 48·4%. Although ozone therapy can be accepted as an alternative treatment modality in the management of masticatory muscle pain, sham ozone therapy (placebo) showed significant improvements in the tested parameters.


Development of a rapid immunoassay system: Luminescent detection of antigen-associated antibody-luciferase in the presence of a dye that absorbs light from free antibody-luciferase.
In this report, we developed a rapid immunoassay system, designated the bioluminescent interference gathering optical (BINGO) assay, which required no time-consuming washing steps for removal of unbound antibodies. This system employed a luciferase (Luc)-conjugated antibody (LucAb) and a dye that absorbed light from the LucAb. The antigen-associated LucAb was localized by transfer of an antigen to the detector-side of a chamber where a detector photomultiplier tube (PMT) was installed. In contrast, the free LucAb was distributed throughout the solution, and the light emitted by the free LucAb was absorbed by the dye. Therefore, only light from LucAb associated with antigen could be detected by the PMT. The new system could be used to rapidly detect the amount of antigen-antibody-Luc complex by collecting steps, such as centrifugation or magnetic collection of antibody-coated magnetic beads. Proof-of-principle experiments were performed using a model system with streptavidin beads and biotinylated Luc. The feasibility of the system was demonstrated using magnetic beads coated with anti-Escherichia coli O157 antibody, enabling detection of 4 × 103 cells in only 15 min. Thus, this system may have applications in a variety of biomedical fields.


Cytomegalovirus retinitis: decreased risk of bilaterality with increased use of systemic treatment. Swiss HIV Cohort Study Group.
Cytomegalovirus (CMV) retinitis may be treated systemically or intravitreally. We reviewed retrospectively patients with CMV retinitis, in order to determine whether systemic treatment was associated with less spread of CMV retinitis from one eye to the other. Of 222 cases, 92 patients had bilateral disease at onset of CMV retinitis, leaving 130 for analysis. Bilaterality occurred in 10 patients during 12,687 days of systemic treatment and in 34 during 14,791 days without systemic treatment (odds ratio [OR] = 2.92; confidence interval [CI], 1.44-5.90). Patients who had received systemic treatment for <50% of the follow-up period had a greater risk of bilaterality (OR = 3.7; CI, 2.79-4.54) than did the more intensively treated patients. CD4 cell levels also contributed to increased risk, but multivariate analysis showed that CD4 cell counts and treatment intensity were independent risk factors. CMV retinitis was more likely to become bilateral in patients who received less intravenous therapy. Local treatment can complete but does not replace systemically administered therapy.


Effects of the intensity of downregulation on outcome of in vitro fertilization and embryo transfer.
Gonadotropin releasing hormone agonists (GnRHa) are commonly used during in vitro fertilization and embryo transfer (IVF/ET) treatment cycles to downregulate the hypothalamic-pituitary-ovarian axis prior to ovarian stimulation with gonadotropins. It has been suggested that profound downregulation may have an adverse effect on IVF/ET outcome. The aim of this study was to examine the relationship between the degree of downregulation and IVF/ET outcome. A retrospective analysis was performed on 151 IVF/ET cycles conducted over a six month period. Intensity of downregulation was assessed using measurements of serum concentrations of luteinizing hormone (LH) and estradiol (E2) made at the end of a two week downregulation period. There was no correlation between serum concentration of LH (whether used alone or in combination with E2) and IVF/ET pregnancy rates. However, those subjects who were more suppressed according to the E2 concentration (< 148 pmol/l, [median]) required significantly more gonadotropins (3306 IU versus 2863 IU, p < 0.05) and took longer for follicles to reach maturity (10.9 days versus 9.7 days, p < 0.05). They also had a lower pregnancy rate per embryo transfer (10.4% versus 28.6%, p < 0.05) compared with those having a higher basal E2 concentration. We conclude from this study that the basal serum E2 concentration rather than the LH concentration is a more sensitive indicator of the intensity of downregulation by GnRHa and it may be a better predictor of IVF outcome.


Locally adaptive decision in detection of clustered microcalcifications in mammograms.
In computer-aided detection or diagnosis of clustered microcalcifications (MCs) in mammograms, the performance often suffers from not only the presence of false positives (FPs) among the detected individual MCs but also large variability in detection accuracy among different cases. To address this issue, we investigate a locally adaptive decision scheme in MC detection by exploiting the noise characteristics in a lesion area. Instead of developing a new MC detector, we propose a decision scheme on how to best decide whether a detected object is an MC or not in the detector output. We formulate the individual MCs as statistical outliers compared to the many noisy detections in a lesion area so as to account for the local image characteristics. To identify the MCs, we first consider a parametric method for outlier detection, the Mahalanobis distance detector, which is based on a multi-dimensional Gaussian distribution on the noisy detections. We also consider a non-parametric method which is based on a stochastic neighbor graph model of the detected objects. We demonstrated the proposed decision approach with two existing MC detectors on a set of 188 full-field digital mammograms (95 cases). The results, evaluated using free response operating characteristic (FROC) analysis, showed a significant improvement in detection accuracy by the proposed outlier decision approach over traditional thresholding (the partial area under the FROC curve increased from 3.95 to 4.25, p-value <10-4). There was also a reduction in case-to-case variability in detected FPs at a given sensitivity level. The proposed adaptive decision approach could not only reduce the number of FPs in detected MCs but also improve case-to-case consistency in detection.


Revision of the genus Parasphaerolaimus (Nematoda: Sphaerolaimidae) with description of new species.
The family Sphaerolaimidae Filipjev, 1918 includes nematodes that are characterized by the finely striated cuticle, round amphids, broad buccal cavity with longitudinal ribs, and single anterior ovary in females. Parasphaerolaimus species from this family are found in intertidal and subtidal sediments and have also been reported from mangroves and estuaries. Parasphaerolaimus pilosus sp. n. is characterized by the moderately plump body, presence of lateral alae, long cervical setae, small amphids in males, and relatively short spicules. As a result of a comprehensive evaluation of species descriptions, eight species in the genus Parasphaerolaimus are recognized valid, and an identification key to species level is provided.


BioFed: federated query processing over life sciences linked open data.
Biomedical data, e.g. from knowledge bases and ontologies, is increasingly made available following open linked data principles, at best as RDF triple data. This is a necessary step towards unified access to biological data sets, but this still requires solutions to query multiple endpoints for their heterogeneous data to eventually retrieve all the meaningful information. Suggested solutions are based on query federation approaches, which require the submission of SPARQL queries to endpoints. Due to the size and complexity of available data, these solutions have to be optimised for efficient retrieval times and for users in life sciences research. Last but not least, over time, the reliability of data resources in terms of access and quality have to be monitored. Our solution (BioFed) federates data over 130 SPARQL endpoints in life sciences and tailors query submission according to the provenance information. BioFed has been evaluated against the state of the art solution FedX and forms an important benchmark for the life science domain. The efficient cataloguing approach of the federated query processing system 'BioFed', the triple pattern wise source selection and the semantic source normalisation forms the core to our solution. It gathers and integrates data from newly identified public endpoints for federated access. Basic provenance information is linked to the retrieved data. Last but not least, BioFed makes use of the latest SPARQL standard (i.e., 1.1) to leverage the full benefits for query federation. The evaluation is based on 10 simple and 10 complex queries, which address data in 10 major and very popular data sources (e.g., Dugbank, Sider). BioFed is a solution for a single-point-of-access for a large number of SPARQL endpoints providing life science data. It facilitates efficient query generation for data access and provides basic provenance information in combination with the retrieved data. BioFed fully supports SPARQL 1.1 and gives access to the endpoint's availability based on the EndpointData graph. Our evaluation of BioFed against FedX is based on 20 heterogeneous federated SPARQL queries and shows competitive execution performance in comparison to FedX, which can be attributed to the provision of provenance information for the source selection. Developing and testing federated query engines for life sciences data is still a challenging task. According to our findings, it is advantageous to optimise the source selection. The cataloguing of SPARQL endpoints, including type and property indexing, leads to efficient querying of data resources over the Web of Data. This could even be further improved through the use of ontologies, e.g., for abstract normalisation of query terms.


A neural theory of attentive visual search: interactions of boundary, surface, spatial, and object representations.
Visual search data are given a unified quantitative explanation by a model of how spatial maps in the parietal cortex and object recognition categories in the inferotemporal cortex deploy attentional resources as they reciprocally interact with visual representations in the prestriate cortex. The model visual representations are organized into multiple boundary and surface representations. Visual search in the model is initiated by organizing multiple items that lie within a given boundary or surface representation into a candidate search grouping. These items are compared with object recognition categories to test for matches or mismatches. Mismatches can trigger deeper searches and recursive selection of new groupings until a target object is identified. The model provides an alternative to Feature Integration and Guided Search models.


