MEP50/PRMT5-mediated methylation activates GLI1 in Hedgehog signalling through inhibition of ubiquitination by the ITCH/NUMB complex.
Transcription factor GLI1 is an effecter of Hedgehog (HH) signalling and activated in a broad spectrum of cancers. However, the role of the HH-GLI1 pathway in cancer and the activation mechanism of GLI1 in HH signalling after dissociation from its inhibitor, SUFU, are not fully understood. Here, we found that GLI1 associated with the methylosome protein 50 (MEP50)/protein arginine methyltransferase 5 (PRMT5) complex and was methylated. Association of MEP50/PRMT5 with GLI1 was enhanced and expression of MEP50 and PRMT5 was activated by HH signals, suggesting their role in positive feedback regulation. Methylated GLI1 lost its ability to bind ubiquitin ligase ITCH/NUMB, resulting in nuclear accumulation and activation of GLI1. Moreover, protein expression of GLI1 was enhanced by MEP50/PRMT5 and expression of MEP50, PRMT5, and GLI1 target genes was upregulated in HH-expressing cancers. These results suggest that MEP50/PRMT5 is important for HH signal-induced GLI1 activation, especially in cancers.


Development, implementation and evaluation of Australia's first national continuing medical education program for the timely diagnosis and management of dementia in general practice.
Dementia is the second leading cause of death in Australia. Over half of patients with dementia are undiagnosed in primary care. This paper describes the development, implementation and initial evaluation of the first national continuing medical education program on the timely diagnosis and management of dementia in general practice in Australia. Continuing medical education workshops were developed and run in 16 urban and rural locations across Australia (12 were delivered as small group workshops, four as large groups), and via online modules. Two train-the-trainer workshops were held. The target audience was general practitioners, however, international medical graduates, GP registrars, other doctors, primary care nurses and other health professionals were also welcome. Self-complete questionnaires were used for the evaluation. Of 1236 people (GPs, other doctors, nurses and other health professionals) who participated in the program, 609 completed the full program (small group workshops (282), large group workshops (75), online modules (252)); and 627 elected to undertake one or more individual submodules (large group workshops (444), online program (183)). Of those who completed the full program as a small group workshop, 14 undertook the additional Train-the-trainer program. 76% of participants felt that their learning needs were entirely met and 78% felt the program was entirely relevant to their practice. Continuing medical education programs are an effective method to deliver education to GPs. A combination of face-to-face and online delivery modes increases reach to primary care providers. Train-the-trainer sessions and online continuing medical education programs promote long-term delivery sustainability. Further research is required to determine the long-term knowledge translation effects of the program.


POSS as building-blocks for the preparation of polysilsesquioxanes through an innovative synthetic approach.
A novel solvent-free solid-state synthesis was used to prepare a non-crystalline polysilsesquioxane sample, with a peculiar viscous form. The material was synthesized through direct self-condensation of a partially condensed polyhedral oligomeric silsesquioxane (POSS) and its physico-chemical properties, in terms of composition/structure, thermal stability and hydrophobicity, were investigated.


The social determinants of health: is there a role for health promotion foundations?
If they are to respond effectively to health inequities, organisations involved in health promotion need to refocus on the social determinants of health (SDH) and the distribution of resources for health. This paper examines the potential of health promotion foundations (HPFs), a semi-autonomous arm of the state, to act at several policy and program intervention points to address the SDH and reduce health inequities. The public purpose, enterprise and innovation potential of health promotion foundations provides them with unique capacity to respond to SDH. In the complex and contested policy environment surrounding action on the determinants of health, the role that foundations can most usefully play is that of a change agent in a broader social movement seeking health equity.


Repeatability of Weightbearing Computed Tomography Measurement of First Metatarsal Alignment and Rotation.
Weightbearing computed tomography (WBCT) can be used to assess alignment and rotation of the first metatarsal. It is unknown whether these measures remain consistent on sequential WBCTs in the same patient when a patient's standing position may be different. The aim of this study was to establish the repeatability (test-retest) of measurements of first metatarsal alignment and rotation in patients without forefoot pathology on WBCT. We retrospectively identified 42 feet in 26 patients with sequential WBCT studies less than 12 months apart. Patients with surgery between scans, previous forefoot surgery or hallux rigidus were excluded. Hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured using digitally reconstructed radiographs. Two methods of calculating metatarsal rotation (metatarsal pronation angle [MPA] and alpha angle) were measured on standardized coronal CT slices. Interobserver agreement and test-retest repeatability were assessed using intraclass correlation coefficients (ICCs). Standard error of measurement (SEM) and minimally detectable change (MDC95) were calculated. Interobserver agreement was excellent for HVA and IMA (ICC 0.96 and 0.90, respectively) and was good for MPA and alpha angle (ICC 0.81 and 0.80, respectively). There was excellent test-retest repeatability for HVA (ICC=0.90) and good test-retest repeatability for IMA (ICC=0.77). There was excellent test-retest repeatability for MPA (ICC=0.91) and good test-retest repeatability for alpha angle (ICC=0.87). The MDC95 was 4.6 degrees for MPA and 6.1 degrees for alpha angle. Five percent of patients had a difference outside of the MDC95 for the alpha angle, compared with 2% for the MPA. Measurements of first metatarsal alignment and rotation are reliable between assessors and repeatable between sequential WBCTs in patients without forefoot pathology. Subtle differences in patient positioning during image acquisition do not significantly affect measurements, supporting the validity of this method of assessment in longitudinal patient care. Level IV, retrospective case series.


Immunoreactive forms of cationic trypsin in plasma and ascitic fluid of dogs in experimental pancreatitis.
A canine model of bile-induced pancreatitis has been employed to investigate time-dependent changes in the molecular forms of trypsin in blood and ascitic fluid in this disease. The distribution of immunoreactive trypsin as trypsinogen and trypsin bound to plasma inhibitors in ascitic fluid and plasma during the course of the disease has been investigated by means of a radioimmunoassay for canine pancreatic cationic trypsin. In addition, trypsinlike amidase activity was determined in plasma and ascitic fluid using Z-Gly-Gly-Arg-beta-Nap as substrate. Early plasma and ascitic fluid samples in four dogs that died contained primarily trypsinogen, while extensive activation of trypsinogen to alpha 2-macroglobulin and alpha 1-protease inhibitor-bound trypsin occurred in the course of the disease. A fifth dog survived and showed little activation of trypsinogen. In the four dogs that died, the levels of trypsinlike amidase activity in the ascitic fluid were substantial throughout the course of the disease. The plasma levels of trypsinlike activity in these animals were much lower, but increased during the disease process. The dog that survived had lower concentrations of trypsinlike activity in ascitic fluid and plasma. These results suggest that activation of trypsinogen resulting in inhibitor-bound forms of trypsin in ascitic fluid and plasma is important in the pathogenesis of acute pancreatitis.


The Information Bottleneck and Geometric Clustering.
The information bottleneck (IB) approach to clustering takes a joint distribution P(X,Y) and maps the data X to cluster labels T , which retain maximal information about Y (Tishby, Pereira, & Bialek, 1999 ). This objective results in an algorithm that clusters data points based on the similarity of their conditional distributions P(Y∣X) . This is in contrast to classic geometric clustering algorithms such as k -means and gaussian mixture models (GMMs), which take a set of observed data points {xi}i=1:N and cluster them based on their geometric (typically Euclidean) distance from one another. Here, we show how to use the deterministic information bottleneck (DIB) (Strouse & Schwab, 2017 ), a variant of IB, to perform geometric clustering by choosing cluster labels that preserve information about data point location on a smoothed data set. We also introduce a novel intuitive method to choose the number of clusters via kinks in the information curve. We apply this approach to a variety of simple clustering problems, showing that DIB with our model selection procedure recovers the generative cluster labels. We also show that, in particular limits of our model parameters, clustering with DIB and IB is equivalent to k -means and EM fitting of a GMM with hard and soft assignments, respectively. Thus, clustering with (D)IB generalizes and provides an information-theoretic perspective on these classic algorithms.


Evaluation of the effect of time on the distribution of zinc oxide nanoparticles in tissues of rats and mice: a systematic review.
To evaluate the time effect on the distribution of zinc oxide nanoparticles (ZnO NPs) in tissues from rats and mice, a search on the PubMed, Embase, SpringerLink, Scopus, Science Direct, Cochrane, CNKI, Wanfang, and vip databases up to September 2014 was performed, followed by screening, data extraction, and quality assessment. Thirteen studies were included. At 24 h, Zn content was mainly distributed in the liver, kidney, and lung. At ≥7 days, Zn content was mainly distributed in the liver, kidney, lung, and brain. ZnO NPs are readily deposited in tissues. Furthermore, as time increases, Zn content decreases in the liver and kidney, but increases in the brain.


Biochemical and teratogenic effects of a mixture of pyriproxyfen and glyphosate.
The mixture of agrochemicals can be made to improve pest control or accidentally. In this way, the effects on non-target organisms are a critical aspect of the environment and heath. Thus, this work aimed to show how a mixture of pyriproxyfen, and glyphosate can impair biochemical routes and embryonic development. Zebrafish embryos 0-72 hpf were exposed to 0.001-1 μg/mL of pyriproxyfen, glyphosate, and a mixture of both pesticides. The ADMETox was evaluated in silico. The FET-test was used to estimate teratogenic effects. The biochemical effects were estimated using AChE, SOD, and CAT as parameters. ROS generation was estimated using 30 μM H2DCF-DA and 5 μM DHE. The ADMETox reveals that intestinal absorption and P-glycoprotein are the main sites for PPx and Gly adsorption. The distribution parameters were diverse. PPx + Gly at 0.1 μg/mL leads to 50 % of lethality and at 1 μg/mL 100 % of lethality. PPx + Gly leads to a 22 % of lack of somite formation at 1 μg/mL. The heart rate was reduced by >10 % in all concentrations tested. The AChE has a decrease with IC20 19.6 μM and IC50 261.5 μM. SOD showed a reduction of 28 % to PPx and CAT was reduced by 58 % to PPx + Gly and Gly at 1 μg/mL. Glyphosate does not increase unspecific ROS generation. The superoxide generation was 2× higher in the PPx + Gly at 1 μg/mL. Summarily, was observed that the mixture of PPx + Gly potentiated the toxic effects. This finding suggests a possible synergism between the PPx and Gly even at lower concentrations.


