Staphylococcus aureus α-toxin: nearly a century of intrigue.
Staphylococcus aureus secretes a number of host-injurious toxins, among the most prominent of which is the small β-barrel pore-forming toxin α-hemolysin. Initially named based on its properties as a red blood cell lytic toxin, early studies suggested a far greater complexity of α-hemolysin action as nucleated cells also exhibited distinct responses to intoxication. The hemolysin, most aptly referred to as α-toxin based on its broad range of cellular specificity, has long been recognized as an important cause of injury in the context of both skin necrosis and lethal infection. The recent identification of ADAM10 as a cellular receptor for α-toxin has provided keen insight on the biology of toxin action during disease pathogenesis, demonstrating the molecular mechanisms by which the toxin causes tissue barrier disruption at host interfaces lined by epithelial or endothelial cells. This review highlights both the historical studies that laid the groundwork for nearly a century of research on α-toxin and key findings on the structural and functional biology of the toxin, in addition to discussing emerging observations that have significantly expanded our understanding of this toxin in S. aureus disease. The identification of ADAM10 as a proteinaceous receptor for the toxin not only provides a greater appreciation of truths uncovered by many historic studies, but now affords the opportunity to more extensively probe and understand the role of α-toxin in modulation of the complex interaction of S. aureus with its human host.


Proteomic analysis of duck fatty liver during post-mortem storage related to the variability of fat loss during cooking of "foie gras".
Fat loss during cooking of duck "foie gras" is the main problem for both manufacturers and consumers. Despite the efforts of the processing industry to control fat loss, the variability of fatty liver cooking yields remains high and uncontrolled. To understand the biochemical effects of postslaughter processing on fat loss during cooking, this study characterizes for the first time the protein expression of fatty liver during chilling using a proteomic approach. For this purpose the proteins were separated according to their solubility: the protein fraction soluble in a buffer of low ionic strength (S) and the protein fraction insoluble in the same buffer (IS). Two-dimensional electrophoresis was used to analyze the S fraction and mass spectrometry for the identification of spots of interest. This analysis revealed 36 (21 identified proteins) and 34 (26 identified proteins) spots of interests in the low-fat-loss and high-fat-loss groups, respectively. The expression of proteins was lower after chilling, which revealed a suppressive effect of chilling on biological processes. The shot-gun strategy was used to analyze the IS fraction, with the identification of all the proteins by mass spectrometry. This allowed identification of 554 and 562 proteins in the low-fat-loss and high-fat-loss groups, respectively. Among these proteins, only the proteins that were up-regulated in the high-fat-loss group were significant (p value = 3.17 × 10(-3)) and corresponded to protein from the cytoskeleton and its associated proteins. Taken together, these results suggest that the variability of technological yield observed in processing plants could be explained by different aging states of fatty livers during chilling, most likely associated with different proteolytic patterns.


The emerging role of exercise testing and stress echocardiography in valvular heart disease.
Exercise testing has an established role in the evaluation of patients with valvular heart disease and can aid clinical decision making. Because symptoms may develop slowly and indolently in chronic valve diseases and are often not recognized by patients and their physicians, the symptomatic, blood pressure, and electrocardiographic responses to exercise can help identify patients who would benefit from early valve repair or replacement. In addition, stress echocardiography has emerged as an important component of stress testing in patients with valvular heart disease, with relevant established and potential applications. Stress echocardiography has the advantages of its wide availability, low cost, and versatility for the assessment of disease severity. The versatile applications of stress echocardiography can be tailored to the individual patient with aortic or mitral valve disease, both before and after valve replacement or repair. Hence, exercise-induced changes in valve hemodynamics, ventricular function, and pulmonary artery pressure, together with exercise capacity and symptomatic responses to exercise, provide the clinician with diagnostic and prognostic information that can contribute to subsequent clinical decisions. Nevertheless, there is a lack of convincing evidence that the results of stress echocardiography lead to clinical decisions that result in better outcomes, and therefore large-scale prospective randomized studies focusing on patient outcomes are needed in the future.


Butylidenephthalide facilitates contractions via nonspecific binding to receptors in isolated guinea-pig vas deferens.
Context: Butylidenephthalide (Bdph) has been reported to inhibit rat uterine contractions, but significantly potentiate the noradrenaline (NA)-induced contractions in guinea-pig vas deferens (GPVDs). Objective: The present study elucidates the binding specificity of Bdph in GPVD to potentiate contractions. Materials and methods: Electrical field stimulation (EFS, supramaximal voltage, 1 ms and 1 Hz) or exogenous NA (50 μM) was applied to the GPVD in Krebs or 1/10 Mg-Tyrode's solution, respectively. After the clonidine (10 nM)-induced twitch inhibition or the exogenous NA-induced contractions reached a constant, Bdph (50 µM) was added 2 min prior to the subsequent addition of NA (50 µM). Three experiments were performed. In the presence of Bdph (100 μM), the release of NA in the medium and remaining NA content in the tissues were determined after EFS-stimulation. Results: Bdph (100 μM) significantly antagonized the clonidine (10 nM)-induced twitch inhibition from 22.5 ± 2.1 to -11.4 ± 1.6% (n = 6) and dibutyryl-cAMP (300 μM) from 25.7 ± 3.2 to 7.9 ± 4.0% (n = 8). Bdph (100 μM) significantly increased the electrically stimulated release of NA from 393.0 ± 109.5 to 1000.0 ± 219.1 ng/g (n = 6). Bdph (50 μM) potentiated the exogenous NA (50 μM)-induced contractions from 3.0 ± 0.06 to 3.9 ± 0.06 g (n = 3), but after washout of Bdph, the response to NA gradually curtailed. Discussion and conclusions: Bdph action may be through the nonspecific binding of the butylidene group to prejunctional α2- and postjunctional α1-adrenoceptors to reversibly block K+ channels, and irreversibly block VDCCs on the smooth muscle cell membrane, respectively.