Male Breast Cancer Incidence and Mortality Risk in the Japanese Atomic Bomb Survivors - Differences in Excess Relative and Absolute Risk from Female Breast Cancer.
There are well-known associations of ionizing radiation with female breast cancer, and emerging evidence also for male breast cancer. In the United Kingdom, female breast cancer following occupational radiation exposure is among that set of cancers eligible for state compensation and consideration is currently being given to an extension to include male breast cancer. We compare radiation-associated excess relative and absolute risks of male and female breast cancers. Breast cancer incidence and mortality data in the Japanese atomic-bomb survivors were analyzed using relative and absolute risk models via Poisson regression. We observed significant (p ≤ 0.01) dose-related excess risk for male breast cancer incidence and mortality. For incidence and mortality data, there are elevations by factors of approximately 15 and 5, respectively, of relative risk for male compared with female breast cancer incidence, the former borderline significant (p = 0.050). In contrast, for incidence and mortality data, there are elevations by factors of approximately 20 and 10, respectively, of female absolute risk compared with male, both statistically significant (p < 0.001). There are no indications of differences between the sexes in age/time-since-exposure/age-at-exposure modifications to the relative or absolute excess risk. The probability of causation of male breast cancer following radiation exposure exceeds by at least a factor of 5 that of many other malignancies. There is evidence of much higher radiation-associated relative risk for male than for female breast cancer, although absolute excess risks for males are much less than for females. However, the small number of male cases and deaths suggests a degree of caution in interpretation of this finding. Citation: Little MP, McElvenny DM. 2017. Male breast cancer incidence and mortality risk in the Japanese atomic bomb survivors - differences in excess relative and absolute risk from female breast cancer. Environ Health Perspect 125:223-229; http://dx.doi.org/10.1289/EHP151.


Distance metric learning using random forest for cytometry data.
Visualization and clustering of single-cell mass cytometry (CyTOF) data are analytic techniques to identify different cell types. Most of such techniques, such as Euclidean norm, lose their effectiveness when the data dimension increases due to the curse of dimensionality. In this paper, we propose a new cell distance (called CytoRFD) that works based on Random Forest (RF) concept. The experimental results show that the proposed distance can achieve a much higher quality and effectiveness in large data analysis than traditional metrics specially for CyTOF data.


ATP Binding Cassette Transporter A1 is Involved in Extracellular Secretion of Acetylated APE1/Ref-1.
Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associated with its extracellular secretion, despite the lack of an N-terminal protein secretion signal. In this study, we investigated plasma membrane targeting and translocation of APE1/Ref-1 in HEK293T cells with enhanced acetylation. While APE1/Ref-1 targeting was not affected by inhibition of the endoplasmic reticulum/Golgi-dependent secretion, its secretion was reduced by inhibitors of ATP-binding cassette (ABC) transporters, and siRNA-mediated down-regulation of ABC transporter A1. The association between APE1/Ref-1 and ABCA1 transporter was confirmed by proximal ligation assay and immunoprecipitation experiments. An APE1/Ref-1 construct with mutated acetylation sites (K6/K7R) showed reduced co-localization with ABC transporter A1. Exposure of trichostatin A (TSA) induced the acetylation of APE1/Ref-1, which translocated into membrane fraction. Taken together, acetylation of APE1/Ref-1 is considered to be necessary for its extracellular targeting via non-classical secretory pathway using the ABCA1 transporter.


The impact of school smoking policies and student perceptions of enforcement on school smoking prevalence and location of smoking.
The purpose of this study was to comprehensively assess the impact of school tobacco policy intention, implementation and students' perceptions of policy enforcement on smoking rates and location of tobacco use during the school day. Data were obtained from all students in Grades 10-11 (n = 22,318) in 81 randomly selected schools from five Canadian provinces. Policy intention was assessed by coding written school tobacco policies. School administrators most familiar with the tobacco policy completed a survey to assess policy implementation. Results revealed policy intention and implementation subscales did not significantly predict school smoking prevalence but resulted in moderate prediction of tobacco use on school property (R(2) = 0.21-0.27). Students' perceptions of policy enforcement significantly predicted school smoking prevalence (R(2) = 0.36) and location of tobacco use (R(2) = 0.23-0.63). The research findings emphasize: (i) the need to consider both written policy intention and actual policy implementation and (ii) the existence of a policy is not effective in controlling tobacco use unless the policy is implemented and is perceived to be strongly enforced.


The interplay of FLT3 and CXCR4 in acute myeloid leukemia: an ongoing debate.
FLT3 mutations are very frequent in AML and utilization of FLT3 inhibitors as approved treatment options are very common. Despite the initial success of inhibitor treatment, the development of resistances against this treatment is a major challenge in AML therapy. One of the mechanisms causing resistance is the homing of the leukemic cells in the protective niche of the bone marrow microenvironment (BMM). A pathway mediating homing to the BMM and leukemic cell survival is the CXCL12/CXCR4 axis. The analysis of patient samples in several independent studies indicated that FLT3-ITD expression led to higher CXCR4 surface expression. However, several in vitro studies reported contradictory findings, suggesting that FLT3-ITD signaling negatively influenced CXCR4 expression. In this commentary, we provide an overview summarizing the studies dealing with the relationship of FLT3 and CXCR4. Taken together, the current research status is not sufficient to answer the question whether FLT3 and CXCR4 act together or independently in leukemia progression. Systematic analyses in model cell systems are needed to understand the interplay between FLT3 and CXCR4, since this knowledge could lead to the development of more effective treatment strategies for AML patients.


Pd/P(t-Bu)(3): a mild and general catalyst for Stille reactions of aryl chlorides and aryl bromides.
Pd/P(t-Bu)(3) serves as an unusually reactive catalyst for Stille reactions of aryl chlorides and bromides, providing solutions to a number of long-standing challenges. An unprecedented array of aryl chlorides can be cross-coupled with a range of organotin reagents, including SnBu(4). Very hindered biaryls (e.g., tetra-ortho-substituted) can be synthesized, and aryl chlorides can be coupled in the presence of aryl triflates. The method is user-friendly, since a commercially available complex, Pd(P(t-Bu)(3))(2), is effective. Pd/P(t-Bu)(3) also functions as an active catalyst for Stille reactions of aryl bromides, furnishing the first general method for room-temperature cross-couplings.


Common pathway coagulopathy and hemorrhagic edema of infancy.
When screening tests of haemostasis are abnormal, it is important to identify at which point in the coagulation cascade dysfunction may be occurring. This may assist to identify a specific deficiency/dysfunction, the type of bleeding to be anticipated, and replacement therapy if required. Unmasking of an inherited coagulopathy or the development of an acquired coagulopathy may occur in the setting of a second (febrile) illness. Differentiating between inherited and acquired coagulopathies will rely on clinicians taking a thorough personal and family bleeding history, and correlating these findings with the haemostasis screening results.


Extracellular Vesicles altered by a Per- and Polyfluoroalkyl Substance Mixture: In Vitro Dose-Dependent Release, Chemical Content, and MicroRNA Signatures involved in Liver Health.
Per- and polyfluoroalkyl substances (PFAS) have emerged as high priority contaminants due to their ubiquity and pervasiveness in the environment. Numerous PFAS co-occur across sources of drinking water, including areas of North Carolina (NC) with some detected concentrations above the Environmental Protection Agency's health advisory levels. While evidence demonstrates PFAS exposure induces harmful effects in the liver, the involvement of extracellular vesicles (EVs) as potential mediators of these effects has yet to be evaluated. This study set out to evaluate the hypothesis that PFAS mixtures induce dose-dependent release of EVs from liver cells, with exposures causing differential loading of microRNAs (miRNAs) and PFAS chemical signatures. To test this hypothesis, a defined PFAS mixture was prioritized utilizing data collected by the NC PFAS Testing Network. This mixture contained three substances, PFOS, PFOA, and PFHxA, selected based upon co-occurrence patterns and the inclusion of both short-chain (PFHxA) and long-chain (PFOA and PFOS) substances. HepG2 liver cells were exposed to equimolar PFAS, and secreted EVs were isolated from conditioned media and characterized for count and molecular content. Exposures induced a dose-dependent release of EVs carrying miRNAs that were differentially loaded upon exposure. These altered miRNA signatures were predicted to target mRNA pathways involved in hepatic fibrosis and cancer. Chemical concentrations of PFOS, PFOA, and PFHxA were also detected in both parent HepG2 cells and their released EVs, specifically within a 15-fold range after normalizing for protein content. This study therefore established EVs as novel biological responders and measurable endpoints for evaluating PFAS-induced toxicity.


Exercise performance during inspiratory resistance breathing under exhaustive constant load work.
The purpose of this study was to determine the effects of different inspiratory resistances on exercise performance and to describe physiological and subjective responses during constant load work of an intensity that elicits the maximum sensitivity to respiratory factors of respirator wear. Nine subjects (mean age 25.8 +/- 4.8 years) performed exhaustive treadmill exercise during constant load work of 80% of maximal aerobic capacity while inspiring against one of five randomly assigned inspiratory resistance conditions. For inspiratory resistances of 0.20 kPa (R1), 0.29 kPa (R2), 0.39 kPa (R3), and 0.49 kPa (R4), measured at a steady air flow rate of 85 L min-1, average performance times were 84, 75, 54, and 30% of the control condition. Performance time reductions were significant for R3 and R4 trials. Results also indicated a significantly reduced mean respiration rate, minute ventilation, and oxygen ventilatory equivalent (VE/VO2) for the R4 condition at exercise breakpoint compared to control. For resistances R1-R4, mean VE/VO2 were significantly reduced from control by approximately 12, 17, 19, and 31%. At breakpoint, mean ratings of perceived exertion were similar for control, R1, R2, and R3 conditions but were significantly lower for R4 versus control. Breathing comfort did not differ significantly between resistances below the R3 level, but discomfort was significantly greater for conditions R3 and R4. These findings suggest that the impact of the respiratory limitations of respirators can be diminished by employing respirators with inspiratory resistances below the R3 level.