Multidimensional measures of impulsively driven stochastic systems based on the Kullback-Leibler distance.
By subjecting a dynamical system to a series of short pulses and varying several time delays, we can obtain multidimensional characteristic measures of the system. Multidimensional Kullback-Leibler response function (KLRF), which are based on the Kullback-Leibler distance between the initial and final states, are defined. We compare the KLRF, which are nonlinear in the probability density, with ordinary response functions obtained from the expectation value of a dynamical variable, which are linear. We show that the KLRF encode different level of information regarding the system's dynamics. For overdamped stochastic dynamics two-dimensional KLRF shows a qualitatively different variation with the time delays between pulses, depending on whether the system is initially in a steady state or in thermal equilibrium.


Prior Distribution Estimation of Monitored Information in the Intensive Care Unit with the Hidden Markov Model and Decision Tree Methods.
In the intensive care unit, the monitored variables collected from sensors may have different behaviors among patients with different clinical basic information. Giving prior information of the monitored variables based on their specific basic information as soon as the patient is admitted will support the clinicians with better decisions during the surgery. Instead of black box models, the explainable hidden Markov model is proposed, which can estimate the possible distribution parameters of the monitored variables under different clinical basic information. A Student's t-test or correlation test is conducted further to test whether the parameters have a significant relationship with the basic variables. The specific relationship is explored by using a conditional inference tree, which is an explainable model giving deciding rules. Instead of point estimation, interval forecast is chosen as the performance metrics including coverage rate and relative interval width, which provide more reliable results. By applying the methods to an intensive care unit data set with more than 20 thousand patients, the model has good performance with an area under the ROC Curve value of 0.75, which means the hidden states can generally be correctly labelled. The significant test shows that only a few combinations of the basic and monitored variables are not significant under the 0.01 significant level. The tree model based on different quantile intervals provides different coverage and width combination choices. A coverage rate around 0.8 is suggested, which has a relative interval width of 0.77.


Quantitative assessment of root canal roughness with calcium-based hypochlorite irrigants by 3D CLSM.
Chemical solutions play important roles in endodontic treatment and promote ultrastructural changes in dentin surface. The aim of this study was to quantify root canal roughness at different concentrations of calcium hypochlorite (Ca(OCl)2) and sodium hypochlorite (NaOCl) by confocal laser scanning microscopy (CLSM). Fifty-two human mandibular premolars were sectioned and randomly organized into thirteen groups (n=8): saline (control); 1%, 2.5% and 5% NaOCl; 1%, 2.5% and 5% Ca(OCl)2; the hypochlorite groups were further divided into with or without EDTA. The chlorine concentrations of the different solutions were measured by iodine titration (%). The superficial roughness (Sa) was quantified by CLSM. Ca(OCl)2 presented substantial decrease in chlorine concentration that differed from the package indication, but without compromising the dentin ultrastructure changes. There were no significant differences in dentin roughness between Ca(OCl)2 or NaOCl at all studied concentrations. The combination with EDTA provided similar roughness values among the solutions (p>0.05). The 5% Ca(OCl)2 and NaOCl solutions significantly increased dentin roughness and did not differ from the EDTA association (p>0.05). Ca(OCl)2 promoted similar dentin roughness as the NaOCl at the same concentrations and combined with EDTA. It may be concluded that Ca(OCl)2 modified the root canal dentin roughness similarly to NaOCl, at the same concentrations and EDTA combinations used in this study. Ca(OCl)2 and NaOCl, both at 5%, significantly altered dentin roughness, overcoming EDTA association, thus Ca(OCl)2 concentrations ranging from 1% to 2.5% may be suitable solutions for root canal irrigation protocols.


Design and implementation of a 120 GHz tracking interferometer with near diffraction limited focal spot.
The design and implementation of a 120 GHz monostatic tracking interferometer with near diffraction limited focal spot size, used to measure line-averaged plasma density in the source of a plasma opening switch (POS), is described. Physical dimensions of the switch source place an upper limit on the focal spot size. Focusing quasioptics utilize a standard pyramidal horn and a pair of cylindrical lenses that are easily fabricated. The combination of the two cylindrical lenses transforms the asymmetric and approximately Gaussian beam produced by the pyramidal horn into a small focal spot. The circuit utilizes a tracking receiver configuration to track oscillator frequency drifts, which allow for full heterodyne quadrature operation, while avoiding the added complexity of phase or frequency locking of the sources. In order to reduce system noise in the POS pulsed power environment, all sources and amplifiers are battery powered and other noise-reducing techniques are employed. Finally, an improved Gaussian optics design methodology, which tracks the phase center of the Gaussian beam, is proposed. While not critical to this application, this method may yield improvements in systems with short focal lengths.


Strongly luminescent binuclear aluminium chelate with polymer-like molecular packing and solution-processibility.
A binuclear aluminium(III) chelate with rigid and flexible mixed ligands has been synthesized and structurally characterized, which exhibits polymer-like molecular packing and solution-processiblity, as well as high photoluminescence quantum yield for organic light-emitting diodes (OLEDs); with this new compound as the emissive and host layer, the multi-layer OLEDs prepared via low-cost spin-coating showed encouraging performance.


Effects of temperature and salinity on antioxidant responses in livers of temperate (Dicentrarchus labrax) and tropical (Chanos Chanos) marine euryhaline fish.
Temperature and salinity are abiotic factors that affect physiological responses in aquaculture species. The European sea bass (Dicentrarchus labrax) is a temperate species that is generally farmed at 18 °C in seawater (SW). In the wild, its incursions in shallow habitats such as lagoons may result in hyperthermal damage despite its high thermal tolerance. Meanwhile, the milkfish (Chanos chanos), a tropical species, is generally reared at 28 °C, and in winter, high mortality usually occurs under hypothermal stress such as cold snaps. This study compared changes in hepatic antioxidant enzymes (superoxide dismutase, SOD; and catalase, CAT) in these two important marine euryhaline aquaculture species in Europe and Southeast Asia, respectively, under temperature challenge combined with hypo-osmotic (fresh water, FW) stress. After a four-week hyper- or hypo-thermal treatment, hepatic SOD activity was upregulated in both species reared in SW and FW, indicating enhanced oxidative stress in European sea bass and milkfish. The expression profiles of sod isoforms suggested that in milkfish, the increase in reactive oxygen species (ROS) was mainly at the cytosol level, leading to increased sod1 expression. In European sea bass, however, no obvious difference was found between the expression of sod isoforms at different temperatures. A lower expression of sod2 was observed in FW compared to SW in the latter species. Moreover, no significant change was observed in the mRNA expression and activity of CAT in the livers of these two species under the different temperature treatments, with the exception of the lower CAT activity in milkfish challenged with SW at 18 °C. Taken together, our results indicated that the antioxidant responses were not changed under long-term hypoosmotic challenge but were enhanced during the four-week temperature treatments in livers of both the temperate and tropical euryhaline species.


Successful treatment of an unresectable inflammatory myofibroblastic tumor of the frontal bone using a cyclooxygenase-2 inhibitor and methotrexate.
Inflammatory myofibroblastic tumor (IMT) is a disease characterized by tumorous lesions consisting of myofibroblastic spindle cells and inflammatory cells that occur primarily in the soft tissues and viscera of children and young adults. Total excision is the most effective therapy. Steroids have been used to treat unresectable lesions with some success. We herein report a case of IMT involving the frontal bone accompanied by pachymeningitis. The tumor was characterized by an aggressive clinical course that was refractory to prednisolone. Performing total excision seemed difficult. Celecoxib and methotrexate were effective treatments. Our experience suggests the efficacy of celecoxib and methotrexate as alternatives for treating unresectable IMT.


Expression of EGFR and survivin in ameloblastoma, odontogenic keratocyst and calcifying odontogenic cyst - An immunohistochemical study.
Odontogenic lesions have diverse biological behaviour which is characterised by local invasiveness, and a high recurrence rate. EGFR and survivin was found to be involved in the aggressiveness, recurrences and metastasis of a variety of epithelial malignancies. To assess and compare the expression of EGFR and survivin in Ameloblastoma (AB), Odontogenic keratocyst (OKC) and Calcifying odontogenic cyst (COC). The study's goal was to use immunohistochemistry to assess the qualitative and quantitative expression of EGFR and survivin and to correlate their expression patterns in AB, OKC and COC. Study included 30 AB, 15 OKC and 10 COC. All the slides were immunohistochemically analysed for qualitative, quantitative and semi-quantitative data. In each group, the presence of EGFR and survivin was assessed in terms of stain localisation, intensity and percentage of positive cells. Data were analysed using Chi-square test and one-way ANOVA, P value < 0.05 was considered statistically significant. EGFR positivity was found in all cases. Survivin was found to be 96% positive in AB and 100% positive in OKC and COC. Both EGFR and survivin showed predominant cytoplasmic staining. All the slides that are stained with EGFR are also stained with survivin. The intensity varied significantly between the layers. OKC showed higher immunoreactive scores (IRSs). The current study provides insight into the role of EGFR and survivin in the pathogenesis of AB, OKC and COC. OKC appears to be more aggressive than ameloblastoma and COC, owing to its higher IRS.