Morphine suppresses lymphocyte apoptosis by blocking p53-mediated death signaling.
Opiates such as morphine or heroin may promote cell apoptosis and cause dysfunction of immune cells. In simian immunodeficiency virus (SIV)-infected lymphocytic cells, however, morphine may protect the cells from apoptotic lysis and allow the virus to continue to replicate. To further explore this apparently antithetical effect of opiates, we evaluated in the present study the effects of morphine on human lymphocytic CEM x174 cells induced to undergo apoptosis in the presence of actinomycin D. It was found that induction of apoptosis (characterized by DNA laddering) by actinomycin D was accompanied by a stimulation of the expression of active (phosphorylated) form of p53. Pretreatment of the cells with 10nM morphine caused a transient, naloxone-reversible suppression of the appearance of activated p53 and the generation of DNA laddering. Parallel evaluation of the growth of CEM x174 indicated that morphine treatment delays the inception of cell death triggered by actinomycin D. Inasmuch as Bcl-2 suppresses while Bax accelerates apoptosis, treatment of cells with morphine reduced the expression of Bax and enhanced the expression of Bcl-2. Taken together, morphine, through binding at the opioid receptor, may protect lymphocytic cells from apoptotic lysis if cell death is initiated by apoptosis-inducing agents such as human immunodeficiency virus (HIV), SIV or actinomycin D.


Genetic Tracing of Jatropha curcas L. from Its Mesoamerican Origin to the World.
Jatropha curcas L. (Jatropha), a shrub species of the family Euphorbiaceae, has been recognized as a promising biofuel plant for reducing greenhouse gas emissions. However, recent attempts at commercial cultivation in Africa and Asia have failed because of low productivity. It is important to elucidate genetic diversity and relationship in worldwide Jatropha genetic resources for breeding of better commercial cultivars. Here, genetic diversity was analyzed by using 246 accessions from Mesoamerica, Africa and Asia, based on 59 simple sequence repeat markers and eight retrotransposon-based insertion polymorphism markers. We found that central Chiapas of Mexico possesses the most diverse genetic resources, and the Chiapas Central Depression could be the center of origin. We identified three genetic groups in Mesoamerica, whose distribution revealed a distinct geographic cline. One of them consists mainly of accessions from central Chiapas. This suggests that it represents the original genetic group. We found two Veracruz accessions in another group, whose ancestors might be shipped from Port of Veracruz to the Old World, to be the source of all African and Asian Jatropha. Our results suggest the human selection that caused low productivity in Africa and Asia, and also breeding strategies to improve African and Asian Jatropha. Cultivars improved in the productivity will contribute to expand mass commercial cultivation of Jatropha in Africa and Asia to increase biofuel production, and finally will support in the battle against the climate change.


RNA-dependent RNA polymerase activity in murine coronavirus-infected cells.
The multiplication of murine coronavirus strains A59 or JHM in Sac(-) cells was unaffected by the presence of alpha-amanitin at concentrations which inhibited the host cell DNA-dependent RNA polymerase activity. In cells infected with the A59 virus strain, actinomycin D-resistant RNA synthesis could readily be detected by pulse-labelling with [3H]uridine; this virus-specific RNA synthesis was not induced in the presence of the protein synthesis inhibitor anisomycin. A new RNA-dependent RNA polymerase activity was detected in the large particle fraction of A59 virus-infected cells. Optimal conditions for enzyme activity in vitro were established. Maximum activity occurred 5 h after infection, coincident with the peak of virus-specific RNA synthesis detected by pulse-labelling in vivo.


A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.
In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.


Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice.
We have recently shown that administration of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine (PA) biosynthesis reduces pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. The present experiments were designed to further explore PA involvement in breast cancer metastasis, using GFP-tagged MDA-MB-435 cells that can be tracked at the single cell level. Administration of DFMO significantly reduced the number of mice with pulmonary metastasis as well as the number of metastases per mouse. Both single-cell and multicellular metastatic deposits were similarly suppressed, thus suggesting that DFMO was inhibiting lung colonization by tumor cells rather than preventing progression of single-cell deposits to overt metastasis. DFMO administration also significantly reduced local recurrences following removal of the primary tumor. Prolongation of DFMO treatment to 14 weeks did not yield a superior antimetastatic effect beyond that provided by a 10-week course of therapy. Discontinuation of DFMO, on the other hand, was associated with local regrowth of the tumors and, possibly, recurrence of pulmonary metastasis. These data provide a rationale for testing the efficacy of anti-PA treatment within the context of adjuvant therapy of breast cancer.


ADHERENCE TO THERAPY AND QUALITY OF LIFE IN HYPERTENSIVE PATIENTS.
This cross-sectional study aimed to evaluate the association between medication adherence and Health-Related Quality of Life (HRQoL) in 120 hypertensive patients. Personal Information Form, SF-36 Quality of Life Scale (SF-36 QoL) and Medication Adherence Self-Efficacy Scale (MASES) were used for data collection. Data were analyzed with SPSS program using percentage, mean value, standard deviation, significance test of difference between two means, analysis of variance, Mann-Whitney U test, Kruskal-Wallis test and X²-test. MASES and SF-36 QoL scores of the patients were found to be low. Adherence to medication and compliance were found to be low in males, patients using two or more drugs, and those that did not control their blood pressure regularly. In addition, a statistically significant positive relationship was found between adherence to medication/compliance, self-efficacy and quality of life (p < 0.001). Regular and continuous adaptation programs addressing patients on antihypertensive therapy will improve the quality of life of these patients.