Mechanisms of contrast in NMR imaging.
Nuclear magnetic resonance pixel intensity and contrast-to-noise has been computed and presented in graphical form for various tissues in the normal central nervous system, on the assumption that the signal intensity is proportional to the macroscopic transverse spin magnetization at the time of detection. T1, T2, and spin density values were experimentally determined using chi-square minimization techniques. Additionally, spin density was derived from partial saturation scans obtained with a long repetition time compared with the spin-lattice relaxation time. Pulse sequences discussed comprise partial saturation, saturation recovery, spin echo, and Carr- Purcell - Meiboom -Gill ( CPMG ). The complicated dependence of signal and contrast-to-noise on the pulse timing parameters and the specific pulse sequence makes it appear desirable to display image intensity so that the dependence on the extrinsic (operator-selectable parameter) is eliminated. Whereas T2 images can be derived from CPMG scans without excessive time penalty, this is not the case for T1 and spin density.


A dilated cardiomyopathy mutation blunts adrenergic response and induces contractile dysfunction under chronic angiotensin II stress.
We investigated cardiac contractility in the ACTC E361G transgenic mouse model of dilated cardiomyopathy (DCM). No differences in cardiac dimensions or systolic function were observed in young mice, whereas young adult mice exhibited only mild diastolic abnormalities. Dobutamine had an inotropic and lusitropic effect on the mouse heart. In papillary muscle at 37°C, dobutamine increased relaxation rates [∼50% increase of peak rate of force decline normalized to force (dF/dtmin/F), 25% reduction of time to 90% relaxation (t90) in nontransgenic (NTG) mice], but in the ACTC E361G mouse, dF/dtmin/F was increased 20-30%, and t90 was only reduced 10% at 10 Hz. Pressure-volume measurements showed increases in maximum rate of pressure decline and decreases in time constant of left ventricular pressure decay in the ACTC E361G mouse that were 25-30% of the changes in the NTG mouse, consistent with blunting of the lusitropic response. The inotropic effect of dobutamine was also blunted in ACTC E361G mice, and the dobutamine-stimulated increase in cardiac output (CO) was reduced from 2,100 to 900 μl/min. Mice were treated with high doses of ANG II for 4 wk. The chronic stress treatment evoked systolic dysfunction in ACTC E361G mice but not in NTG. There was a significant reduction in rates of pressure increase and decrease, as well as reduced end-systolic pressure and increased volume. Ejection fraction and CO were reduced in the ACTC E361G mouse, indicating DCM. In vitro DCM-causing mutations uncouple the relationship between Ca(2+) sensitivity and troponin I phosphorylation. We conclude that this leads to the observed, reduced response to β1 agonists and reduced cardiac reserve that predisposes the heart to DCM under conditions of chronic stress.


Fine mapping of Leishmania major susceptibility Locus lmr2 and evidence of a role for Fli1 in disease and wound healing.
Genetic linkage studies of the host response to Leishmania major, the causative agent of cutaneous leishmaniasis, have identified significant genetic complexity in humans and mice. In the mouse model, multiple loci have been implicated in susceptibility to infection, but to date, the genes underlying these loci have not been identified. We now describe the contribution of a novel candidate gene, Fli1, to both L. major resistance and enhanced wound healing. We have previously mapped the L. major response locus, lmr2, to proximal chromosome 9 in a genetic cross between the resistant C57BL/6 strain and the susceptible BALB/c strain. We now show that the presence of the resistant C57BL/6 lmr2 allele in susceptible BALB/c mice confers an enhanced L. major resistance and wound healing phenotype. Fine mapping of the lmr2 locus permitted the localization of the lmr2 quantitative trait locus to a 5-Mb interval comprising 21 genes, of which microarray analysis was able to identify differential expression in 1 gene-Fli1. Analysis of Fli1 expression in wounded and L. major-infected skin and naïve and infected lymph nodes validated the importance of Fli1 in lesion resolution and wound healing and identified 3 polymorphisms in the Fli1 promoter, among which a GA repeat element may be the important contributor.


Topiroxostat ameliorates oxidative stress and inflammation in sepsis-induced lung injury.
Sepsis-induced lung injury was the most common cause of death in patients. Topiroxostat, a novel xanthine oxidoreductase inhibitors, possessed obvious organ protectives effects. Xanthine oxidase played a vital role in acute lung injury. The study aimed to investigate the roles of Topiroxostat in sepsis-induced lung injury. The sepsis rats were established using cecum ligation and perforation. The lung damage induced by sepsis was evaluated by Hematoxylin and Eosin staining and lung tissue wet to dry ratio. The oxidative stress was detected by measurement of reactive oxygen species, malondialdehyde, myeloperoxidase and superoxide dismutase (SOD). The pro-inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1, were measured by Enzyme-Linked Immunosorbent Assay. The cell apoptosis in lung was detected by TUNNEL staining and western blot analysis of apoptosis-related proteins including pro-apoptosis proteins, Bax, cleaved caspase9, cleaved caspase3 and anti-apoptosis protein Bcl2. The results showed that Topiroxostat significantly reduced lung damage, along with decreased oxidative stress, inflammation response and apoptosis in sepsis rats. Topiroxostat exerted markedly protective effects in sepsis-induced lung injury and could be an antioxidant in treating sepsis-induced lung injury.


Preoperatory Anxiety in Patients Undergoing Cardiac Surgery.
Anxiety is a feeling of discomfort produced in face of an unknown event, as an impending cardiac surgery, that can lead to inconveniences in the intervention and subsequent recovery. Being the purpose of this research to analyze pre-surgical anxiety, a descriptive cross-sectional study among patients undergoing cardiac surgery was carried out. Data about sociodemographic variables were collected and the level of anxiety prior to surgery was assessed using the STAI-S scale. Subsequently, descriptive data analyses were performed, relationships among variables were analyzed, and a binary logistic regression model was developed in order to analyze the role of the variables involved in the development of preoperative anxiety. Sixty subjects were finally included; more than 80% had a moderate to high level of anxiety. 26.7% underwent valve surgery and 47% underwent coronary artery bypass graft (CABG) surgery, in the latter case presenting higher levels of anxiety. Statistically significant relationships were found among the level of anxiety and (a) level of studies, (b) first surgical intervention, and (c) the rating given to their previous surgical experience. We concluded that preoperative anxiety in people undergoing cardiac surgery is high and yet it is an underestimated phenomenon. The relationship between the received information and their anxiety level is inversely proportional, so that people programmed for cardiac surgery should be provided with all the information they required, through an individualized intervention.


Treatment implications of predominant polarity and the polarity index: a comprehensive review.
Bipolar disorder (BD) is a serious and recurring condition that affects approximately 2.4% of the global population. About half of BD sufferers have an illness course characterized by either a manic or a depressive predominance. This predominant polarity in BD may be differentially associated with several clinical correlates. The concept of a polarity index (PI) has been recently proposed as an index of the antimanic versus antidepressive efficacy of various maintenance treatments for BD. Notwithstanding its potential clinical utility, predominant polarity was not included in the DSM-5 as a BD course specifier. Here we searched computerized databases for original clinical studies on the role of predominant polarity for selection of and response to pharmacological treatments for BD. Furthermore, we systematically searched the Pubmed database for maintenance randomized controlled trials (RCTs) for BD to determine the PI of the various pharmacological agents for BD. We found support from naturalistic studies that bipolar patients with a predominantly depressive polarity are more likely to be treated with an antidepressive stabilization package, while BD patients with a manic-predominant polarity are more frequently treated with an antimanic stabilization package. Furthermore, predominantly manic BD patients received therapeutic regimens with a higher mean PI. The calculated PI varied from 0.4 (for lamotrigine) to 12.1 (for aripiprazole). This review supports the clinical relevance of predominant polarity as a course specifier for BD. Future studies should investigate the role of baseline, predominant polarity as an outcome predictor of BD maintenance RCTs.