Computationally predicting binding affinity in protein-ligand complexes: free energy-based simulations and machine learning-based scoring functions.
Accurately predicting protein-ligand binding affinities can substantially facilitate the drug discovery process, but it remains as a difficult problem. To tackle the challenge, many computational methods have been proposed. Among these methods, free energy-based simulations and machine learning-based scoring functions can potentially provide accurate predictions. In this paper, we review these two classes of methods, following a number of thermodynamic cycles for the free energy-based simulations and a feature-representation taxonomy for the machine learning-based scoring functions. More recent deep learning-based predictions, where a hierarchy of feature representations are generally extracted, are also reviewed. Strengths and weaknesses of the two classes of methods, coupled with future directions for improvements, are comparatively discussed.


Streptococcus mutans counts obtained by a dip-slide method in relation to caries frequency, sucrose intake and flow rate of saliva.
The level of Streptococcus mutans in saliva was determined by a dip-slide method in 841 13-year-old children in order to identify children with high caries risk. For each child, the flow rate of saliva was determined. Caries scores were obtained from Public Dental Health records. A sucrose intake score was calculated based on self-reported frequency of intake of six types of sugary products. As S. mutans counts increased, there was a significant trend of increased DMFS and DS scores. No linear correlation was observed between reported intake of sucrose and S. mutans counts, but the children with the highest counts (class 3) tended to have significantly higher sucrose intake than the rest of the children. The flow rate of saliva decreased significantly as S. mutans increased.


Effect of desvenlafaxine 50 mg and 100 mg on energy and lassitude in patients with major depressive disorder: A pooled analysis.
Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder ( n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D17) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D17 psychomotor retardation factor, and Montgomery-Åsberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p⩽0.005). Both early improvement in HAM-D17 psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p⩽0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D17 psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement.


Heterogeneity of EGFR Aberrations and Correlation with Histological Structures: Analyses of Therapy-Naive Isogenic Lung Cancer Lesions with EGFR Mutation.
EGFR gene somatic mutation is reportedly homogeneous. However, there are few data regarding the heterogeneity of expression of mutant EGFR protein and EGFR gene copy number, especially in extrathoracic lesions. These types of data may enhance our understanding of the biology of EGFR-mutated lung cancer and our understanding of the heterogeneous response patterns to EGFR TKIs. An 81-year-old never-smoking female with lung adenocarcinoma could not receive any systemic therapy because of her poor performance status. After her death, 15 tumor specimens from different sites were obtained by autopsy. Expression of mutant EGFR protein and EGFR gene copy numbers were assessed by immunohistochemical analysis and by silver in situ hybridization, respectively. Heterogeneity in these EGFR aberrations was compared between metastatic sites (distant versus lymph node) or histological structures (micropapillary versus nonmicropapillary). All lesions showed positive staining for mutant EGFR protein, except for 40% of the papillary component in one of the pulmonary metastases (weak staining below the 1+ threshold). Expression of mutant-specific EGFR protein, evaluated by H-score, was significantly higher in the micropapillary components than in the nonmicropapillary components (Mann-Whitney U test, p = 0.014). EGFR gene copy number was quite different between lesions but not correlated with histological structure or metastatic form. However, EGFR gene copy numbers were similar between histological structures in each lesion. These data indicate that expression of EGFR mutant protein and EGFR gene copy number do not change as a consequence of tumor progression. This also justifies using the biopsy specimens from metastases as a surrogate for primary tumors.


Cascades in Compartments: En Route to Machine-Assisted Biotechnology.
Biological compartmentalization is a fundamental principle of life that allows cells to metabolize, propagate, or communicate with their environment. Much research is devoted to understanding this basic principle and to harness biomimetic compartments and catalytic cascades as tools for technological processes. This Review summarizes the current state-of-the-art of these developments, with a special emphasis on length scales, mass transport phenomena, and molecular scaffolding approaches, ranging from small cross-linkers over proteins and nucleic acids to colloids and patterned surfaces. We conclude that the future exploration and exploitation of these complex systems will largely benefit from technical solutions for the integrated, machine-assisted development and maintenance of a next generation of biotechnological processes. These goals should be achievable by implementing microfluidics, robotics, and added manufacturing techniques supplemented by theoretical simulations as well as computer-aided process modeling based on big data obtained from multiscale experimental analyses.


Quantification of effective connectivity in the brain using a measure of directed information.
Effective connectivity refers to the influence one neural system exerts on another and corresponds to the parameter of a model that tries to explain the observed dependencies. In this sense, effective connectivity corresponds to the intuitive notion of coupling or directed causal influence. Traditional measures to quantify the effective connectivity include model-based methods, such as dynamic causal modeling (DCM), Granger causality (GC), and information-theoretic methods. Directed information (DI) has been a recently proposed information-theoretic measure that captures the causality between two time series. Compared to traditional causality detection methods based on linear models, directed information is a model-free measure and can detect both linear and nonlinear causality relationships. However, the effectiveness of using DI for capturing the causality in different models and neurophysiological data has not been thoroughly illustrated to date. In addition, the advantage of DI compared to model-based measures, especially those used to implement Granger causality, has not been fully investigated. In this paper, we address these issues by evaluating the performance of directed information on both simulated data sets and electroencephalogram (EEG) data to illustrate its effectiveness for quantifying the effective connectivity in the brain.


Isolation of an active heavy-chain variable domain from a homogeneous rabbit antibody by cathepsin B digestion of the aminoethylated heavy chain.
Cathepsin B from bovine liver has been used to cleave the heavy chain of partially reduced and aminoethylated rabbit allotype a1 IgG. Three major cleavages have been identified, one of which appears to be at the peptide bond carboxy terminal to the two adjacent (aminoethyl)cysteine residues at positions 133 and 134. The variable domain of the heavy chain (VH) was isolated by gel filtration from both pooled heterogeneous rabbit IgG and a homogenous rabbit antitype III pneumococcal polysaccharide antibody. This VH inhibited the binding of 125I-labeled (allotype a) IgG to anti-a1 allotypic antibodies. The recombinant molecule consisting of VH and light chain from the homogeneous antibody is active in an antigen binding assay.


Endomyocardial firbrosis and Löffler's endocarditis parietalis fibroplastica.
The morphological features of endomyocardial fibrosis and Löffler's endocarditis are described. Sixteen cases of the chronic stage of Löffler's endocarditis were compared with pathological material of thirty-two patients with endomyocardial fibrosis. No morphological differences were noted. It is suggested that endomyocardial fibrosis and LOffler's endocarditis are part of the same disease spectrum, the origin of which can be traced back to the presence of eosinophils in the myocardium.


Knowledge translation in family nursing: does a short-term therapeutic conversation intervention benefit families of children and adolescents in a hospital setting? Findings from the Landspitali University Hospital Family Nursing Implementation Project.
In an effort to examine translation of family nursing knowledge to practice, the Landspitali University Hospital Family Nursing Implementation Project (2007-2011), was thoughtfully initiated in Reykjavik, Iceland and systematically evaluated. The mission was to implement family nursing in every department of the hospital. This publication is the first formal research report from this landmark project. The purpose of this research was to evaluate the effectiveness of a short-term therapeutic conversation intervention with families who were receiving health care services at the Children's Hospital at Landspitali University Hospital in Iceland related to childhood and adolescent acute and chronic illnesses. The therapeutic conversation was guided by Family Systems Nursing and used the Calgary Family Assessment and Intervention Models (Wright & Leahey, 2005, 2009). Families (N = 76) were randomly assigned to either an experimental group (short-term therapeutic conversation: n = 41) or to a control group (traditional care: n = 35). Parents in the experimental group reported significantly higher family support after the intervention, compared to the parents in the control group. Differences were noted between families experiencing acute versus chronic illnesses. Recommendations are made for conducting and designing intervention research with families experiencing the hospitalization of a child or adolescent.


An approach to maximizing treatment adherence of children and adolescents with psychotic disorders and major mood disorders.
Mental health research has consistently focused on high rates of treatment non-adherence, and how inpatient programs and health professionals can effectively confront this reality. The literature has centred almost exclusively on adult populations. Unfortunately, psychotic and major mood disorders are serious and persistent mental health problems that are increasingly recognized as having an early onset, affecting children and adolescents. This article draws on a review of the literature and Habermas's three domains of knowledge: technical, practical, and emancipatory. This article has incorporated current research, adherence theories, and the facilitation of the unique local expertise of health professionals to generate a framework. This framework is designed to teach health professionals working in child and adolescent psychiatric inpatient units how they and the larger unit can practice to enhance patient treatment adherence during and after admission. A five-step approach to teach health professionals to enhance treatment adherence has been developed based on current research and educational theories and principles. Health professionals working in child and adolescent psychiatry can practice to enhance patient treatment adherence, and improve patient and family outcomes.


A diet rich in omega-3 fatty acids enhances expression of soluble epoxide hydrolase in murine brain.
Several studies suggest that intake of omega-3 polyunsaturated fatty acids (n3-PUFA) beneficially influences cognitive function. However, effects on the adult brain are not clear. Little is known about the impact of dietary intervention on the fatty acid profile in adult brain, the modulation in the expression of enzymes involved in fatty acid biosynthesis and metabolism as well as changes in resulting oxylipins. These questions were addressed in the present study in two independent n3-PUFA feeding experiments in mice. Supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA, 1% each in the diet) for 30days to adult NMRI and C57BL/6 mice led to a distinct shift in the brain PUFA pattern. While n3-PUFAs EPA, n3 docosapentaenoic acid and DHA were elevated, many n6-PUFAs were significantly decreased (except, e.g. C20:3 n6 which was increased). This shift in PUFAs was accompanied by immense differences in concentrations of oxidative metabolites derived from enzymatic conversion of PUFAs, esp. arachidonic acid whose products were uniformly decreased, and a modulation in the activity and expression pattern of delta-5 and delta-6 desaturases. In both mouse strains a remarkable increase in the soluble epoxide hydrolase (sEH) activity (decreased epoxy-FA concentrations and epoxy-FA to dihydroxy-FA-ratios) as well as sEH expression was observed. Taking the high biological activity of epoxy-FA, e.g. on blood flow and nociceptive signaling into account, this finding might be of relevance for the effects of n3-PUFAs in neurodegenerative diseases. On any account, our study suggests a new distinct regulation of brain PUFA and oxylipin pattern by supplementation of n3-PUFAs to adult rodents.