Production of reactive oxygen species on photolysis of dilute aqueous quinone solutions.
We have examined the generation of the reactive oxygen species (ROS) superoxide and hydrogen peroxide (H2O2) by irradiation of dilute aqueous solutions of disodium anthraquinone-2-6-disulfonate (AQDS) with simulated sunlight. Irradiating a solution of AQDS in 2 mM NaHCO3 and 0.01 M NaCl produced superoxide and H2O2 at nanomolar concentrations. Experiments in which initial concentrations of dioxygen, H2O2, the superoxide radical trap nitroblue tetrazolium and the electron donor dimethyl sulfoxide were varied suggested that the interaction of solvent water with photo-excited quinone moieties produces dioxygen-reducing radicals, and that these are the primary source of ROS in the system. A kinetic model for ROS production is proposed based on our experimental data.


Relationship between bitter-taste receptor genotype and solid medication formulation usage among young children: a retrospective analysis.
Children often refuse to take medication in liquid formulation because of its unpleasant taste. Recent advances in taste genetics have provided some insight into individual differences in taste among children: due to their genotype, some prefer more intense sweetness and are more sensitive to bitter tastes and thus may have different needs for medication formulation. The aims of this study were to: (1) test the a priori hypothesis that children with the bitter-sensitive genotypes are more likely to have experienced solid medication formulations than those with the bitter-insensitive genotype; and (2) conduct post hoc analyses to examine the relationship between genotype and most preferred level of sucrose in water because sweeteners are a common component of liquid formulations. The following data were obtained from healthy, 3- to 10-year-old children who participated in 1 of 5 taste-research studies: taste genotype for alleles of the bitter-taste receptor TAS2R38; data from retrospective reports of solid medication formulation usage and favorite beverage; and most preferred level of sucrose in water, as determined psychophysically. Data from 448 children were included (245 girls, 203 boys; mean age, 7.8 years). Children with ≥1 bitter-sensitive allele (TAS2R38 PP or AP genotype) were more likely to have taken medication in solid formulation than were bitter-insensitive (AA genotype) children. Children with the PP genotype preferred higher concentrations of sucrose in water, and their favorite beverage contained more grams of sugar compared with children with the AA genotype. Taste genotype was associated with experience with solid medication formulations and preference for more intense sweetness. This finding suggests that taste genetics might be an important factor in formulation choice and compliance in the pediatric population.


Identification and cross-validation of autophagy-related genes in cardioembolic stroke.
Cardioembolic stroke (CE stroke, also known as cardiogenic cerebral embolism, CCE) has the highest recurrence rate and fatality rate among all subtypes of ischemic stroke, the pathogenesis of which was unclear. Autophagy plays an essential role in the development of CE stroke. We aim to identify the potential autophagy-related molecular markers of CE stroke and uncover the potential therapeutic targets through bioinformatics analysis. The mRNA expression profile dataset GSE58294 was obtained from the GEO database. The potential autophagy-related differentially expressed (DE) genes of CE stroke were screened by R software. Protein-protein interactions (PPIs), correlation analysis, and gene ontology (GO) enrichment analysis were applied to the autophagy-related DE genes. GSE66724, GSE41177, and GSE22255 were introduced for the verification of the autophagy-related DE genes in CE stroke, and the differences in values were re-calculated by Student's t-test. A total of 41 autophagy-related DE genes (37 upregulated genes and four downregulated genes) were identified between 23 cardioembolic stroke patients (≤3 h, prior to treatment) and 23 healthy controls. The KEGG and GO enrichment analysis of autophagy-related DE genes indicated several enriched terms related to autophagy, apoptosis, and ER stress. The PPI results demonstrated the interactions between these autophagy-related genes. Moreover, several hub genes, especially for CE stroke, were identified and re-calculated by Student's t-test. We identified 41 potential autophagy-related genes associated with CE stroke through bioinformatics analysis. SERPINA1, WDFY3, ERN1, RHEB, and BCL2L1 were identified as the most significant DE genes that may affect the development of CE stroke by regulating autophagy. CXCR4 was identified as a hub gene of all types of strokes. ARNT, MAPK1, ATG12, ATG16L2, ATG2B, and BECN1 were identified as particular hub genes for CE stroke. These results may provide insight into the role of autophagy in CE stroke and contribute to the discovery of potential therapeutic targets for CE stroke treatment.


Role of the ATP-binding cassette transporter Abcg2 in the phenotype and function of cardiac side population cells.
Recently, the side population (SP) phenotype has been introduced as a reliable marker to identify subpopulations of cells with stem/progenitor cell properties in various tissues. We and others have identified SP cells from postmitotic tissues, including adult myocardium, in which they have been suggested to contribute to cellular regeneration following injury. SP cells are identified and characterized by a unique efflux of Hoechst 33342 dye. Abcg2 belongs to the ATP-binding cassette (ABC) transporter superfamily and constitutes the molecular basis for the dye efflux, hence the SP phenotype, in hematopoietic stem cells. Although Abcg2 is also expressed in cardiac SP (cSP) cells, its role in regulating the SP phenotype and function of cSP cells is unknown. Herein, we demonstrate that regulation of the SP phenotype in cSP cells occurs in a dynamic, age-dependent fashion, with Abcg2 as the molecular determinant of the cSP phenotype in the neonatal heart and another ABC transporter, Mdr1, as the main contributor to the SP phenotype in the adult heart. Using loss- and gain-of-function experiments, we find that Abcg2 tightly regulates cell fate and function. Adult cSP cells isolated from mice with genetic ablation of Abcg2 exhibit blunted proliferation capacity and augmented cell death. Conversely, overexpression of Abcg2 is sufficient to enhance cell proliferation, although with a limitation of cardiomyogenic differentiation. In summary, for the first time, we reveal a functional role for Abcg2 in modulating the proliferation, differentiation, and survival of adult cSP cells that goes beyond its distinct role in Hoechst dye efflux.