Evaluation of occupational exposure to static magnetic field in MRI sites based on body pose estimation and SMF analytical computation.
This paper tackles the problem of estimating exposure to static magnetic field (SMF) in magnetic resonance imaging (MRI) sites using a non-invasive approach. The proposed approach relies on a vision-based system to detect people's body parts and on a mathematical model to compute SMF exposure. A multi-view camera system was used to capture the MRI room, and a vision-based system was applied to detect body parts. The detected localization was then fed into a mathematical model to compute SMF exposure. In this study, we focused on exposure at the neck due to two main reasons. First, according to regulations, the limit of exposure at head and trunk for MR workers is higher than that for the general public. Second, it was easier to attach a dosimeter at the neck to perform measurements, which allowed a quantitative evaluation of our approach. This approach was applied to two scenarios simulating the daily movements of medical workers for which dosimeter measurements were also recorded. The results indicated that the proposed approach predicted occupational SMF exposure with reasonable accuracy compared with the dosimeter measurements. The proposed approach is a simple safe working procedure to estimate the exposure of MR workers at different parts of the body without wearing any marker detection. It can be applied to reduce occupational SMF exposure, without changes in workers' performances. For that reason, our non-invasive proposed method can be used as a simple safety tool to estimate occupational SMF exposure in MR sites. Bioelectromagnetics. 39:503-515, 2018.© 2018 Wiley Periodicals, Inc.


Periodontitis management in diabetes care.
Periodontitis is the chronic inflammation of the oral cavity involving the gum, teeth and the supporting bone. Since it appears to have a similar pathophysiology as other microvascular complications of diabetes it can be considered to be the fourth chronic microvascular complication of diabetes mellitus. There is a three-fold increase in risk of periodontal disease among patients with diabetes mellitus. Periodontitis in diabetes is associated with increased myocardial infarctions, strokes and renal related complications, poor glycaemic control and an increase in the risk of dying of cardiorenal causes. However, treatment of periodontal disease has been demonstrated to improve glucose control and reduce inflammatory markers. Improvements in periodontal health among patients with diabetes mellitus can be achieved with better oral health education, oral examination in diabetic clinics during regular visits and annual dental examinations by qualified dentists. Dental treatments for periodontal infections include mechanical disruption of the pathogenic biofilm using scaling and planing, use of systemic antibiotics to treat refractory pathogens and specialized dental surgery in advanced disease.


Detecting and treating occlusal caries lesions: a cost-effectiveness analysis.
The health gains and costs resulting from using different caries detection strategies might not only depend on the accuracy of the used method but also the treatment emanating from its use in different populations. We compared combinations of visual-tactile, radiographic, or laser-fluorescence-based detection methods with 1 of 3 treatments (non-, micro-, and invasive treatment) initiated at different cutoffs (treating all or only dentinal lesions) in populations with low or high caries prevalence. A Markov model was constructed to follow an occlusal surface in a permanent molar in an initially 12-y-old male German patient over his lifetime. Prevalence data and transition probabilities were extracted from the literature, while validity parameters of different methods were synthesized or obtained from systematic reviews. Microsimulations were performed to analyze the model, assuming a German health care setting and a mixed public-private payer perspective. Radiographic and fluorescence-based methods led to more overtreatments, especially in populations with low prevalence. For the latter, combining visual-tactile or radiographic detection with microinvasive treatment retained teeth longest (mean 66 y) at lowest costs (329 and 332 Euro, respectively), while combining radiographic or fluorescence-based detections with invasive treatment was the least cost-effective (<60 y, >700 Euro). In populations with high prevalence, combining radiographic detection with microinvasive treatment was most cost-effective (63 y, 528 Euro), while sensitive detection methods combined with invasive treatments were again the least cost-effective (<59 y, >690 Euro). The suitability of detection methods differed significantly between populations, and the cost-effectiveness was greatly influenced by the treatment initiated after lesion detection. The accuracy of a detection method relative to a "gold standard" did not automatically convey into better health or reduced costs. Detection methods should be evaluated not only against their criterion validity but also the long-term effects resulting from their use in different populations.


Fracture risk and the use of a diuretic (indapamide SR) +/- perindopril: a substudy of the Hypertension in the Very Elderly Trial (HYVET).
The Hypertension in the Very Elderly Trial (HYVET) is a placebo controlled double blind trial of treating hypertension with indapamide Slow Release (SR) +/- perindopril in subjects over the age of 80 years. The primary endpoints are stroke (fatal and non fatal). In view of the fact that thiazide diuretics and indapamide reduce urinary calcium and may increase bone mineral density, a fracture sub study was designed to investigate whether or not the trial anti-hypertensive treatment will reduce the fracture rate in very elderly hypertensive subjects. In the trial considerable care is taken to ascertain any fractures and to identify risk factors for fracture, such as falls, co-morbidity, drug treatment, smoking and drinking habits, levels of activity, biochemical abnormalities, cardiac irregularities, impaired cognitive function and symptoms of orthostatic hypotension. POTENTIAL RESULTS: The trial is expected to provide 10,500 patient years of follow-up. Given a fracture rate of 40/1000 patient years and a 20% difference in fracture rate, the power of the sub study is 58% to detect this difference at the 5% level of significance. The corresponding power for a reduction of 25% is 78%. The trial is well under way, expected to complete in 2009, and on target to detect, if present, the above differences in fracture rate.


Giardia duodenalis infection reduces granulocyte infiltration in an in vivo model of bacterial toxin-induced colitis and attenuates inflammation in human intestinal tissue.
Giardia duodenalis (syn. G. intestinalis, G. lamblia) is a predominant cause of waterborne diarrheal disease that may lead to post-infectious functional gastrointestinal disorders. Although Giardia-infected individuals could carry as much as 106 trophozoites per centimetre of gut, their intestinal mucosa is devoid of overt signs of inflammation. Recent studies have shown that in endemic countries where bacterial infectious diseases are common, Giardia infections can protect against the development of diarrheal disease and fever. Conversely, separate observations have indicated Giardia infections may enhance the severity of diarrheal disease from a co-infecting pathogen. Polymorphonuclear leukocytes or neutrophils (PMNs) are granulocytic, innate immune cells characteristic of acute intestinal inflammatory responses against bacterial pathogens that contribute to the development of diarrheal disease following recruitment into intestinal tissues. Giardia cathepsin B cysteine proteases have been shown to attenuate PMN chemotaxis towards IL-8/CXCL8, suggesting Giardia targets PMN accumulation. However, the ability of Giardia infections to attenuate PMN accumulation in vivo and how in turn this effect may alter the host inflammatory response in the intestine has yet to be demonstrated. Herein, we report that Giardia infection attenuates granulocyte tissue infiltration induced by intra-rectal instillation of Clostridium difficile toxin A and B in an isolate-dependent manner. This attenuation of granulocyte infiltration into colonic tissues paralled decreased expression of several cytokines associated with the recruitment of PMNs. Giardia trophozoite isolates that attenuated granulocyte infiltration in vivo also decreased protein expression of cytokines released from inflamed mucosal biopsy tissues collected from patients with active Crohn's disease, including several cytokines associated with PMN recruitment. These results demonstrate for the first time that certain Giardia infections may attenuate PMN accumulation by decreasing the expression of the mediators responsible for their recruitment.


[Committed suicide in the background of the history of previous suicide attempts--a 5-year prospective study of suicide attempts].
The aim of the study was to estimate the risk factors for eventual suicide in the case of individuals hospitalised for a suicide attempts (or attempted suicide). The group examined comprised 238 patients, who, in the years 2000-2001, were hospitalised in the Department of Clinical Toxicology CM UJ in Kraków for suicidal self-intoxication with medical drugs. The group consisted of 63 males and 175 females ranging in age from 17 to 79 years (the mean age was 36 years). The instruments applied in the examination included a structured interview and a set of psychological tests; complementary information was obtained from the patients' case histories. In the year 2005, on the basis of the data from the Institute of Forensic Medicine in Kraków, it was established that 10 of the patients under consideration--6 females, and 4 males--had eventually committed suicide within the period concerned. The retrospective analysis of the case of each of these 10 individuals revealed that the majority of them had been treated psychiatrically for depression or alcoholic addiction, had experienced parental or marital bereavement, or had experienced serious financial difficulties. The subjects' case histories informed also about the cases of suicidal death in the families of several subjects. As should be pointed out, the results of psychological tests obtained earlier by the 10 subjects concerned did not unequivocally indicated high endangerment by the risk of eventually committing suicide. Finally, it is necessary to observe that alcoholism and depression were the most frequently diagnosed mental disorders in the case of the male suicides. In the case of the female suicides, the results of the analysis reveal a variety of psychological, psychiatric and socio-demographic factors that, eventually, could lead to suicide.


HOX-1 and COX-2: Two differentially regulated key mediators of skeletal myoblast tolerance under oxidative stress.
The exact physiological role of oxidative stress as a primary cause for skeletal muscle pathological conditions involving muscle degeneration remains elusive. Therefore, the present study was performed so as to decipher the signalling pathways orchestrating the potential cytoprotective role of heme oxygenase 1 (HOX-1) as well as cyclooxygenase 2 (COX-2) in skeletal myoblasts exposed to H(2)O(2). Cell treatment with H(2)O(2) (0.5 mM) resulted in a time- and dose-dependent response of HOX-1 and COX-2 mRNA and protein levels, with ERK1/2, p38-MAPK and MSK1 found to mediate these effects. Furthermore, Src and JNKs blockade attenuated COX-2 response. Collectively, these novel findings highlight for the first time HOX-1 and COX-2 fundamental contribution to skeletal myoblast tolerance under oxidative stress, since their inhibition significantly attenuated viability of skeletal myoblasts. The data also delineate the various effectors regulating HOX-1 and COX-2 expression, probably alleviating muscle degeneration in related disorders.