Membrane potential bistability in nonexcitable cells as described by inward and outward voltage-gated ion channels.
The membrane potential of nonexcitable cells, defined as the electrical potential difference between the cell cytoplasm and the extracellular environment when the current is zero, is controlled by the individual electrical conductance of different ion channels. In particular, inward- and outward-rectifying voltage-gated channels are crucial for cell hyperpolarization/depolarization processes, being amenable to direct physical study. High (in absolute value) negative membrane potentials are characteristic of terminally differentiated cells, while low membrane potentials are found in relatively depolarized, more plastic cells (e.g., stem, embryonic, and cancer cells). We study theoretically the hyperpolarized and depolarized values of the membrane potential, as well as the possibility to obtain a bistability behavior, using simplified models for the ion channels that regulate this potential. The bistability regions, which are defined in the multidimensional state space determining the cell state, can be relevant for the understanding of the different model cell states and the transitions between them, which are triggered by changes in the external environment.


Comparative genomic and transcriptional analyses of CRISPR systems across the genus Pyrobaculum.
Within the domain Archaea, the CRISPR immune system appears to be nearly ubiquitous based on computational genome analyses. Initial studies in bacteria demonstrated that the CRISPR system targets invading plasmid and viral DNA. Recent experiments in the model archaeon Pyrococcus furiosus have uncovered a novel RNA-targeting variant of the CRISPR system. Because our understanding of CRISPR system evolution in other archaea is limited, we have taken a comparative genomic and transcriptomic view of the CRISPR arrays across six diverse species within the crenarchaeal genus Pyrobaculum. We present transcriptional data from each of four species in the genus (P. aerophilum, P. islandicum, P. calidifontis, P. arsenaticum), analyzing mature CRISPR-associated small RNA abundance from over 20 arrays. Within the genus, there is remarkable conservation of CRISPR array structure, as well as unique features that are have not been studied in other archaeal systems. These unique features include: a nearly invariant CRISPR promoter, conservation of direct repeat families, the 5' polarity of CRISPR-associated small RNA abundance, and a novel CRISPR-specific association with homologues of nurA and herA. These analyses provide a genus-level evolutionary perspective on archaeal CRISPR systems, broadening our understanding beyond existing non-comparative model systems.


Dietary protein to starch metabolizable energy ratios alter growth performance and gastrointestinal microbiota of calves.
The diet structure is very important for the growth and development of calves. This study aimed to investigate the effects of dietary protein-to-starch metabolizable energy ratios (DPSRs) on growth performance, blood index, and gastrointestinal microbiota of calves. Forty-eight Holstein bull calves were fed six dietary DPSRs including A20-35 (20% CP and 35% starch), B20-30, C20-25, D22-35, E22-30, and F22-25 at d 4 to d 60, and then changed to another six dietary DPSRs at d 61 to d 180 (A18-30, B18-27, C18-24, D20-30, E20-27, and F20-24). Twelve calves (d 60) from groups A20-35, C20-25, D22-35, and F22-25 (n = 3) and another twelve calves (d 180) from groups A18-30, C18-24, D20-30, and F20-24 (n = 3) were euthanized. The growth performance parameters were measured. Blood, ruminal fluid, and cecum digesta were collected for further analysis. Results showed heart girth gain of B18-27 was significantly higher than A18-30, C18-24, and heart girth gain (d 180) was significantly affected by protein × starch (DPSRs; p < 0.05). Blood urea nitrogen (BUN; d 60) in C20-25 was significantly higher than A20-35 and B20-30 (p < 0.05). The BUN (d 180) in D20-30 was significantly higher than A18-30 (p < 0.05). The BUN was significantly affected by protein × starch (p < 0.05) on d 60. The albumin (ALB) levels in C20-25 and C18-24 were significantly higher than that in A20-35 on d 60 and A18-30 on d 180, respectively (p < 0.05). The ALB level in D22-35 on d 60 and E20-27 on d 180 was significantly higher than that in other groups (p < 0.05). The ALB level was significantly affected by protein and starch, respectively, on d 60 (p < 0.05). In the rumen, the genera Roseburia (C20-25) and Dialister (D22-35), Prevotellaceae UCG-001 (C18-24), Erysipelotrichaceae UCG-002, and Anaerovorax (F20-24) were found in significant higher relative abundances than those in other groups (p < 0.05). In the cecum, the genera Bacteroides and Eisenbergiella (F22-25), Ruminiclostridium_1 and Candidatus Stoquefichus (A18-30), Erysipelotrichaceae UCG-004 and Tyzzerella 4 (D20-30), and Prevotellaceae UCG-003 and Klebsiella (F20-24) were found in significant higher abundances than those in other groups (p < 0.05). Collectively, these results indicated that the heart girth, BUN, ALB, and gastrointestinal microbiota responded distinctly to differing DPSRs.


Drug delivery via porous silicon: a focused patent review.
Although silicon is more commonly associated with computer chips than with drug delivery, with the discovery that porous silicon is a viable biocompatible material, mesoporous silicon with pores between 2 and 50 nm has been loaded with small molecule and biomolecule therapeutics and safely implanted for controlled release. As porous silicon is readily oxidized, porous silica must also be considered for drug delivery applications. Since 2010, only a limited number of US patents have been granted, primarily for ophthalmologic and immunotherapy applications, in contrast to the growing body of technical literature in this area.


Ionic Liquids-Driven Cluster-to-Cluster Conversion of Polyhydrido Copper(I) Clusters Cu7H5 to Cu8H6 and Cu12H9.
Although ionic liquids (ILs) are of prime interest for the synthesis of various nanomaterials, they are scarcely utilized for the polyhydrido copper(I) [Cu(I)H] clusters. Herein, two air-stable Cu(I)H clusters, [Cu8H6(dppy)6](NTf2)2 (Cu8H6) and {Cu12H9(dppy)6[N(CN)2]3} (Cu12H9), are synthesized in high yields for the first time from the ILs-driven conversion of an unprecedented cluster [Cu7H5(dppy)6](ClO4)2 (Cu7H5) by a facile three-layers diffusion crystal (TLDC) method, strategically introducing IL-NTf2 and IL-N(CN)2 as two types of unusual interfacial crystallized templates, respectively. Their structures are fully characterized by various spectroscopic methods and X-ray crystallography, which shows that the anion of IL plays an important role as an anion template and an anion ligand in controlling the structural conversion of Cu(I)H clusters. Their photophysical properties are also investigated, and it is found that all reported clusters exhibit red luminescence with λem ranging from 600 to 690 nm.


Inhibitory activity of cartilage growth in serum of young rats.
Humoral factors play an important role in growth regulation. The growth regulatory activity in serum is a complex system with both growth-promoting and growth-inhibiting factors. In this study, using in vitro cartilage from rat nasal septum as target organ, evidence is presented that inhibiting activity does exist in normal rat serum. This activity seems to play a role in modulating cartilage growth rate in young, normal animals. Furthermore, a significant interaction between age in cartilage and age in serum as regards influence on cartilage growth was found.


Promoter and nucleotide sequences of the Zymomonas mobilis pyruvate decarboxylase.
DNA sequence analysis showed that pyruvate decarboxylase (one of the most abundant proteins in Zymomonas mobilis) contains 559 amino acids. The promoter for the gene encoding pyruvate decarboxylase was not recognized by Escherichia coli, although the cloned gene was expressed at relatively high levels under the control of alternative promoters. The promoter region did not contain sequences which could be identified as being homologous to the generalized promoter structure for E. coli. Hydropathy plots for the amino acid sequence indicated that pyruvate decarboxylase contains a large number of hydrophobic domains which may contribute to the thermal stability of this enzyme.


Simultaneous Deployment and Tracking Multi-Robot Strategies with Connectivity Maintenance.
Multi-robot teams composed of ground and aerial vehicles have gained attention during the last few years. We present a scenario where both types of robots must monitor the same area from different view points. In this paper, we propose two Lloyd-based tracking strategies to allow the ground robots (agents) to follow the aerial ones (targets), keeping the connectivity between the agents. The first strategy establishes density functions on the environment so that the targets acquire more importance than other zones, while the second one iteratively modifies the virtual limits of the working area depending on the positions of the targets. We consider the connectivity maintenance due to the fact that coverage tasks tend to spread the agents as much as possible, which is addressed by restricting their motions so that they keep the links of a minimum spanning tree of the communication graph. We provide a thorough parametric study of the performance of the proposed strategies under several simulated scenarios. In addition, the methods are implemented and tested using realistic robotic simulation environments and real experiments.


Pyrimidine as constituent of natural biologically active compounds.
This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics--some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.


Targeting Mycolic Acid Transport by Indole-2-carboxamides for the Treatment of Mycobacterium abscessus Infections.
Mycobacterium abscessus is a fast-growing, multidrug-resistant organism that has emerged as a clinically significant pathogen in cystic fibrosis (CF) patients. The intrinsic resistance of M. abscessus to most commonly available antibiotics seriously restricts chemotherapeutic options. Herein, we report the potent activity of a series of indolecarboxamides against M. abscessus. The lead compounds, 6 and 12, exhibited strong activity in vitro against a wide panel of M. abscessus isolates and in infected macrophages. High resistance levels to the indolecarboxamides appear to be associated with an A309P mutation in the mycolic acid transporter MmpL3. Biochemical analyses demonstrated that while de novo mycolic acid synthesis remained unaffected, the indolecarboxamides strongly inhibited the transport of trehalose monomycolate, resulting in the loss of trehalose dimycolate production and abrogating mycolylation of arabinogalactan. Our data introduce a hereto unexploited chemical structure class active against M. abscessus infections with promising translational development possibilities for the treatment of CF patients.