Enhanced interactions of excitonic complexes in free-standing WS2.
Excitonic complexes, bound states of electrons and holes, provide a promising platform in monolayer transition-metal dichalcogenide (TMDC) semiconductors for investigating diverse many-body interaction phenomena. The surrounding dielectric environment has been found to strongly influence the excitonic properties of the TMDC monolayers. While the impact of different dielectric surroundings on two-dimensional semiconductor materials and their strong correlations have been well studied, the effects on exciton formation and its properties resulting from a further reduction in dielectric screening remain elusive. In this study, we examined free-standing tungsten disulfide (WS2) monolayers, where the efficient generation of higher-order correlated excitonic complexes is readily observed. This phenomenon arises from the effective mutual interactions among excitons and internal carriers, attributed to the modulated exciton dynamics generated by the further reduced dielectric screening effect in the freestanding structure. The formation efficiency of excitonic complexes is enhanced and the multiple biexciton species (five particles such as charged biexcitons and acceptor/donor-bound biexcitons) are successfully induced under low excitation intensity and moderate temperature conditions. Our findings offer valuable insights into the influence of the dielectric environment on exciton interactions and enable a productive avenue for exploring fundamental many-body interactions, providing new possibilities for dielectric engineering of atomic thin semiconductors.


Positive correlation of airway resistance and serum asymmetric dimethylarginine level in COPD patients with systemic markers of low-grade inflammation.
The major feature of COPD is a progressive airflow limitation caused by chronic airway inflammation and consequent airway remodeling. Modified arginase and nitric oxide synthase (NOS) pathways are presumed to contribute to the inflammation and fibrosis. Asymmetric dimethylarginine (ADMA) may shunt L-arginine from the NOS pathway to the arginase one by uncoupling and competitive inhibition of NOS and by enhancing arginase activity. To attest the interplay of these pathways, the relationship between ADMA and airflow limitation, described by airway resistance (Raw), was investigated in a cohort of COPD patients. Every COPD patient willing to give consent to participate (n=74) was included. Case history, laboratory parameters, serum arginine and ADMA, pulmonary function (whole-body plethysmography), and disease-specific quality of life (St George's Respiratory Questionnaire) were determined. Multiple linear regression was used to identify independent determinants of Raw. The final multiple model was stratified based on symptom control. The log Raw showed significant positive correlation with log ADMA in the whole sample (Pearson's correlation coefficient: 0.25, P=0.03). This association remained significant after adjusting for confounders in the whole data set (β: 0.42; confidence interval [CI]: 0.06, 0.77; P=0.022) and in the worse-controlled stratum (β: 0.84; CI: 0.25, 1.43; P=0.007). Percent predicted value of forced expiratory flow between 25% and 75% of forced vital capacity showed that significant negative, elevated C-reactive protein exhibited significant positive relationship with Raw in the final model. Positive correlation of Raw with ADMA in COPD patients showing evidence of a systemic low-grade inflammation implies that ADMA contributes to the progression of COPD, probably by shunting L-arginine from the NOS pathway to the arginase one.


Noradrenaline excites non-cholinergic laterodorsal tegmental neurons via two distinct mechanisms.
Cholinergic neurons of the laterodorsal tegmental nucleus have been hypothesized to play a critical role in the-generation and maintenance of rapid eye movement sleep. Less is known about the function of non-cholinergic laterodorsal tegmental nucleus neurons. As part of our ongoing studies of the brainstem circuitry controlling behavioral state, we have begun to investigate the functional properties of these neurons. In the course of these experiments, we have observed a novel response to the neurotransmitter noradrenaline. Whole-cell patch-clamp recordings of laterodorsal tegmental nucleus neurons were carried out in 21- to 35-day-old rat brain slices. A subpopulation of laterodorsal tegmental nucleus cells responded to a 30-s application of 50 microM noradrenaline with depolarization and a decrease in input resistance which lasted several minutes. Following return to resting membrane potential, these cells invariably exhibited barrages of excitatory postsynaptic potentials which lasted at least 12 min. These excitatory postsynaptic potentials were reversibly abolished by bath application of tetrodotoxin, as well as by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, but were insensitive to application of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid. To examine whether these neurons were cholinergic, the recorded cells were labeled with biocytin and tested for co-localization with reduced nicotinamide adenine dinucleotide phosphate-diaphorase, a marker for laterodorsal tegmental nucleus cholinergic neurons. In every instance, neurons with these properties were non-cholinergic. However, they were always located in close proximity to reduced nicotinamide adenine dinucleotide phosphate-diaphorase-positive laterodorsal tegmental nucleus cells. The present data indicate that noradrenaline, in addition to directly inhibiting cholinergic cells of the laterodorsal tegmental nucleus, also results in the direct and indirect excitation of non-cholinergic cells of the laterodorsal tegmental nucleus. The indirect excitation is long lasting and mediated by glutamatergic mechanisms. Our working hypothesis is that these non-cholinergic cells are local circuit inhibitory interneurons and that prolonged excitation of these neurons by noradrenaline may serve as a mechanism for inhibition of cholinergic laterodorsal tegmental nucleus cells during wakefulness, when noradrenaline tone is high.