Detection of small cell lung cancer bone marrow involvement by discontinuous gradient sedimentation.
Marrow involvement by small cell lung cancer (SCLC) is detected in 10-23% of patients at initial diagnosis by marrow aspirate and biopsy techniques. To improve the detection and potentially monitor marrow involvement by SCLC we have attempted to concentrate malignant cells with clonogenic potential on a discontinuous density gradient (DDG). The bone marrow from 43 patients with SCLC (36 with histologically negative marrow aspirates and biopsies) were separated on a Ficoll-based DDG. Samples were also separated by conventional Ficoll-diatrizoate (FD) (density, 1.077) gradient sedimentation. The cellular interphase from three fractions (F X) corresponding to specific densities 1.050 (F X 1), 1.055 (F X 2), and 1.060 (F X 3) as well as cells separated by Ficoll-diatrizoate (F X FD) centrifugation were isolated and 2.5 X 10(5) cells from each fraction were cultured in 2 ml of 0.3% agar in McCoy's media with 10% fetal calf serum, 2.5 micrograms transferrin, 1 microgram insulin, and 1% penicillin-streptomycin. Colony growth was assessed after 14 days of culture at 37 degrees C and 6% CO2. Tumor colony growth was seen in eight of 36 (22%) patients with histologically negative marrows as well as in four of seven (57%) patients with known involvement. Mean colony growth per 2.5 X 10(5) cells for all 12 patients was 4.3 colonies for F X 1; 8.8 for F X 2; and 2.7 for F X 3. In contrast mean growth from the F X FD was 1.0 colonies. Cells with clonogenic potential could be demonstrated from F X 2 and F X 3 in seven of 12 and eight of 12 patients, respectively; in F X FD four of 12 patients had tumor growth. We conclude that separation of marrow samples by DDG concentrates malignant cells with clonogenic potential at least 8-fold compared to FD separation and that the sensitivity of the clonogenic assay in detecting marrow involvement by SCLC is enhanced by DDG sedimentation.


Influence of the period after ovariectomy on femoral and mandibular bone density and on induced periodontal disease.
This study investigated the influence of the period after ovariectomy on femoral and mandibular bone mineral density (BMD) and on induced periodontal disease. One hundred and twenty-six female Holtzman rats were divided into nine groups: control, sham surgery (SHAM) with and without induction of periodontal disease for 51 and 150 days, and ovariectomy (OVX) with and without induction of periodontal disease for 51 and 150 days. Periodontal disease was induced by placing ligatures on the first lower molars during the last 30 days of each period. BMD was measured by dual-energy x-ray absorptiometry. Vertical bone loss was determined by measuring the distance from the alveolar bone crest to the cemento-enamel junction on the mesial side of the first lower molar. Statistical analyses (Kruskal-Wallis test) revealed a significant difference between the OVX and SHAM groups' global and femoral proximal epiphysis BMD (P <0.001) for 150 days and in the global evaluation for 51 days. For mandibular BMD, no difference was found between the groups of each period. Influence of the period on femoral BMD was found only for the SHAM groups, with lower BMD for the 51-day period compared to the 150-day period (P <0.05). In the global evaluation of the mandible, a lower BMD was found after 51 days. The period was a contributing factor for the vertical bone loss, and it resulted in higher values for the 51-day period (P <0.05). The period influenced the femoral BMD and the vertical bone loss in induced periodontal disease.


Gender differences in the association between mental health status, hypertension, and emergency department visits in the United States.
Hypertension has been found to be elevated in people with mental illness, and this comorbidity may lead to differential emergency department use by gender. Gender differences in this association were assessed using the 2016 Medical Expenditure Panel Survey (n = 20,443). A combined effect variable for mental health and hypertension was created for stratified, multivariable logistic regression analysis. The likelihood of emergency department visits was higher for women compared to men in all categories of the combined effect variable. In particular, regardless of hypertension status, women with poor mental health had 35 percent and 39 percent increased likelihood of emergency department visits compared to men.


[Emission of volatile and semivolatile organic compounds from water-based akrylate paints].
Identification and testing of organic compounds emissions from water-based akrylate paints were conducted. TD-GC/MS system was applied for identification of compounds. Emission was monitored in an environmental chamber with controlled temperature, relative humidity, and air exchange. Quantitative analysis was measured by GC method. Emission of main volatile organic compounds (VOC) semivolatile organic compounds (SVOC) and total volatile organic compounds (TVOC) were defined in various periods of time, within 30 days after paints application. The main organic compounds indicated high level of an initial emission after 24 hours. Some of water-based akrylate paints may release small quantities of SVOC (texanol) even 30 days after their application. It was demonstrated that the first-order emission decay model well describes the emission course from water-based paints.


Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse.
BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.


Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary Microglia.
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.


Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.
These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.


Small sample studies: unique contributions for large sample outcome studies.
There are many important issues relevant to the course of illness and outcome of chronic psychiatric disorders that are not readily amenable to investigation with existing large sample, quantitative methodology. For example, complex interactive phenomena that change over time, such as the longitudinal impact of changes in social and work function on levels of symptomatology, are particularly difficult to quantify and assess in large n studies. Small sample studies are advantageous because they offer the ability to examine the longitudinal interplay of a wide range of variables in individual patients. The small n approach is useful for delineating important new course variables, developing models of course change, and generating unique research hypotheses. In this article, small sample "qualitative" methodology is reviewed, and data derived from recent small n, intensive longitudinal studies are presented. Methodological issues related to addressing qualitative data in large sample, controlled studies are addressed, and specific research hypotheses generated by small sample studies for consideration in future large sample outcome studies are suggested. It is concluded that small sample studies offer unique contributions to the understanding of the determinants of course of illness.


POLYMORPHISM REGENERATION FOR A NEUTRALIZED SELFISH B CHROMOSOME.
Long-run evolution of B chromosomes is mainly made up by an evolutionary arms race between these selfish genetic elements and the standard genome. The suppression of B drive is one of the clearest expressions of genome defense against B chromosomes. After drive neutralization, the B is condemned to extinction unless a new variant showing drive can emerge and replace it. This paper reports the first empirical evidence for the substitution of a neutralized B variant by a new selfish B variant. Such a polymorphism regeneration has recently taken place in a natural population of the grasshopper Eyprepocnemis plorans.


Sertraline in children and adolescents with major depressive disorder.
To explore time to first response and time to first persistent response of sertraline versus placebo and compare these parameters between children (6-11 years old, n = 177) and adolescents (12-17 years old, n = 199) with major depressive disorder. A 10-week placebo-controlled treatment was followed by a 24-week open-label sertraline treatment. The double-blind studies were not powered to detect efficacy differences between age groups. A post hoc analysis explored time to first response and first persistent response using the Children's Depression Rating Scale-Revised and Clinical Global Impressions-Improvement predefined criteria. There were no statistically significant differences in time to first response or first persistent response between sertraline and placebo in children, except for time to first response on Clinical Global Impressions-Improvement. Sertraline had a significantly faster time to first persistent response in adolescents compared to placebo. Within treatment groups, children had a significantly faster time to first response than adolescents, whether treated with placebo or sertraline, but not on time to first persistent response. Both age groups showed similar improvement over 34 weeks of treatment. In the double-blind studies, children and adolescents had different patterns of response with sertraline vs. placebo.


Sub-acute Changes on MRI Measures of Cerebral Blood Flow and Venous Oxygen Saturation in Concussed Australian Rules Footballers.
Sports-related concussion (SRC) is common in collision sport athletes. There is growing evidence that repetitive SRC can have serious neurological consequences, particularly when the repetitive injuries occur when the brain has yet to fully recover from the initial injury. Hence, there is a need to identify biomarkers that are capable of determining SRC recovery so that they can guide clinical decisions pertaining to return-to-play. Cerebral venous oxygen saturation (SvO2) and cerebral blood flow (CBF) can be measured using magnetic resonance imaging (MRI) and may provide insights into changing energy demands and recovery following SRC. In this study we therefore investigated SvO2 and CBF in a cohort of concussed amateur Australian Football athletes (i.e., Australia's most participated collision sport). Male and female Australian footballers (n = 13) underwent MRI after being cleared to return to play following a mandatory 13-day recovery period and were compared to a group of control Australian footballers (n = 16) with no recent history of SRC (i.e., > 3 months since last SRC). Despite the concussed Australian footballers being cleared to return to play at the time of MRI, we found evidence of significantly increased susceptibility in the global white matter (p = 0.020) and a trend (F5,21 = 2.404, p = 0.071) for reduced relative CBF (relCBF) compared to the control group. Further, there was evidence of an interaction between sex and injury in straight sinus susceptibility values (F1,25 = 3.858, p = 0.061) which were decreased in female SRC athletes (p = 0.053). Of note, there were significant negative correlations between straight sinus susceptibility and relCBF suggesting impaired metabolic function after SRC. These findings support the use of quantitative susceptibility mapping (QSM) and relCBF as sensitive indicators of SRC, and raise further concerns related to SRC guidelines that allow for return-to-play in less than two weeks.