Recent Changes in the Scaffold Diversity of Organic Chemistry As Seen in the CAS Registry.
A large set of organic compounds extracted from the CAS Registry is analyzed to study recent changes in structural diversity. The diversity is characterized using the framework content of the compounds; the framework of a molecule is the scaffold consisting of all its ring systems and all the chain fragments connecting them. The compounds are partitioned based on their year of first report in the literature, which allows framework occurrence frequencies to be compared across a 10-year interval. The results are consistent with a process in which frameworks with the greatest frequency of use in the past are the most likely to be used again, but it is also found that the frequency ordering changes over time. These fluctuations in ordering are attributed to stochastic factors, scientific and economic, that can affect how chemical space is explored. Framework diversity is found to have increased over time despite the extensive reuse of a relatively small number of frameworks; this increase is due to the large number of new frameworks. The long tail of the framework distribution, composed of frameworks that occur in few compounds or only one compound, is found to be a large and growing part of framework space.


A cost analysis of first-line chemotherapy for low-risk gestational trophoblastic neoplasia.
To determine the optimal approach to first-line treatment for low-risk gestational trophoblastic neoplasia (GTN) using a cost analysis of 3 commonly used regimens. A decision tree of the 3 most commonly used first-line low-risk GTN treatment strategies was created, accounting for toxicities, response rates and need for second- or third-line therapy. These strategies included 8-day methotrexate (MTX)/folinic acid, weekly MTX, and pulsed actinomycin-D (act-D). Response rates, average number of cycles needed for remission, and toxicities were determined by review of the literature. Costs of each strategy were examined from a societal perspective, including the direct total treatment costs as well as the indirect lost labor production costs from work absences. Sensitivity analysis on these costs was performed using both deterministic and probabilistic cost-minimization models with the aid of decision tree software (TreeAge Pro 2011, TreeAge Inc., Williamstown, Massachusetts). We found that 8-day MTX/folinic acid is the least expensive to society, followed by pulsed act-D ($4,867 vs. $6,111 average societal cost per cure, respectively), with act-D becoming more favorable only with act-D per-cycle cost <$231, or response rate to first-line therapy > 99%. Weekly MTX is the most expensive first-line treatment strategy to society ($9,089 average cost per cure), despite being least expensive to administer per cycle, based on lower first-line response rate. Absolute societal cost of each strategy is driven by the probability of needing expensive third-line multiagent chemotherapy, however relative cost differences are robust to sensitivity analysis over the reported range of cycle number and response rate for all therapies. Based on similar efficacy and lower societal cost, we recommend 8-day MTX/folinic acid for first-line treatment of low-risk GTN.


When power does not corrupt: superior individuation processes among powerful perceivers.
To examine whether powerful people fail to individuate the less powerful, the authors assigned participants to either a high-power or low-power role for a computer E-mail role play. In 3 studies, participants in the high-power role made decisions and determined the outcomes of interactions; low-power role players had no power and relied on high-power targets for outcome decisions. Studies I and 2 found that high-power perceivers better individuated low-power targets. Study 3 demonstrated that high-power role players' superior judgment can be impaired by including a task that directs their responsibility toward organizational rather than interpersonal concerns. In all, results suggest that the effect of power on social judgment may be more complex and multifaceted than has previously been acknowledged.


An exploratory mixed methods analysis of adherence predictors following acute coronary syndrome.
Adherence to cardiac health behaviors is a critical predictor of prognosis in the months following an acute coronary syndrome (ACS). However, there has been minimal concomitant study of multiple nonadherence risk factors, as assessed via record review, structured assessments, and qualitative interviews, among hospitalized ACS patients. Accordingly, we completed an exploratory mixed methods study with 22 individuals who were admitted for ACS and had suboptimal pre-ACS adherence to physical activity, heart-healthy diet, and/or medications, defined by a Medical Outcomes Study Specific Adherence Scale (MOS SAS) score <15/18. During hospitalization, participants underwent quantitative assessments of sociodemographic, medical, and psychological variables, followed by in-depth semi-structured interviews to explore intentions, plans, and perceived barriers related to post-discharge health behavior changes. The MOS SAS was readministered at 3 months and participants were designated as persistently nonadherent (MOS SAS <15; n = 9) or newly adherent (n = 13). Interviews were transcribed and coded by trained raters via content analysis, and quantitative variables were compared between groups using chi-square analysis and independent-samples t-tests. On our primary qualitative analysis, we found that participants with vaguely described intentions/plans regarding health behavior change, and those who focused on barriers to change that were perceived as static, were more likely to be persistently nonadherent. On exploratory quantitative analyses, greater medical burden, diabetes, depressive symptoms, and low optimism/positive affect at baseline were associated with subsequent post-ACS nonadherence (all p < .05). In conclusion, this appears to be the first study to prospectively examine all of these constructs in hospitalized ACS patients, and we found that specific factors were associated with nonadherence to key health behaviors 3 months later. Therefore it may be possible to predict future nonadherence in ACS patients, even during hospitalization, and specific interventions during admission may be indicated to prevent adverse outcomes among patients at highest risk for post-ACS nonadherence.


[Medical treatment for calcium metabolism and balance in terms of the anti-aging medicine].
The aging balance and the risk factor are considered from a whole body viewpoint whenever it thinks about the anti-aging treatment for calcium metabolism. The aging balance attaches to the muscles, the blood vessel, the nerve, the hormone, and the bone, and the aging risk factor evaluates immunity, the oxidation stress, the mental stress, the lifestyle, and the metabolic states. The basis of treatment is improvement of life styles in daily meal, physical activities, and the spirit. The drug therapy is used to the end assisting. It thought about the aging risk factor by describing the calcium abnormal metabolizing according to aging influence on the whole body, the prevention, and treatment in this text.


Hypoplastic left heart syndrome: color Doppler sonographic and magnetic resonance imaging features in utero.
A 26-year-old Japanese woman, gravida 2, para 1, was referred to our ultrasonography clinic at 27 weeks' gestation, because of a suspected fetal heart anomaly. The hemodynamic examination, specific for hypoplastic left heart syndrome and obtained with color Doppler sonography, gave a clue to an accurate diagnosis of this entity. Moreover, the use of magnetic resonance imaging provided information complementary to the sonographic findings. The sophisticated type of fetal cardiac examination with color Doppler sonography and magnetic resonance imaging was very effective to interpret hypoplastic left heart syndrome with total anomalous pulmonary venous return. An accurate prenatal diagnosis of congenital heart anomalies is useful for obstetrical management.


Residual analysis of the water resonance signal in breast lesions imaged with high spectral and spatial resolution (HiSS) MRI: a pilot study.
High spectral and spatial resolution magnetic resonance imaging (HiSS MRI) yields information on the local environment of suspicious lesions. Previous work has demonstrated the advantages of HiSS (complete fat-suppression, improved image contrast, no required contrast agent, etc.), leading to initial investigations of water resonance lineshape for the purpose of breast lesion classification. The purpose of this study is to investigate a quantitative imaging biomarker, which characterizes non-Lorentzian components of the water resonance in HiSS MRI datasets, for computer-aided diagnosis (CADx). The inhomogeneous broadening and non-Lorentzian or "off-peak" components seen in the water resonance of proton spectra of breast HiSS images are analyzed by subtracting a Lorentzian fit from the water peak spectra and evaluating the difference spectrum or "residual." The maxima of these residuals (referred to hereafter as "off-peak components") tend to be larger in magnitude in malignant lesions, indicating increased broadening in malignant lesions. The authors considered only those voxels with the highest magnitude off-peak components in each lesion, with the number of selected voxels dependent on lesion size. Our voxel-based method compared the magnitudes and frequencies of off-peak components of all voxels from all lesions in a database that included 15 malignant and 8 benign lesions (yielding ≈ 3900 voxels) based on the lesions' biopsy-confirmed diagnosis. Lesion classification was accomplished by comparing the average off-peak component magnitudes and frequencies in malignant and benign lesions. The area under the ROC curve (AUC) was used as a figure of merit for both the voxel-based and lesion-based methods. In the voxel-based task of distinguishing voxels from malignant and benign lesions, off-peak magnitude yielded an AUC of 0.88 (95% confidence interval [0.84, 0.91]). In the lesion-based task of distinguishing malignant and benign lesions, average off-peak magnitude yielded an AUC 0.83 (95% confidence interval [0.61, 0.98]). These promising AUC values suggest that analysis of the water-resonance in each HiSS image voxel using "residual analysis" could have high diagnostic utility and could be used to enhance current CADx methods and allow detection of breast cancer without the need to inject contrast agents.


[Tissue-specific autoimmunity in patients with idiopathic diabetes].
According to the WHO classification, type 1 diabetes is divided into type 1A - autoimmune and type 1B - idiopathic. The pathogenesis of the latter remains unknown. Clinical observations confirm that type 1 diabetes is often associated with the presence of other organ-specific autoantibodies. Besides, the idiopathic type 1 diabetes is suggested as resulted form immune-related beta cell destruction with the defect of humoral response. of the study was to verify the above-mentioned hypothesis by an evaluation of the prevalence of thyroid and coeliac antibodies in children with idiopathic diabetes. The study groups consisted of 37 patients with idiopathic diabetes (group 1B) and 108 patients with autoimmune diabetes (1A). The examined groups were chosen from 569 children with newly diagnosed type 1 diabetes. Anti-islet antibodies (ICA) and antibodies to endomysium were detected by indirect immunofluorescence. Antibodies to tissue transglutaminase were measured by the immunoenzymatic method, whereas the measurement of autoantibodies to insulin, to tyrosine phosphatase and to glutamic acid decarboxylase was determined by radioimmunoassay. Thyroid antibodies were detected in 5.9% of the examined patients from group 1B and 14.7% from group 1A. The frequency of the presence of tissue transglutaminase autoantibodies in both groups was similar (9.4% in 1B and 8.3% in 1A) and in case of endomysial antibodies it was slightly higher in group 1B (9.4% vs 4.8%, p=0.39). Since the prevalence of tissue specific autoantibodies is similar in both presentations of type 1 diabetes it is unlikely that a humoral defect of immune response in idiopathic diabetes is observed in this group of patients.