The Population of Fusarium oxysporum f. sp. lactucae in California and Arizona.
Fusarium wilt of lettuce, caused by Fusarium oxysporum f. sp. lactucae, is now found in all major lettuce producing regions in California and Arizona. The population structure of F. oxysporum f. sp. lactucae in California and Arizona was characterized based on somatic compatibility and sequences of the translation elongation factor 1-α gene (EF-1α) and rDNA intergenic spacer region (IGS). In this study, 170 isolates were tested for somatic compatibility based on heterokaryon formation, using complementary nitrate nonutilizing (nit) mutants. Five subgroups (A to E) of somatic compatibility group 0300 were identified. Isolates associated with the same subgroup had a strong complementation reaction, whereas reactions between isolates of different subgroups were weak or delayed. An isolate from the first known infestation of Fusarium wilt of lettuce in California was associated with subgroup A, which predominated among isolates in our collection. Isolates representative of each subgroup were confirmed to be associated with race 1, based on the reaction of differential lettuce cultivars. It is possible that somatic compatibility subgroups B to E of F. oxysporum f. sp. lactucae were derived from subgroup A, as a consequence of somatic mutations affecting compatibility. If so, subgroups of F. oxysporum f. sp. lactucae may represent an intermediate step in divergence that will lead to clearly separable compatibility groups. Sequences of EF-1α and IGS were both identical for 58 isolates of F. oxysporum f. sp. lactucae that represented all somatic compatibility subgroups and locations from which isolates were obtained, indicating that subgroups were derived from the same clonal lineage (VCG 0300).


Non-soya legume-based therapeutic lifestyle change diet reduces inflammatory status in diabetic patients: a randomised cross-over clinical trial.
The present randomised cross-over clinical trial investigated the effects of two intervention diets (non-soya legume-based therapeutic lifestyle change (TLC) diet v. isoenergetic legume-free TLC diet) on inflammatory biomarkers among type 2 diabetic patients. A group of thirty-one participants (twenty-four women and seven men; weight 74.5 (SD 7.0) kg; age 58.1 (SD 6.0) years) were randomly assigned to one of the two following intervention diets for 8 weeks: legume-free TLC diet or non-soya legume-based TLC diet. The latter diet was the same as the legume-free TLC diet, except that two servings of red meat were replaced with different types of cooked non-soya legumes such as lentils, chickpeas, peas and beans over a period of 3 d per week. The intervention period was followed by a washout period of 4 weeks, after which the groups followed the alternate treatment for 8 weeks. Concentrations of inflammatory markers were measured at baseline and after the intervention periods. Compared with the legume-free TLC diet, the non-soya legume-based TLC diet significantly decreased high-sensitivity C-reactive protein, IL-6 and TNF-α in overweight diabetic patients. The replacement of two servings of red meat by non-soya legumes in the isoenergetic TLC diet for a period of 3 d per week reduced the plasma concentrations of inflammatory markers among overweight diabetic patients, independent of weight change.


Marginal dietary copper restriction induces cardiomyopathy in rats.
Prior studies have provided evidence of marginal dietary copper restriction in humans. The present study was undertaken to examine in a rat model the effect of a long-term marginal dietary Cu deficiency on the heart. Male adult Sprague-Dawley rats were fed AIN-76 diet containing 6.0 (control), 3.0, or 1.5 mg Cu/kg starting at 11 wk of age. Groups of rats were killed at 6, 9, 12, 15, or 18 mo after initiation of feeding, and the same experiment was repeated once. The only systemic change induced by marginal dietary Cu restriction (P < 0.05) was depression of organ Cu concentrations in rats fed 1.5 mg Cu/kg diet. Cardiac pathological manifestations in rats fed lower Cu diets were evidenced by histopathological, ultrastructural, and functional alterations. Myocyte hypertrophy and excessive collagen deposition in the heart occurred in rats fed 1.5 mg Cu/kg diet. Ultrastructural changes, including increased number and volume of mitochondria along with disruption of cristae structure, diastolic and systolic dysfunction, and electrocardiograph alterations, occurred in rats fed 1.5 or 3.0 mg Cu/kg diet. These results demonstrate that, in the absence of most indications of systemic Cu deficiency, heart morphology and function are sensitive to marginal Cu deficiency.


Sequence-specific cleavage of hepatitis C virus RNA by DNAzymes: inhibition of viral RNA translation and replication.
DNAzyme (Dz) molecules have been shown to be highly efficient inhibitors of virus replication. Hepatitis C virus RNA translation is mediated by an internal ribosome entry site (IRES) element located mostly in the 5' untranslated region (UTR), the mechanism of which is fundamentally different from cap-dependent translation of cellular mRNAs, and thus an attractive target for designing antiviral drugs. Inhibition of HCV IRES-mediated translation has drastic consequences for the replication of viral RNA as well. We have designed several Dzs, targeting different regions of HCV IRES specific for 1b and also sequences conserved across genotypes. The RNA cleavage and translation inhibitory activities of these molecules were tested in a cell-free system and in cell culture using transient transfections. The majority of Dzs efficiently inhibited HCV IRES-mediated translation. However, these Dz molecules did not show significant inhibition of coxsackievirus B3 IRES-mediated translation or cap-dependent translation of reporter gene, showing high level of specificity towards target RNA. Also, Northern blot hybridization analysis showed significant cleavage of HCV IRES by the Dz molecules in Huh7 cells transiently transfected with the HCV-FLuc monocistronic construct. Interestingly, one of the Dzs was more effective against genotype1b, whereas the other showed significant inhibition of viral RNA replication in Huh7 cells harbouring a HCV 2a monocistronic replicon. As expected, mutant-Dz failed to cleave RNA and inhibit HCV RNA translation, showing the specificity of inhibition. Taken together, these findings suggest that the Dz molecule can be used as selective and effective inhibitor of HCV RNA replication, which can be explored further for development of a potent therapeutic agent against HCV infection.


Prediction of bone metastases by combination of tartrate-resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients with prostate cancer.
The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated. TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis. Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers. Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.