Glucagon-like peptide-1-(7-36)amide increases pulmonary surfactant secretion through a cyclic adenosine 3',5'-monophosphate-dependent protein kinase mechanism in rat type II pneumocytes.
Glucagon-like peptide-1 (GLP-1) receptor messenger RNA has been identified in cells considered type II pneumocytes that are involved in the synthesis and secretion of the pulmonary surfactant. In an attempt to open new insights into the control of surfactant secretion, we studied the effects of glucagon-related peptides in this process. Accordingly, type II pneumocytes were isolated from Wistar rat lungs and cultured overnight with [methyl-14C]choline, and then the basal and stimulated secretions of [14C]phosphatidylcholine were measured. GLP-1(7-36)amide stimulated phosphatidylcholine secretion in a concentration-dependent manner in the 1-100 nM range; the concentration of the peptide that produced a half-maximal response was 10 nM. Exendin-4 induced similar effects. No changes were observed when GLP-1-(1-37), GLP-2, or exendin-(9-39) was added to the medium. However, the latter reversed the stimulatory effects of GLP-1-(7-36)amide and exendin-4. A study of the mechanism through which GLP-1-(7-36)amide exerts its stimulatory effect was carried out using different agents that are well known stimulants of phosphatidylcholine secretion. GLP-1-(7-36)amide did not produce any change in the stimulatory effect observed with terbutaline or 8-bromo-cAMP, suggesting the involvement of a cAMP-dependent protein kinase in the stimulatory effect of this peptide on phosphatidylcholine secretion. It was further supported by the use of inhibitors of protein kinases and by the stimulation of cAMP production in type II pneumocytes incubated with either GLP-1-(7-36)amide or exendin-4.


Identifying predictive features in drug response using machine learning: opportunities and challenges.
This article reviews several techniques from machine learning that can be used to study the problem of identifying a small number of features, from among tens of thousands of measured features, that can accurately predict a drug response. Prediction problems are divided into two categories: sparse classification and sparse regression. In classification, the clinical parameter to be predicted is binary, whereas in regression, the parameter is a real number. Well-known methods for both classes of problems are briefly discussed. These include the SVM (support vector machine) for classification and various algorithms such as ridge regression, LASSO (least absolute shrinkage and selection operator), and EN (elastic net) for regression. In addition, several well-established methods that do not directly fall into machine learning theory are also reviewed, including neural networks, PAM (pattern analysis for microarrays), SAM (significance analysis for microarrays), GSEA (gene set enrichment analysis), and k-means clustering. Several references indicative of the application of these methods to cancer biology are discussed.


Expression of MRE11 complex (MRE11, RAD50, NBS1) and hRap1 and its relation with telomere regulation, telomerase activity in human gastric carcinomas.
The MRE11 complex (MRE11, RAD50, NBS1) are required for the repair of DNA double-strand breaks and have another important function in regulating telomere length. The silent information regulator (Sir) proteins required for telomere position effect also bind telomeres. hRap1 protein is a human ortholog of yeast Rap1 which regulates telomere length by interacting with TRF2 and is recruited to telomeres by TRF2. We examined the expression of the MRE11 complex (MRE11, RAD50, NBS1), Sir2 and hRAP1 in 20 gastric carcinomas by reverse transcription polymerase chain reaction and then analyzed the relation between telomerase activity and other telomerase components such as human telomerase reverse transcriptase (TERT), human telomerase RNA component (hTR), human telomerase-associated protein (TEP1), telomeric repeat binding factor 1 (TRF1), TRF2- and TRF1-interacting, ankyrin-related ADP-ribose polymerase (tankyrase) as well as TRF1-interacting nuclear protein 2 (TIN2). Of twenty gastric carcinomas examined, 13 (65%), 14 (70%), 16 (80%), 12 (60%) and 13 (65%) expressed MRE11, RAD50, NBS1, Sir2 and hRap1 at higher levels than corresponding nonneoplastic gastric mucosa, respectively. No obvious correlation was observed between MRE11 complex expression and telomerase activity or expression of TERT, hTR, TEP1, tankyrase and TIN2. Carcinomas with high TRF1 expression expressed significantly higher levels of MRE11 and RAD50 than those with low TRF1 expression (p < 0.05). On the other hand, carcinomas with high TRF2 expression expressed significantly higher levels of MRE11, NBS1 and hRap1 than those with low TRF2 expression (p < 0.05). These results suggest that gastric carcinomas with high TRF1 and TRF2 expression may need a large quantity of the MRE11 complex. Moreover, gastric carcinomas with high TRF1 expression may require a large quantity of hRap1.


Cognitive Fluctuations and the Lucid Interval in Dementia: Implications for Testamentary Capacity.
The lucid interval is a long-held legal concept widely accepted in case law as a possible means of countering a challenge to testamentary and related capacities. In parallel, the clinical phenomenon of cognitive fluctuations has been considered a common element of several neurodegenerative disorders (dementias), including Alzheimer Disease, but is especially prevalent in vascular dementia and dementia with Lewy bodies. In this article, we review the objective evidence for cognitive fluctuations in dementia and the implications for the validity of the legal notion of the lucid interval cited in recent case law. The literature on cognitive fluctuations in dementia shows that such fluctuations largely affect attention and alertness, rather than memory or the higher level executive functions that are essential components of testamentary capacity. Moreover, these fluctuations are small in magnitude and very short in duration. These findings cast doubt on the validity of the lucid interval and invite a critical rethinking of this legal concept as applied to will challenges involving testators with dementia.


Demonstration of intradyne BPSK optical free-space transmission in representative atmospheric turbulence conditions for geostationary uplink channel.
Binary phase-shift keying optical transmission in the C-band with coherent intradyne reception is demonstrated over a long-range (10.45 km) link through the atmosphere. The link emulates representative channel conditions for geostationary optical feeder uplinks in satellite communications. The digital signal processing used in recovering the transmitted data and the performed measurements are described. Finally, the bit error rate results for 10 Gbit/s, 20 Gbit/s, and 30 Gbit/s of the outdoor experiments are presented and compared with back-to-back measurements and theory.


A randomized trial of an education program to enhance older driver performance.
This study was designed to determine whether an education program consisting of classroom and on-road training could enhance driving performance. This randomized controlled trial with blinded endpoint assessment enrolled 126 community-living drivers 70 years old or older who were recruited from clinic and community sources. Treatment assignment was concealed until eligibility was established. Participants randomized to intervention underwent two 4-hour classroom and two 1-hour on-road sessions focused on common problem areas of older drivers. Controls received modules directed at vehicle, home, and environmental safety. A knowledge test and driving performance were assessed at baseline and 8 weeks. On-road driving performance was assessed by an experienced evaluator in a dual-brake-equipped vehicle in urban, residential, and highway traffic. Driving performance was rated on a 36-item scale with potential scores from 0 to 72 (higher score better). The knowledge test included 20 road knowledge and eight road sign questions, scored from 0 to 28 correct. The least squares mean change in road test score relative to baseline was 2.87 points higher in the intervention than in the control group (p =.001). The least squares mean change in knowledge test scores relative to baseline was 3.45 points higher in the intervention than in the control group (p <.001). An education program consisting of classroom and on-road training targeted to common errors of older drivers enhanced performance on knowledge and on-road tests. Such interventions offer older drivers the potential to continue driving safely longer and to maintain their out-of-home mobility.


Parapharyngeal neurilemmoma of the hypoglossal nerve.
Although neurilemmomas are uncommon cervical neoplasms, they account for a significant percentage of parapharyngeal space tumors. These neoplasms may originate from any nerve traversing this space, but the vast majority arise from the vagus nerve and sympathetic chain. Satisfactory treatment of neurilemmomas consists of total excision which is best accomplished via an external approach. Immediate nerve grafting is advocated when a segment of cranial nerve must be sacrificed in order to achieve complete tumor removal. A case of a parapharyngeal neurilemmoma arising from the hypoglossal which required treatment in this manner is presented. Electromyographic studies performed 15 months postoperatively demonstrate reinervation of the lingual musculature via the nerve graft.