Incidence of cutaneous adverse drug reactions among medical inpatients of Sultanah Aminah Hospital Johor Bahru.
Cutaneous adverse drug reactions (cADRs) are common. There are only few studies on the incidence of cADRs in Malaysia. To determine the incidence, clinical features and risk factors of cADRs among hospitalized patients. A prospective study was conducted among medical inpatients from July to December 2014. A total of 43 cADRs were seen among 11 017 inpatients, yielding an incidence rate of 0.4%. cADR accounted for hospitalization in 26 patients. Previous history of cADR was present in 14 patients, with 50% exposed to the same drug taken previously. Potentially lifethreatening severe cutaneous adverse reactions (SCAR), namely drug reaction with eosinophilia and systemic symptoms (DRESS: 14 cases) and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN: 6 cases) comprise almost 50% of cADRs. The commonest culprit drug group was antibiotics (37.2%), followed by anticonvulsants (18.6%). Cotrimoxazole, phenytoin and rifampicin were the main causative drugs for DRESS. Anticonvulsants were most frequently implicated in SJS/TEN (66.7%). Most cases had "probable" causality relationship with suspected drug (69.8%). The majority of cases were of moderate severity (65.1%), while 18.6% had severe reaction with 1 death recorded. Most cases were not preventable (76.7%). Older age (> 60 years) and mucosal involvement were significantly associated with a more severe reaction. The incidence of cADRs was 0.4%, with most cases classified as moderate severity and not preventable. The commonest reaction pattern was DRESS, while the main culprit drug group was antibiotics. Older age and mucosal membrane involvement predicts a severe drug reaction.


[Cerebrospinal fluid and blood kinins of patients with cerebral circulatory disorders].
The kallikrein-kinin system components were examined in the cerebrospinal fluid and the blood of patients with acute cerebral circulation disorders at various intervals after the vascular episode. A considerable increase in the content of all the substances being examined in the patients' cerebrospinal fluid was shown, this increase being not dependent on the stroke character. An activation of the kallikrein-kinin system was observed in the blood plasma within the first 20 days after the vascular episode. In young patients, these changes were more pronounced. The changes in the kallikrein-kinin system components, along with those of other vasoactive substances may take a certain part in the pathogenetic mechanisms of the cerebral stroke.


Characterization of Plasma-Derived Extracellular Vesicles Isolated by Different Methods: A Comparison Study.
Extracellular vesicles (EV) are small membrane structures released by cells that act as potent mediators of intercellular communication. The study of EV biology is important, not only to strengthen our knowledge of their physiological roles, but also to better understand their involvement in several diseases. In the field of biomedicine they have been studied as a novel source of biomarkers and drug delivery vehicles. The most commonly used method for EV enrichment in crude pellet involves serial centrifugation and ultracentrifugation. Recently, different protocols and techniques have been developed to isolate EV that imply less time and greater purification. Here we carry out a comparative analysis of three methods to enrich EV from plasma of healthy controls: ultracentrifugation, ExoQuickTM precipitation solution (System Biosciences), and Total Exosome Isolation kit (Invitrogen). Our results show that commercial precipitation reagents are more efficient and enable higher EV enrichment factors compared with traditional ultracentrifugation, although subsequent imaging analysis is not possible with some of them. We hope that this work will contribute to the current research on isolation techniques to assist the progress of clinical applications with diagnostic or therapeutic objectives.


Redox-Active Phenolic Compounds Mediate the Cytotoxic and Antioxidant Effects of Carpodesmia tamariscifolia (=Cystoseira tamariscifolia).
Carpodesmia tamariscifolia is a brown alga rich in (poly)phenols with important cytotoxic and antioxidant effects. However, the relationship between its chemical composition and its effects is unknown. The aim of this study is to identify the potential compounds and mechanisms responsible for its main effects. The alga was extracted consecutively with hexane, dichloromethane and methanol and further fractionated using Sephadex LH-20 and silica gel columns when appropriate. The fractions were subjected to thin-layer chromatography and liquid chromatography-mass spectrometry analysis and evaluated for their total phenolic content (Folin-Ciocalteu assay), radical scavenging activity (DPPH assay), cytotoxic activity (MTT assay on the SH-SY5Y cell line), and ability to generate H2 O2 (Amplex Red assay). Chromatographic and phenolic analyses of the fractions indicate that abundant redox-active phenols are present in all the fractions and that a high amount of prenylated hydroquinone derivatives is present in the apolar ones. In the hexane and dichloromethane fractions, the cytotoxic and antioxidant activities are closely related to their phenolic content, whereas in the methanol fractions, the cytotoxicity is negatively related to the phenolic content and the antioxidant activity is positively related to it. In the same tests, hydroquinone behaves as both strong cytotoxic and antioxidant agent. H2 O2 assay shows that C. tamariscifolia fractions and hydroquinone can autoxidize and generate H2 O2 . Our results suggest that redox-active phenols produce the pharmacological effects described for C. tamariscifolia and that the hydroquinone moiety of prenylated hydroquinone derivatives is responsible for both cytotoxic (through a pro-oxidant mechanism secondary to its autoxidation) and antioxidant effects of the apolar fractions.


Polymorphisms of insulin receptor substrate 2 are putative biomarkers for pediatric medulloblastoma: considering the genetic susceptibility and pathological diagnoses.
Molecular profiling subgrouped medulloblastoma (MB) into four subtypes featured by distinct footprints. However, germline studies on genetic susceptibility in Chinese population have not been reported. To investigate the correlation of polymorphisms involved in the AKT signaling pathway with clinicopathological parameters in pediatric MB, and their contribution to the clinical outcome, we performed a case-controlled cohort consisting of 48 patients with pediatric MB and 190 healthy controls from Han population. Significant association in rs7987237 of insulin receptor substrate 2 (IRS2) was identified as risk allele/genotype between MB patients and control group (P<0.05). The allele "C" of rs7987237 in IRS2 gene was associated with an increased risk of MB (P=0.025; OR=2.95, 95%CI 1.43-6.11) after Bonferroni correction. Among 48 patients, various genotypes of rs7987237 show significant association with pathological diagnosis and metastases risk (P<0.05). Furthermore, the survival curve of patients with genotype "CC" of rs7987237 was confirmed with better outcome (P<0.001). Combined with previous results, our study suggests that polymorphisms of IRS2 putatively participated in the development of pediatric MB development. Therefore, it may benefit the early diagnosis and indicate the prognosis of patients with MB in Han population.


Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty.
Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories.


Wetting film dynamics during evaporation under weightlessness in a near-critical fluid.
By performing near-critical fluid experiments in the weightlessness of an orbiting space vehicle, we have suppressed buoyancy-driven flows and gravitational constraints on the liquid-gas interface of a large gas bubble. At equilibrium, the liquid completely wets the walls of a cylindrical cell, and the bubble is pushed to the sidewall. In these experiments the system's temperature T is increased at a constant rate past the critical temperature T(C), pushing it slightly out of equilibrium. The wetting film shows a large mechanical response to this heating, including contact lines that recede on a solid surface and a spreading bubble. Near T(C), the receding contact lines make the entire bubble appear to spread along the copper sidewall. The spreading bubble is a manifestation of the boiling crisis near the critical point. We present quantitative data of the receding contact lines that are observed prior to the near-critical boiling crisis. We analyze the receding contact lines in detail, and find that they are driven by vapor recoil from evaporation, as is the spreading bubble of the boiling crisis.


Randomized, placebo-controlled trial of Lactobacillus rhamnosus GG as treatment of atopic dermatitis in infancy.
Some studies have suggested that supplementation of food with lactobacilli may prevent or improve atopic dermatitis in children. This study was designed to investigate the therapeutic effect of Lactobacillus rhamnosus GG (LGG) as a food supplement in infants suffering from atopic dermatitis. Infants aged 3-12 months suffering from mild-to-moderate atopic dermatitis (severity scoring of atopic dermatitis or SCORAD index of 15-40) without current antiinflammatory treatment were randomized to receive LGG (5 x 10(9) colony forming units b.i.d.) or placebo as a food supplement for 12 weeks. Severity scoring of atopic dermatitis index and use of hydrocortisone 1% ointment as rescue medication (2 points per application) were recorded at 4, 8, and 12 weeks of treatment and combined as symptom load (SL). Fifty-four infants (LGG group, mean +/- SD SCORAD index 24.6 +/- 8.8) and 48 infants (placebo group, SCORAD index 23.6 +/- 7.8) were randomized and completed the treatment period (intention-to-treat analysis). Symptom load generally improved over time at 4 weeks (LGG vs placebo, 23.8 +/- 12.4 vs 20.6 +/- 9.9), 8 weeks (22.5 +/- 14.6 vs 17.9 +/- 13.1), and 12 weeks (19.6 +/- 15.4 vs 15.1 +/- 12.1), without statistically significant group differences. When stratified for age, eczema severity or use of rescue medication, no statistically significant group differences, in improvement, were found. No significant group differences were found for the use of rescue medication (0.8 +/- 45.0 g vs 3.5 +/- 29.8 g), increase in mean logarithmic total serum IgE (0.17 +/- 0.30 kU/l vs 0.26 +/- 0.45 kU/l), and newly developed allergic sensitization against hen's egg or cow's milk (18.8%vs 10.0%). This placebo-controlled trial showed no therapeutic effect of LGG against mild-to-moderate atopic dermatitis in infancy.


Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity.
Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review aims to provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. It focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation. Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage.


Porphyria variegata: failure of chloroquin treatment.
A 27-year-old woman affected by porphyria variegata was treated with chloroquin for 1 1/2 years without any clinical improvement. Urinary excretion of porphyrins was not convincingly altered during treatment.


Open-source 3-D printable autoinjector: Design, testing, and regulatory limitations.
Autoinjectors have become popular modern injectable medical devices used as drug delivery systems. Due to their ease, capability and reliability compared to other conventional injectable medical devices, the market and manufacturing demand for autoinjector devices are increasing rapidly and expected to reach a market of $37.5 billion globally by 2025. Although autoinjectors can offset healthcare treatment costs through self-administered medication, they can be expensive for consumers, which limit their accessibility. This study describes the design and manufacture of a spring-driven and 3-D printed autoinjector to overcome this economic accessibility challenge. The digitally replicable device is released as open-source hardware to enable low-cost distributed manufacturing. The bill of materials and assembly instructions are detailed, and the effectiveness of the autoinjector is tested against the current standard (ISO 11608-1:2022) for needle-based injection systems. The safety and dosing accuracy was tested by measuring the weight of 100% ethyl alcohol expelled from six BD Insulin syringes with varying capacities or needle lengths. A one-way analysis assessed the variability between the dose delivery efficiency of 1mL, 0.5mL, and 0.3mL syringes. Testing indicated that the entire dose was delivered over 97.5% of the time for 1mL and 0.5mL syringes, but the autoinjector's loaded spring force and size exceeded structural limitations of 0.3mL or smaller syringes. Components can be manufactured in about twelve hours using an open-source desktop RepRap-class fused filament 3-D printer. The construction requires two compression springs and 3-D printed parts. The total material cost of CAD$6.83 is less than a tenth of comparable commercial autoinjectors, which makes this approach promising. The autoinjector, however, is a class two medical device and must be approved by regulators. Future work is needed to make distributed manufacturing of such medical devices feasible and reliable to support individuals burdened by healthcare costs.


Antinuclear antibody positive pleural effusion in a patient with tuberculosis.
A patient with tuberculosis presented with a pleural effusion that was highly positive for antinuclear antibody (ANA). The pleural fluid autoimmune profile was positive for ANA IgG at a titre of 1 : 1280. Antibodies to double-stranded DNA were not detected in the pleural fluid or in serum. The serum autoimmune profile was positive for ANA IgG at 1 : 160 and IgM at 1 : 40. Pleural fluid was positive on culture for Mycobacterium tuberculosis after 8 weeks. Pleural biopsy for histology showed chronic inflammation and culture revealed no growth. The pleural fluid resolved with the anti-tuberculous treatment, and signs and symptoms of systemic lupus erythematosus or malignancy did not occur, which suggests that tuberculous pleural effusion is one of the causes of high ANA in pleural fluid.


N-Butyl Cyanoacrylate Embolization of a Peripheral Pulmonary Artery Aneurysm in a Patient with Patent Ductus Arteriosus.
N-Butyl cyanoacrylate embolization of peripheral pulmonary artery aneurysms has rarely been performed. This report presents a young woman with a history of patent ductus arteriosus and massive hemoptysis secondary to pulmonary artery aneurysm, successfully managed by embolotherapy using n-Butyl cyanoacrylate. This is the first report of n-Butyl cyanoacrylate embolization treatment of a bleeding pulmonary artery aneurysm in the setting of patent ductus arteriosus. The pertinent literature has been reviewed and the clinical background and the procedure have been explained.


The Use of Modular, Electronic Neuron Simulators for Neural Circuit Construction Produces Learning Gains in an Undergraduate Anatomy and Physiology Course.
During the spring of 2016 at the University of Wisconsin-Milwaukee, we implemented a novel educational technology designed to teach undergraduates about the nervous system while allowing them to physically construct their own neural circuits. Modular, electronic neuron simulators called NeuroBytes were used by the students in BIOSCI202 Anatomy and Physiology I, a four-credit course consisting of three hours per week each of lecture and laboratory time. 162 students participated in the laboratory sessions that covered reflexes; 83 in the experimental sections used the NeuroBytes to build a model of the patellar tendon reflex, while 79 in the control sections participated in alternate reflex curricula. To address the question of whether or not the NeuroBytes-based patellar tendon reflex simulation brought about learning gains, the control and experimental group students underwent pre/post testing before and after their laboratory sections. We found that for several of the neuroscience and physiology concepts assessed on the test, the experimental group students had significantly greater declarative learning gains between the pre- and post-test as compared to the control group students. While there are numerous virtual neuroscience education tools available to undergraduate educators, there are relatively few designed to engage students in the basics of electrophysiology and neural circuitry using physical manipulatives, and none to our knowledge that allow them to build circuits from functioning hand-held "neurons."


Incidence of A-V Fistulas after Renal Biopsy of Native and Transplanted Kidney - Two Centers Experience.
The aim of the study is to make a retrospective analysis of the incidence of AV fistulas after renal biopsy (RB) of native and transplanted kidney. Five hundred and sixteen (516) RB were analyzed. One hundred twenty nine (129) were native kidneys RB performed in Clinic of Nephrology (CN), 190 were performed in Clinic of Nephrology and transplantation (CNT) and 197 were transplanted kidney biopsies from the same clinic. Biopsy technique type Gun with needle 14G, 16 and 18 G was used in CN, CNT used the same technique with needles 16G. Doppler ultrasound was made for A-V fistulas diagnosis. The A-V fistulas incidence was 0.8%. The frequency of A-V fistulas registered in CN was significantly higher than that registered in CNT (2.3% vs. 0.5%, p < 0.01). Biopsies performed by 14 G needles provide a higher percentage of A-V fistulas compared to those done by 16 G. (3.3% vs. 2.4%, p < 0.5). The frequency of the A-V fistulas in native and transplanted kidneys in CNT was similar (0.5% vs. 0.5%, p > 0.05). The A-V fistulas incidence is very low. The needle thickness is an important factor relevant to the risk of occurrence of A-V fistulas.


[A Study on Radiation Dermatitis Grading Support System Based on Deep Learning by Hybrid Generation Method].
Radiation dermatitis is one of the most common adverse events in patients undergoing radiotherapy. However, the objective evaluation of this condition is difficult to provide because the clinical evaluation of radiation dermatitis is made by visual assessment based on Common Terminology Criteria for Adverse Events (CTCAE). Therefore, we created a radiation dermatitis grading support system (RDGS) using a deep convolutional neural network (DCNN) and then evaluated the effectiveness of the RDGS. The DCNN was trained with a dataset that comprised 647 clinical skin images graded with radiation dermatitis (Grades 1-4) at our center from April 2011 to May 2019. We created the datasets by mixing data augmentation images generated by image conversion and images generated by Poisson image editing using the hybrid generation method (Hyb) against lowvolume severe dermatitis (Grade 4). We then evaluated the classification accuracy of RDGS based on the hybrid generation method (Hyb-RDGS). The overall accuracy of the Hyb-RDGS was 85.1%, which was higher than that of the data augmentation method generally used for image generation. Effectiveness of the Hyb-RDGS using Poisson image editing was suggested. This result shows a possible supporting system for objective evaluation in grading radiation dermatitis.


Cost-benefit analysis of a plateletapheresis program.
We determined costs and benefits of a community donor plateletapheresis program (CDPP) designed to provide HLA-matched platelet transfusions for patients who were refractory to random-donor platelets (RDPs). Costs of establishing and maintaining the CDPP were $127,520 for the first year (1982). Benefits were expressed as cost savings attributed to the CDPP. After the program began, the use of RDP in the community was 17,458 units less than projected. Estimates of net cost savings during the first year ranged from $177,570 to $272,253 (1982 dollars; cost-to-benefit ratios were 1:1.39 to 1:2.14.) In a matched cohort study of marrow transplant patients, CDPP platelet transfusions were as effective as those from family donors while total platelet and red cell use was unchanged. In patients with acute leukemia treated with chemotherapy, significant reduction in both platelet and red cell use was seen after institution of CDPP support. We conclude that the CDPP is a cost-effective approach to platelet support.


Binder syndrome: literature review and long-term follow-up on two cases.
Binder syndrome has a characteristic clinical appearance including midface hypoplasia, flattened nose, convex upper lip, broad philtrum, crescent-shaped nostrils, and a deep fold or fossa between nose and upper lip. The incisors may be in crossbite with overangulation of the maxillary incisors, and a Class III occlusion is common. Radiographic features include small or absent anterior nasal spine, thin labial plate over incisor roots, nasomaxillary hypoplasia, and skeletal Class III relation. This article reviews the literature in reference to Binder syndrome and presents two patients treated by two different techniques with long-term follow-up. The first patient was treated with traditional orthognathic procedures, whereas the second was treated with a growth-center implant to the nose and orthodontics to treat the occlusion.


Cross-classified multilevel models for severity of commercial motor vehicle crashes considering heterogeneity among companies and regions.
This study analyzes 86,622 commercial motor vehicle (CMV) crashes (large truck, bus and taxi crashes) in South Korea from 2010 to 2014. The analysis recognizes the hierarchical structure of the factors affecting CMV crashes by examining eight factors related to individual crashes and six additional upper level factors organized in two non-nested groups (company level and regional level factors). The study considers four different crash severities (fatal, major, minor, and no injury). The company level factors reflect selected characteristics of 1,875 CMV companies, and the regional level factors reflect selected characteristics of 230 municipalities. The study develops a single-level ordinary ordered logit model, two conventional multilevel ordered logit models, and a cross-classified multilevel ordered logit model (CCMM). As the study develops each of these four models for large trucks, buses and taxis, 12 different statistical models are analyzed. The CCMM outperforms the other models in two important ways: 1) the CCMM avoids the type I statistical errors that tend to occur when analyzing hierarchical data with single-level models; and 2) the CCMM can analyze two non-nested groups simultaneously. Statistically significant factors include taxi company's type of vehicle ownership and municipality's level of transportation infrastructure budget. An improved understanding of CMV related crashes should contribute to the development of safety countermeasures to reduce the number and severity of CMV related crashes.