Trust Miscalibration Is Sometimes Necessary: An Empirical Study and a Computational Model.
The literature on trust seems to have reached a consensus that appropriately calibrated trust in humans or machines is highly desirable; miscalibrated (i.e., over- or under-) trust has been thought to only have negative consequences (i.e., over-reliance or under-utilization). While not invalidating the general idea of trust calibration, a published computational cognitive model of trust in strategic interaction predicts that some local and temporary violations of the trust calibration principle are critical for sustained success in strategic situations characterized by interdependence and uncertainty (e.g., trust game, prisoner's dilemma, and Hawk-dove). This paper presents empirical and computational modeling work aimed at testing the predictions of under- and over-trust in an extension of the trust game, the multi-arm trust game, that captures some important characteristics of real-world interpersonal and human-machine interactions, such as the ability to choose when and with whom to interact among multiple agents. As predicted by our previous model, we found that, under conditions of increased trust necessity, participants actively reconstructed their trust-investment portfolios by discounting their trust in their previously trusted counterparts and attempting to develop trust with the counterparts that they previously distrusted. We argue that studying these exceptions of the principle of trust calibration might be critical for understanding long-term trust calibration in dynamic environments.


Gross Instability After Hip Arthroscopy: An Analysis of Case Reports Evaluating Surgical and Patient Factors.
Gross hip instability is a rare complication after hip arthroscopy, and there is limited literature surrounding this topic. This systematic review investigates cases of gross hip instability after arthroscopy and discusses the risk factors associated with this complication. A systematic search was performed in duplicate for studies investigating gross hip instability after hip arthroscopy up to October 2015. Study parameters including sample size, mechanism and type of dislocation, surgical procedure details, patient characteristics, postoperative rehabilitation protocol, and level of evidence were analyzed. The systematic review identified 9 case reports investigating gross hip instability after hip arthroscopy (10 patients). Anterior dislocation occurred in 66.7% of patients, and most injuries occurred with a low-energy mechanism. Common surgical factors cited included unrepaired capsulotomy (77.8%) and iliopsoas release (33.3%), whereas patient factors included female gender (77.8%), acetabular dysplasia (22.2%), and general ligamentous laxity (11.1%). Postoperative restrictions and protocols were variable and inconsistently reported, and their relation to post-arthroscopy instability was difficult to ascertain. This systematic review discussed various patient, surgical, and postoperative risk factors of gross hip instability after arthroscopy. Patient characteristics such as female gender, hip dysplasia, and ligamentous laxity may be risk factors for post-arthroscopy dislocation. Similarly, surgical risk factors for iatrogenic hip instability may include unrepaired capsulotomies and iliopsoas debridement, although the role of capsular closure in iatrogenic instability is not clear. The influences of postoperative restrictions and protocols on dislocation are also unclear in the current literature. Surgeons should be cognizant of these risk factors when performing hip arthroscopy and be mindful that these factors appear to occur in combination. Level IV, systematic review of Level IV studies.


Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice.
IL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (-/-) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/-) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18-/- mice are uniformly susceptible. The infected IL-18-/- mice produced significantly lower levels of IFN-gamma and larger amounts of IL-4 compared with similarly infected +/- and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18-/- mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-gamma and TNF-alpha synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory cytokines, and therefore could be an important target for therapeutic intervention.


Pathology of chronic maxillary sinusitis and possible blood changes.
Specimens from the diseased sinuses in cases of long standing chronic maxillary sinusitis were taken during Caldwell-Luc operation. Histopathological examination revealed hyperplasia of the epithelium which may invaginate forming pouches and subepithelial nests. The secretory glands increase both in number and size indicating the chronicity of the disease.


Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes.
To investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers. Two, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials. Clinical research unit. Fifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine. In the first drug-drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on clobazam and its active metabolite N-desmethylclobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4-19, to study clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4. In the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0-∞) ) 54% and decreased clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-∞) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N-CLB has 3-4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-∞) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures. These findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.


Automated detection of wrong-drug prescribing errors.
To assess the specificity of an algorithm designed to detect look-alike/sound-alike (LASA) medication prescribing errors in electronic health record (EHR) data. Urban, academic medical centre, comprising a 495-bed hospital and outpatient clinic running on the Cerner EHR. We extracted 8 years of medication orders and diagnostic claims. We licensed a database of medication indications, refined it and merged it with the medication data. We developed an algorithm that triggered for LASA errors based on name similarity, the frequency with which a patient received a medication and whether the medication was justified by a diagnostic claim. We stratified triggers by similarity. Two clinicians reviewed a sample of charts for the presence of a true error, with disagreements resolved by a third reviewer. We computed specificity, positive predictive value (PPV) and yield. The algorithm analysed 488 481 orders and generated 2404 triggers (0.5% rate). Clinicians reviewed 506 cases and confirmed the presence of 61 errors, for an overall PPV of 12.1% (95% CI 10.7% to 13.5%). It was not possible to measure sensitivity or the false-negative rate. The specificity of the algorithm varied as a function of name similarity and whether the intended and dispensed drugs shared the same route of administration. Automated detection of LASA medication errors is feasible and can reveal errors not currently detected by other means. Real-time error detection is not possible with the current system, the main barrier being the real-time availability of accurate diagnostic information. Further development should replicate this analysis in other health systems and on a larger set of medications and should decrease clinician time spent reviewing false-positive triggers by increasing specificity.


Stability of refraction during two years after myopic epikeratoplasty.
A series of 54 consecutive myopic epikeratoplasty procedures was performed by three surgeons between November 1986 and August 1987. To evaluate the stability of the myopic epikeratoplasty procedure, this study was limited to the 33 eyes that had data 24 months after surgery. One year after surgery, 68% (19/28 eyes) had 20/40 or better uncorrected visual acuity and after two years, 57% (17/30 eyes) had 20/40 or better uncorrected visual acuity. Significant loss of surgical effect (increasing myopia) did not occur during the first six postoperative months (r = 0.09, P = NS). This was due to the large amount of variability in spherical equivalent refraction during this interval. However significant regression was detected between 6 and 12 months after surgery (r = 0.27, F = 4.74, P = 0.03). Even though there was further reduction in variability from 12 to 24 months, significant regression was not found (r = 0.07, P = NS). This suggests stabilization of refraction by approximately 12 months for this population.