Carboxylesterase 1d Inactivation Augments Lung Inflammation in Mice.
Carboxylesterases are members of the serine hydrolase superfamily and metabolize drugs, pesticides, and lipids. Previous research showed that inhibition of carboxylesterase 1 (CES1) in human macrophages altered the immunomodulatory effects of lipid mediators called prostaglandin glyceryl esters, which are produced by cyclooxygenase-catalyzed oxygenation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Ces1d - the mouse ortholog of human CES1 - is the most abundant Ces isoform in murine lung tissues and alveolar macrophages and a major target of organophosphate poisons. Monoacylglycerol lipase (Magl) is also expressed in murine lung and is the main enzyme responsible for 2-AG catabolism. Several metabolic benefits are observed in Ces1d-/- mice fed a high-fat diet; thus, we wondered whether pharmacological and genetic inactivation of Ces1d in vivo might also ameliorate the acute inflammatory response to lipopolysaccharide (LPS). C57BL/6 mice were treated with WWL229 (Ces1d inhibitor) or JZL184 (Magl inhibitor), followed 30 min later by either LPS or saline. Wild-type (WT) and Ces1d-/- mice were also administered LPS to determine the effect of Ces1d knockout. Mice were sacrificed at 6 and 24 h, and cytokines were assessed in serum, lung, liver, and adipose tissues. Lipid mediators were quantified in lung tissues, while activity-based protein profiling and enzyme assays determined the extent of lung serine hydrolase inactivation by the inhibitors. WWL229 was shown to augment LPS-induced lung inflammation in a female-specific manner, as measured by enhanced neutrophil infiltration and Il1b mRNA. The marked Ces inhibition in female lung by 4 h after drug treatment might explain this sex difference, although the degree of Ces inhibition in female and male lungs was similar at 6 h. In addition, induction of lung Il6 mRNA and prostaglandin E2 by LPS was more pronounced in Ces1d-/- mice than in WT mice. Thus, WWL229 inhibited lung Ces1d activity and augmented the female lung innate immune response, an effect observed in part in Ces1d-/- mice and Ces1d/CES1-deficient murine and human macrophages. In contrast, JZL184 attenuated LPS-induced Il1b and Il6 mRNA levels in female lung, suggesting that Ces1d and Magl have opposing effects. Mapping the immunomodulatory molecules/pathways that are regulated by Ces1d in the context of lung inflammation will require further research.


Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles County.
Genetic polymorphisms in the activation or detoxication of carcinogens, such as those in tobacco smoke, may produce differences in individual susceptibility to lung cancer. The cytochrome P450 CYP2E1 is an enzyme involved in the metabolism of nitrosamines in tobacco smoke. A polymorphism of CYP2E1 detectable by the restriction enzyme Rsa I may be functionally important because it is located in a putative binding site for the transcription factor HNF-1 and has been associated with higher levels of CYP2E1 transcription. It is conceivable that this CYP2E1 Rsa I polymorphism might contribute to differences in susceptibility to lung cancer. We conducted a case-control study of patients with incident lung cancer and population controls in Los Angeles County to examine the association between the CYP2E1 Rsa I polymorphism and lung cancer risk among African-Americans and Caucasians. Samples of white blood cell DNA sufficient for determination of the CYP2E1 Rsa I genotype by a polymerase chain reaction-based assay were obtained from 341 cases and 706 controls with data on lifetime smoking history. No subjects were homozygous for the CYP2E1 Rsa I rare c2 allele. The rare c2 allele was not associated with an increased risk of lung cancer (adjusted odds ratio, OR 0.72; 95% confidence interval, CI = 0.35-1.46). Among the population controls the percentage of subjects carrying the rare c2 allele was lower (p = 0.002) among African-Americans (2%) compared with Caucasians (8%). However, the association between the CYP2E1 Rsa I genotype and lung cancer risk did not differ between ethnic groups. There was no important association between the CYP2E1 Rsa I genotype and lung cancer risk in analyses stratified by cell-type, smoking history, gender, occupational asbestos exposure, and dietary intake of antioxidants vitamin C, vitamin E or beta carotene. Due to the low frequency of the c2 allele in these populations, larger studies would be necessary to rule out a modest association between the CYP2E1 Rsa I polymorphism and lung cancer risk.


Endemic infectious diseases of Afghanistan.
The current crisis in Afghanistan has resulted in an influx of Western military personnel, peacekeepers, humanitarian workers, and journalists. At the same time, unprecedented numbers of internally displaced persons and refugees have overwhelmed much of the already fragile infrastructure, setting the stage for outbreaks of infectious diseases among both foreigners and local populations. This review surveys the literature concerning the infectious diseases of Afghanistan and south-central Asia, with particular emphasis on diseases not typically seen in the Western world.


Oxidative stress in the hybrid fish jundiara (Leiarius marmoratus × Pseudoplatystoma reticulatum) exposed to Roundup Original®.
The aim of this study was to investigate the effects of Roundup Original®, a glyphosate-based herbicide, against biochemical parameters including thiobarbituric acid-reactive substances (TBARS), protein carbonyl, enzymatic and nonenzymatic antioxidant responses and acetylcholinesterase (AChE) of jundiara fish (Leiarius marmoratus × Pseudoplatystoma reticulatum) at a sublethal concentration of 1.357 mg L-1. Fish exposed to the herbicide for different periods (6-96 h) showed a significant increase of both hepatic and muscular TBARS and protein carbonyl. Enzymatic antioxidant activity was decreased in the liver and brain after 48 h of exposure. Glutathione-S-tranferase (GST) had its levels raised in the brain and gills, probably as a toxicity event response. Non protein thiols (GSH) demonstrated a reduction after 6 and 24 h of exposure in the hepatic tissue, followed by an increase at 48 and 96 h in the same tissue. GSH brain levels, however, increased only after 96 h. AChE activity in muscle decreased for all the times tested (26.5, 45, 38 and 14% for 6, 24, 48 and 96 h respectively), but only at 96 h (34%) in the brain. We found that Roundup Original® is able to trigger important changes in the biochemical parameters tested, showing it can be a potential threat for the health and survival of fish in the environment.


Frequent attenders in primary care: impact of medical, psychiatric and psychosomatic diagnoses.
Anxiety, mild depression and somatization are common in primary care (PC). Several studies have suggested that they may play a role in causing an excessive use of health care services, especially when combined with medical morbidity. The present case-control study explored how psychiatric and psychosomatic diagnoses and perceived quality of life are associated with the phenomenon of frequent attendance. Fifty most frequent attenders (FAs) in a 1-year period at a PC clinic in Italy were compared with 50 randomly selected average frequency attenders at the same clinic. Sociodemographic and medical data were collected from PC files. The SCID-brief version for research and the Structured Interview for Diagnostic Criteria for Use in Psychosomatic Research (DCPR) were administered to both patient groups. Quality of life was also assessed. FA status was associated with being female, older, less well educated, and living with their spouses and/or children. Medical-psychiatric comorbidity was more frequent in the FA group than in the control group. The median number of psychosomatic-DCPR syndromes per patient was 4 among FAs compared to only 1 in controls. Functional somatic symptoms secondary to a psychiatric disorder, type A behavior, irritable mood, and demoralization were significantly associated with being an FA. Perceived quality of life was significantly lower among FAs, although this was no longer significant after adjusting for sociodemographic variables. The present study confirms the association between medical-psychiatric comorbidity and frequent utilization of PC resources. It suggests a role for DCPR criteria in revealing subthreshold psychiatric comorbidity predicting a pattern of frequent attendance.


Childhood parapneumonic effusions: biochemical and inflammatory markers.
Biochemical and inflammatory markers in pleural inflammation were evaluated in pediatric cases of parapneumonic effusions, and interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha concentrations were tested for possible differentiation of the complicated nature of effusions. Twenty-eight patients (12 female) who were admitted to Hacettepe University Childrens' Hospital over a 2-year period were included in the study. Patients were grouped according to the stage of effusion. Pleural fluid leukocyte count, neutrophil ratio, pH, protein, glucose levels, lactate dehydrogenase (LDH) levels, TNF-alpha levels, IL-8 levels, and nitrite levels were obtained. Of these patients, 13 had empyema, 10 had complicated parapneumonic effusions (CPEs), and 5 had uncomplicated parapneumonic effusions (UPEs). Protein and glucose levels decreased, leukocyte count, neutrophil ratio, TNF-alpha levels, nitrite levels, and IL-8 levels increased progressively as the stage of the disease progressed. IL-8 levels, but not TNF-alpha and nitrite levels, were statistically different among the groups. IL-8, TNF-alpha, and nitrite levels all correlated positively with each other (all p < or = 0.001), and pH correlated negatively with these markers (all p < or = 0.001). At a cutoff value of 76.6 pg/mL, TNF-alpha discriminated between CPEs and UPEs with a sensitivity of 50%, a specificity of 100%, and an accuracy of 78%. At a cutoff value of 701.6 pg/mL, IL-8 differentiated CPE and UPE with a sensitivity of 80%, a specificity of 80%, and an accuracy of 86%. Progressive changes in common biochemical markers (ie, pH, and protein, glucose, and LDH levels) are interrelated during stages of pleural inflammation. IL-8 may be used as an alternative marker for discriminating between CPEs and UPEs in pediatric parapneumonic effusions.