Isolation and some properties of the site-specific endonuclease and methylase Bme2161 from Bacillus megaterium 216.
The site-specific endonuclease Bme2161 was isolated as a homogeneous preparation by chromatography on phosphocellulose, hydroxyapatite and heparin-agarose. The molecular mass of the enzyme, determined by gel filtration and by electrophoresis under denaturing conditions, was found to be 60 kDa and 30 kDa respectively. These data indicate that the native enzyme consists of two identical subunits. The enzyme recognized the decreases pentanucleotide sequence 5'-GGACC-3' X 3'-CCTGG-5' and cleaves the sequence as indicated by arrows. The increases optimal concentration for endonuclease reaction is 6-7 mM Mg2+. The endonuclease relaxes its specificity in the presence of glycerol or dimethyl sulfoxide at low Mg2+ concentration (1-3 mM). Methylase Bme2161, which protects DNA against endonuclease Bme2161 action by DNA methylation, was isolated from the same bacterial strain.


Hepatoma-derived growth factor upregulation is correlated with prognostic factors of early-stage cervical adenocarcinoma.
Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor that plays an important role in the progression of different types of cancer. A total of 63 patients with early-stage cervical adenocarcinoma (Cx) were enrolled in this retrospective study. The expression of HDGF was significantly increased compared with adjacent non-tumor tissue samples (p < 0.001). Moreover, elevated nuclear HDGF levels were correlated with lymph-vascular space invasion (LVSI; p < 0.05), lymph node metastasis (LNM; p < 0.001), recurrence (p < 0.001) and advanced grade (AG; p < 0.001). The growth of cervical cancer cells (Hela cells) was enhanced by HDGF treatment. The HDGF mRNA and protein level were significantly higher in malignant cervical cancer cells compared with primary ones. By adenovirus gene delivery, HDGF overexpression enhanced, whereas HDGF knockdown perturbed the tumorigenic behaviors of cervical cancer cells. HDGF overexpression is common in early-stage cervical adenocarcinoma and is involved in the carcinogenesis of cervical adenocarcinoma. Cytoplasmic HDGF expression is strongly correlated with pelvic lymph node metastasis and recurrence, indicating that HDGF may serve as a novel prognostic marker for patients with Cx.


Emerging immunomodulatory therapies targeting the co-stimulatory pathways for the prevention of transplant rejection.
The continued discovery of novel immune molecules and pathways over the last decade has spurred a tremendous amount of research into the targeting of these pathways for the prevention of transplant rejection. Of particular interest are members of the ever-growing family of T-cell co-stimulatory pathways; the classic co-stimulatory pathways are the CD28/CTLA4:B7-1/2 and CD40:CD154, while the ICOS:ICOSL and PD-1:PD-L1/PD-L2 pathways are novel. Various chimeric molecules and monoclonal antibodies have been developed for targeting these pathways with promising results, especially with the newer generation of agents and in combination among themselves, with other immunomodulatory therapies and/or with conventional immunosuppressive agents. These novel immunomodulatory strategies have the potential to bring us a step closer to achieving transplantation tolerance.


Abnormal antenatal ultrasound findings and subsequent handicap.
The modern ultrasound technique in its various modes, real-time B-mode, M-mode, continuous and pulsed wave Doppler ultrasound, makes it possible to study in detail the fetal anatomy and function in utero. Fetometry allows for the evaluation of fetal size and growth and for detecting growth-retarded or macrosomic fetuses. Ultrasound seems, at present, to be the best method available in the detection of the growth-retarded fetus who is at risk of developing perinatal complications and subsequent handicap. Ultrasound can also be used when fetal growth retardation is suspected on clinical grounds. An absolute prerequisite for the proper use of ultrasound fetometry is the estimation of gestational age in early pregnancy. The high resolution of modern ultrasound scanners allows the antenatal detection of even minor fetal structural abnormalities. When lethal malformations are detected early in pregnancy, selective termination of pregnancy can be considered. Fetal abnormality detected in late pregnancy allows for optimal timing and mode of delivery leading to improved management and outcome, thus lowering the risks of subsequent handicap. Ultrasound examination of the extrafetal structures, e.g. umbilical cord, placenta and amniotic fluid volume, may add valuable clinical information. The finding of severe oligohydramnios is associated with increased perinatal mortality and morbidity. Fetal circulation can be evaluated by using the combination of real-time and pulsed Doppler ultrasound or, alternatively, by employing continuous wave Doppler ultrasound alone. Pathological changes in the blood velocity waveforms recorded from the fetal and umbilical arteries may signify very early signs of fetal hypoxia. The method has the potential of becoming a useful clinical method for fetal surveillance. The guidelines for a proper application in the perinatal medicine of the Doppler method have, however, not yet been established. In fetuses with cardiac arrhythmia and/or cardiac malformation, the Doppler investigation of the fetal circulation can be used to evaluate the haemodynamic alterations and, in cases of intrauterine treatment, to supervise and monitor the therapeutic effects. Fetal motor function can be followed and quantified with real-time ultrasound. Abnormal motor activity might indicate bad perinatal outcome. The predictive capacity of the test is increased when several variables are combined (e.g. the fetal biophysical profile score).(ABSTRACT TRUNCATED AT 400 WORDS)


PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838.
Battlefield blast exposure related to improvised explosive devices (IEDs) has become the most common cause of traumatic brain injury (TBI) in the recent conflicts in Iraq and Afghanistan. Mental health problems are common after TBI. A striking feature in the most recent veterans has been the frequency with which mild TBI (mTBI) and posttraumatic stress disorder (PTSD) have appeared together, in contrast to the classical situations in which the presence of mTBI has excluded the diagnosis of PTSD. However, treatment of PTSD-related symptoms that follow blast injury has become a significant problem. BCI-838 (MGS0210) is a Group II metabotropic glutamate receptor (mGluR2/3) antagonist prodrug, and its active metabolite BCI-632 (MGS0039) has proneurogenic, procognitive, and antidepressant activities in animal models. In humans, BCI-838 is currently in clinical trials for refractory depression and suicidality. The aim of the current study was to determine whether BCI-838 could modify the anxiety response and reverse PTSD-related behaviors in rats exposed to a series of low-level blast exposures designed to mimic a human mTBI or subclinical blast exposure. BCI-838 treatment reversed PTSD-related behavioral traits improving anxiety and fear-related behaviors as well as long-term recognition memory. Treatment with BCI-838 also increased neurogenesis in the dentate gyrus (DG) of blast-exposed rats. The safety profile of BCI-838 together with the therapeutic activities reported here, make BCI-838 a promising drug for the treatment of former battlefield Warfighters suffering from PTSD-related symptoms following blast-induced mTBI.


Mild neuritic changes are increased in the brains of fatally injured older motor vehicle drivers.
Given the expected increase in the older population and driving in this age group, concerns have been raised about the safety of older drivers. People over 65 years are over-represented in motor vehicle fatalities when calculated by distance driven. They are also at risk of neurodegenerative diseases, such as Alzheimer's disease, that affect cognitive function. We have examined the brains of older drivers (15M:12F) who died as a result of a motor vehicle accident (MVA) to determine the extent of Alzheimer's disease-related neurofibrillary changes (neuritic plaques and neurofibrillary tangles), Lewy body pathology and cerebrovascular disease and compared them to a control group of older licenced drivers (23M:5F) who died of other causes. The prevalence of moderate or severe neuritic plaque pathology was less than expected for the general population of this age and there was no difference between the groups. However, mild neuritic plaque pathology was increased for MVA deaths compared to controls. There was no evidence of vascular dementia or dementia with Lewy bodies. The current mandatory age-related re-licencing procedures in NSW may contribute to the low percentage of drivers with severe pathology. Further research into the role of mild pathology in cognitive impairment and older drivers is warranted.


Artificial Lipid Biomembranes for Full-Length SARS-CoV-2 Receptor.
The angiotensin-converting enzyme 2 (ACE2), as a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for assessing potential hosts and treatments. However, many studies are based on its truncated version but not full-length structure. Indeed, a single transmembrane (TM) helix presents in the full-length ACE2, influencing its interaction with SARS-CoV-2. Therefore, synthesis of the full-length ACE2 is an urgent requirement. Here, cell-free membrane protein synthesis systems (CFMPSs) are constructed for full-length membrane proteins. MscL is screened as a model among ten membrane proteins based on their expression and solubility. Next, CFMPSs are constructed and optimized based on natural vesicles, vesicles with four membrane proteins removed or two chaperonins added, and 37 types of nanodiscs. They all increase membrane protein solubility to over 50%. Finally, the full-length ACE2 of 21 species are successfully expressed with yields between 0.4 and 0.9 mg mL-1 . The definite functional differences from the truncated version suggest that the TM region affects ACE2's structure and function. CFMPSs can be extended to more membrane proteins, paving the way for further applications.


Noninvolvement of histamine and prostaglandins in the dermatosis of magnesium-deficient hairless rats.
Hairless rats receiving a deprived Mg2+ diet developed long-lasting inflammatory dermatosis which was not influenced by treatments with mepyramine, cimetidine, aspirin or indomethacin. Dermatosis did not appear in deprived rats treated with intraperitoneal injections of Mg2+, or with dexamethasone. Histamine and prostaglandins did not seem to be involved in this dermatosis. The possible role of leucotrienes is discussed.