Immunity to malaria: more questions than answers.
Malaria is one of the main health problems facing developing countries today. At present, preventative and treatment strategies are continuously hampered by the issues of the ever-emerging parasite resistance to newly introduced drugs, considerable costs and logistical problems. The main hope for changing this situation would be the development of effective malaria vaccines. An important part of this process is understanding the mechanisms of naturally acquired immunity to malaria. This review will highlight key aspects of immunity to malaria, about which surprisingly little is known and which will prove critical in the search for effective malaria vaccines.


Specialty bias in obstetric care for high-risk socioeconomic groups in Maine.
From 1982 to 1984, 46,501 infants were born in Maine hospitals in 46,286 deliveries, of which 6,343 were born to women on state Medicaid (Title 19), and 6,307 were born to women with no health insurance. In comparison with others born in Maine during those years, more infants in these presumed low socioeconomic groups died, were transferred immediately to other hospitals, had low birthweights, or were readmitted to a hospital within 30 days of birth. Of all deliveries, 105 family physicians or general practitioners performed 22 percent, 82 obstetricians performed 69 percent, and 16 osteopathic physicians performed 5 percent; but of Medicaid deliveries, obstetricians delivered only 59 percent, while family physicians-general practitioners and osteopaths did commensurately more. The decreased proportion of Medicaid patients cared for by obstetricians was especially prominent in Maine's urban hospital service areas. Pediatricians, on the other hand, cared for the same proportion of Medicaid children as they did all children in all hospital service areas in the state. The distribution of low socioeconomic, higher obstetric risk patient groups among various medical specialties as demonstrated in these data should be considered by health planners, malpractice insurers, and health insurers including state Medicaid programs.


Treatment beliefs and techniques of clinicians serving child maltreatment survivors.
A significant focus in the child maltreatment field is greater dissemination and implementation of evidence-based treatments (EBTs). Research has attempted to identify attitudes toward EBTs and training experiences that predict clinicians' use of EBTs; however, these findings have yielded mixed results. This study reports on the results of a nationwide (United States) sample of 256 clinicians serving child maltreatment survivors, who completed questionnaires assessing beliefs about the clinical process, treatment technique selection, and attitudes toward EBTs. Psychometric data are presented on two new scales. The first scale examines clinicians' beliefs about two components of the clinical process: (1) the extent to which treatment should be structured/directed by the clinician and (2) children's verbal capacity to discuss traumatic events. The second scale assesses clinician-reported selection of various treatment techniques and contains four subscales: Cognitive-Behavioral, Play/Experiential, Psychodynamic, and Uncommon. Using these scales, a series of analyses were performed to determine which attitudes, beliefs, and training variables were associated with the selection of treatment techniques. After controlling for the impact of other variables, significant associations between the two clinical process beliefs and cognitive-behavioral and play/experiential techniques utilization were observed. Implications of these results for increasing implementation of EBTs with child maltreatment survivors are discussed.


The influence of social comparison on visual representation of one's face.
Can the effects of social comparison extend beyond explicit evaluation to visual self-representation--a perceptual stimulus that is objectively verifiable, unambiguous, and frequently updated? We morphed images of participants' faces with attractive and unattractive references. With access to a mirror, participants selected the morphed image they perceived as depicting their face. Participants who engaged in upward comparison with relevant attractive targets selected a less attractive morph compared to participants exposed to control images (Study 1). After downward comparison with relevant unattractive targets compared to control images, participants selected a more attractive morph (Study 2). Biased representations were not the products of cognitive accessibility of beauty constructs; comparisons did not influence representations of strangers' faces (Study 3). We discuss implications for vision, social comparison, and body image.


Associations between oxytocin and vasopressin concentrations, traumatic event exposure and posttraumatic stress disorder symptoms: group comparisons, correlations, and courses during an internet-based cognitive-behavioural treatment.
Background: Posttraumatic stress disorder (PTSD) is characterized by impairments in extinction learning and social behaviour, which are targeted by trauma-focused cognitive behavioural treatment (TF-CBT). The biological underpinnings of TF-CBT can be better understood by adding biomarkers to the clinical evaluation of interventions. Due to their involvement in social functioning and fear processing, oxytocin and arginine vasopressin might be informative biomarkers for TF-CBT, but to date, this has never been tested. Objective: To differentiate the impact of traumatic event exposure and PTSD symptoms on blood oxytocin and vasopressin concentrations. Further, to describe courses of PTSD symptoms, oxytocin and vasopressin during an internet-based TF-CBT and explore interactions between these parameters. Method: We compared oxytocin and vasopressin between three groups of active and former male service members of the German Armed Forces (n = 100): PTSD patients (n = 39), deployed healthy controls who experienced a deployment-related traumatic event (n = 33) and non-deployed healthy controls who never experienced a traumatic event (n = 28). PTSD patients underwent a 5-week internet-based TF-CBT. We correlated PTSD symptoms with oxytocin and vasopressin before treatment onset. Further, we analysed courses of PTSD symptoms, oxytocin and vasopressin from pre- to post-treatment and 3 months follow-up, as well as interactions between the three parameters. Results: Oxytocin and vasopressin did not differ between the groups and were unrelated to PTSD symptoms. PTSD symptoms were highly stable over time, whereas the endocrine parameters were not, and they also did not change in mean. Oxytocin and vasopressin were not associated with PTSD symptoms longitudinally. Conclusions: Mainly due to their insufficient intraindividual stability, single measurements of endogenous oxytocin and vasopressin concentrations are not informative biomarkers for TF-CBT. We discuss how the stability of these biomarkers might be increased and how they could be better related to the specific impairments targeted by TF-CBT.