Epithelial neutrophil-activating peptide-78 recruits neutrophils into pleural effusion.
The aim of this study was to investigate the presence of epithelial neutrophil-activating peptide (ENA)-78 in pleural effusions, as well as the chemoattractant activity of pleural ENA-78 on neutrophils. Pleural effusion and serum samples were collected from 75 patients who presented to the respiratory institute (19 with malignant pleural effusion, 21 with tuberculous pleural effusion, 18 with infectious pleural effusion and 17 with transudative pleural effusion). The concentrations of ENA-78, myeloperoxidase and neutrophil elastase were determined, and the chemoattractant activity of ENA-78 for neutrophils both in vitro and in vivo was also observed. The concentrations of ENA-78, myeloperoxidase and neutrophil elastase in infectious pleural effusion were significantly higher than those in malignant, tuberculous and transudative groups, respectively (all p<0.01). Infectious pleural fluid was chemotactic for neutrophils in vitro and anti-ENA-78 antibody could partly inhibit these chemotactic effects. Intrapleural administration of ENA-78 produced a marked progressive influx of neutrophils into pleural space. Compared with noninfectious pleural effusion, ENA-78 appeared to be increased in infectious pleural effusion. Our data suggested that ENA-78 was able to induce neutrophil infiltration into pleural space and might be responsible for pleural neutrophil degranulation.


Improving geometric accuracy in the presence of susceptibility difference artifacts produced by metallic implants in magnetic resonance imaging.
Geometric and intensity distortions due to the presence of metallic implants in magnetic resonance imaging impede the full exploitation of this advanced imaging modality. The aim of this study is to provide a method for (a) quantifying and (b) reducing the implant distortions in patient images. Initially, a set of reference images (without distortion) was obtained by imaging a custom-designed three-dimensional grid phantom. Corresponding test images (containing the distortion) were acquired with the same imaging parameters, after positioning a specific metallic implant in the grid phantom. After determining: 1) the nonrecoverable; 2) the distorted, but recoverable; and 3) the unaffected areas, a point-based thin-plate spline image registration algorithm was employed to align the reference and test images. The calculated transformation functions utilized to align the image pairs described the implant distortions and could therefore be used to correct any other images containing the same distortions. The results demonstrate successful correction of grid phantom images with a metallic implant. Furthermore, the calculated correction was applied to porcine thigh images bearing the same metallic implant, simulating a patient environment. Qualitative and quantitative assessments of the proposed correction method are included.


Fibronexus in "malignant fibrous histiocytoma" of the bone: a case report of pleomorphic myofibrosarcoma.
The fibronexus (fibronexus junction) has been thought to be a characteristic ultrastructural feature of myofibroblasts, but it is controversial whether the fibronexus is also a characteristic of various myofibroblastic tumors. We report here a case of pleomorphic bone sarcoma (pleomorphic/storiform malignant fibrous histiocytoma) with fibronexus junctions arising in the head of the left humerus of a 70-year-old woman. By light microscopy the tumor was composed of large spindle or polygonal cells occasionally arranged in fascicles. Foamy giant cells with bizarre nuclei were not uncommon. Immunohistochemically, the tumor cells were positive diffusely for vimentin and focally for muscle actin (HHF35) and alpha-smooth muscle actin but were negative for desmin, high-molecular weight caldesmon, and S-100 protein. Ultrastructurally, the tumor cells had indented nuclei and spindle or polygonal cytoplasm, with little rough endoplasmic reticulum and small vesicles, and rather numerous mitochondria. The tumor cells had myofilaments with focal densities in the periphery, fibronectin fibrils adjacent to intracellular myofilaments, and by definition, therefore, fibronexus junctions. These findings suggest myofibroblastic differentiation, and a diagnosis of pleomorphic myofibrosarcoma is thought to be appropriate. We believe that the fibronexus is a characteristic and useful ultrastructural feature for differentiating myofibroblastic tumors from other pleomorphic myogenic sarcomas.


Myofibroblast differentiation and its functional properties are inhibited by nicotine and e-cigarette via mitochondrial OXPHOS complex III.
Nicotine is the major stimulant in tobacco products including e-cigarettes. Fibroblast to myofibroblast differentiation is a key process during wound healing and is dysregulated in lung diseases. The role of nicotine and e-cigarette derived nicotine on cellular functions including profibrotic response and other functional aspects is not known. We hypothesized that nicotine and e-cigarettes affect myofibroblast differentiation, gel contraction, and wound healing via mitochondria stress through nicotinic receptor-dependent mechanisms. To test the hypothesis, we exposed human lung fibroblasts with various doses of nicotine and e-cigarette condensate and determined myofibroblast differentiation, mitochondrial oxidative phosphorylation (OXPHOS), wound healing, and gel contraction at different time points. We found that both nicotine and e-cigarette inhibit myofibroblast differentiation as shown by smooth muscle actin and collagen type I, alpha 1 abundance. Nicotine and e-cigarette inhibited OXPHOS complex III accompanied by increased MitoROS, and this effect was augmented by complex III inhibitor antimycin A. These mitochondrial associated effects by nicotine resulted in inhibition of myofibroblast differentiation. These effects were associated with inhibition of wound healing and gel contraction suggesting that nicotine is responsible for dysregulated repair during injurious responses. Thus, our data suggest that nicotine causes dysregulated repair by inhibition of myofibroblast differentiation via OXPHOS pathway.


Crossbreeding impacts on caecal bacterial count and antibody titres in chickens.
1. A crossbreeding experiment was conducted using 20 sires and 120 dams from each Fayoumi (F) and Rhode Island Red (R) breeds. The F1 chicks of ½F½R and their reciprocal ½R½F crosses were used to estimate direct, maternal and heterotic effects.2. The caecal bacterial counts of Salmonella typhimurium and Enterococcus faecium and the IgA, IgG and IgM antibody titres were determined. Chicks of each genetic group (120 birds) were divided into three groups (40 birds per group) and chicks of the first group were assigned as the control group, while the second group was inoculated with S. typhimurium and E. faecium at 7 and 10 d of age (106 cfu/chick) and the third was inoculated with S. typhimurium at 10 d of age (106 cfu/chick).3. The generalised least square procedure was used to estimate cross-breeding effects. The S. typhimurium counts in the R breed was highly significant, followed by ½F½R cross, ½R½F cross, and F breed. The differences among genetic groups in E. faecium counts and caecal pH was not significant. The estimates of IgA, IgG, and IgM antibody titres were highly significant in the F breed, followed by ½R½F cross, ½F½R cross, and the R breed.4. The estimates of direct additive effects were highly significant F breed for the counts of S. typhimurium and antibody titres of IgA, IgG, and IgM. The maternal effects were highly significant F breed for S. typhimurium, E. faecium count, and antibody titres of IgA, IgG, and IgM. Estimates of direct heterosis were significant for S. typhimurium count and IgA antibody titre but not significant for E. faecium count, caecal pH, and antibody titres of IgG and IgM.5. The results showed that the Fayoumi breed could be used in breeding programmes to improve immunity traits against S. typhimurium in chickens.


A prospective observational cohort study of exposure to womb-like sounds to stabilize breathing and cardiovascular patterns in preterm neonates.
We exposed premature infants to womb-like sounds to evaluate such exposure on breathing and cardiovascular patterns. We hypothesized that these sounds would reduce apnea and intermittent hypoxemia, enhance parasympathetic outflow, and improve cardiovascular patterns. A total of 20 cases and 5 control infants at ≤32-36 weeks corrected gestational age participated in a prospective observational cohort study. Twenty-four hours of continuous ECG, respiratory and oxygen saturation data were collected in all infants. Womb-like sounds were played intermittently in 6-hour blocks. Salivary samples were collected at study beginning and end for cortisol. Apnea, intermittent hypoxemia, and bradycardia were evaluated, and heart rate variability was assessed by time domain and spectral techniques. Intermittent hypoxemia and bradycardia significantly declined after sound exposure. No significant differences in apnea, cortisol levels, or heart rate variability were evident among the study infants. Exposing premature infants to womb-like sounds has the potential to reduce hypoxemic and bradycardic events, and be used as an intervention to stabilize breathing and cardiac control in preterm infants.


Visualizing jet lag in the mouse suprachiasmatic nucleus and peripheral circadian timing system.
Circadian rhythms regulate most physiological processes. Adjustments to circadian time, called phase shifts, are necessary following international travel and on a more frequent basis for individuals who work non-traditional schedules such as rotating shifts. As the disruption that results from frequent phase shifts is deleterious to both animals and humans, we sought to better understand the kinetics of resynchronization of the mouse circadian system to one of the most disruptive phase shifts, a 6-h phase advance. Mice bearing a luciferase reporter gene for mPer2 were subjected to a 6-h advance of the light cycle and molecular rhythms in suprachiasmatic nuclei (SCN), thymus, spleen, lung and esophagus were measured periodically for 2 weeks following the shift. For the SCN, the master pacemaker in the brain, we employed high-resolution imaging of the brain slice to describe the resynchronization of rhythms in single SCN neurons during adjustment to the new light cycle. We observed significant differences in shifting kinetics among mice, among organs such as the spleen and lung, and importantly among neurons in the SCN. The phase distribution among all Period2-expressing SCN neurons widened on the day following a shift of the light cycle, which was partially due to cells in the ventral SCN exhibiting a larger initial phase shift than cells in the dorsal SCN. There was no clear delineation of ventral and dorsal regions, however, as the SCN appear to have a population of fast-shifting cells whose anatomical distribution is organized in a ventral-dorsal gradient. Full resynchronization of the SCN and peripheral timing system, as measured by a circadian reporter gene, did not occur until after 8 days in the advanced light cycle.