Analysis of Efficacy and Tolerability of Bruton Tyrosine Kinase Inhibitor Ibrutinib in Various B-cell Malignancies in the General Community: A Single-center Experience.
Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels. The present study was a retrospective observational cohort analysis conducted at Abington Jefferson Health. The clinical response was determined from the hematologist's assessment and evaluated independently using the response criteria for each B-cell malignancy. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. The Wilcoxon signed-rank test was used to compare immunoglobulin levels before and after ibrutinib. Forty five patients with B-cell malignancies and receiving ibrutinib therapy were eligible. The median age was 73 years (range, 49-96 years), and 84.4% of the patients had received ≥ 1 previous therapy. The best overall response rate of all cohorts combined was 63.8%. The greatest overall response rate was observed in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (76.1%), followed by those with Waldenström macroglobulinemia (75%). Of the 45 patients, 88.9% experienced adverse effects. Antiplatelet activity of ibrutinib was most commonly observed (30.5%). Of note, 5 patients (11%) developed new-onset atrial fibrillation after drug initiation. Peripheral lymphocytosis after drug initiation was observed in most patients, with a peak level at 1 month (median lymphocyte count, 2.7 × 103 cells/μL). Although the IgG levels at 3, 6, and 12 months had decreased (P = .01 for all) compared with the levels before ibrutinib, the IgA levels had not increased at 3, 6, 12, and 24 months (P = .6, P = .5, P = .3, and P = .9, respectively). Ibrutinib is a highly effective and tolerable drug for B-cell malignancies in the general community. In contrast to the previously reported rate of 5% to 7%, we observed a higher rate (11%) of atrial fibrillation, which might have resulted from the smaller sample size in the present study and the multiple comorbidities. Nonetheless, this treatment-limiting side effect requires further elucidation. Paradoxical lymphocytosis at the outset of therapy was a common and benign finding. In conjunction with the reported trials, the IgG levels decreased in the first year of continued therapy. However, the IgA levels did not increase, even after 2 years of therapy.


Pharmacokinetics of biosynthetic human insulin and characteristics of its effect.
In the last 2 years we have developed a new method for determining insulin biologic activity with the help of the glucose-controlled insulin infusion system (GCIIS). Primarily this closed-loop system infuses insulin. But to prevent hypoglycemia, it can in addition, infuse glucose below a certain blood glucose minimum. This effect is used to reproduce insulin biologic activity. After subcutaneous injection of the insulin to be tested in healthy persons (not in insulin-dependent diabetic subjects), the blood glucose level falls, and this is checked by the counterregulatory glucose delivery from the apparatus. The time and intensity of glucose delivery from the GCIIS reflect the insulin effect, so that each insulin manifests its own particular biologic activity.


Indirect effect of alpha-1-antitrypsin on endotoxin-induced IL-1β secretion from human PBMCs.
Human alpha-1-antitrypsin (AAT) encoded by the SERPINA1 gene, is an acute phase glycoprotein that regulates inflammatory responses via both protease inhibitory and non-inhibitory activities. We previously reported that AAT controls ATP-induced IL-1β release from human mononuclear cells by stimulating the release of small bioactive molecules. In the current study, we aimed to elucidate the identity of these putative effectors released from human PBMCs in response to AAT, which may inhibit the LPS-induced release of IL-1β. We pre-incubated human PBMCs alone or with different preparations of AAT (4 mg/ml) for 30 min at 37°C, 5% CO2, and collected cell supernatants filtered through centrifugal filters (cutoff 3 kDa) to eliminate AAT and other high molecular weight substances. Supernatants passed through the filters were used to culture PBMCs isolated from the autologous or a heterologous donors with or without adding LPS (1 μg/ml) for 6 h. Unexpectedly, supernatants from PBMCs pre-incubated with AAT (Zemaira®), but not with other AAT preparations tested or with oxidized AAT (Zemaira®), lowered the LPS-induced release of IL-1β by about 25%-60% without affecting IL1B mRNA. The reversed-phase liquid chromatography coupled with mass spectrometry did not confirm the hypothesis that small pro-resolving lipid mediators released from PBMCs after exposure to AAT (Zemaira®) are responsible for lowering the LPS-induced IL-1β release. Distinctively from other AAT preparations, AAT (Zemaira®) and supernatants from PBMCs pre-treated with this protein contained high levels of total thiols. In line, mass spectrometry analysis revealed that AAT (Zemaira®) protein contains freer Cys232 than AAT (Prolastin®). Our data show that a free Cys232 in AAT is required for controlling LPS-induced IL-1β release from human PBMCs. Further studies characterizing AAT preparations used to treat patients with inherited AAT deficiency remains of clinical importance.


Phytates and the inhibitory effect of bran on iron absorption in man.
The cause of marked inhibitory effect of bran on absorption of dietary nonheme iron was studied in man by double-radioiron technique. Washing bran with hydrochloric acid but not with water removed inhibitory factor(s). Inhibition was almost restored by reconstituting phytate level. Removal of phytates in bran by endogenous phytase significantly increased absorption of iron. Removing, by washing with water, phosphates formed from phytates during enzymatic dephytinization led to a bran fraction with only a small remaining inhibitory effect on iron absorption. Half the iron in bran is in the form of monoferric phytate, which is well-absorbed. When potassium and magnesium phytates were added in amounts present in bran, the same inhibitory effect on iron absorption was seen. Although there appear to be other factors in bran that partly explain the inhibition, phytates are the main cause of the inhibitory effect of bran on iron absorption.


Topographic patterns of brain activity in response to swim stress: assessment by 2-deoxyglucose uptake and expression of Fos-like immunoreactivity.
Alterations in brain activity patterns were assessed in response to swim stress by immunocytochemical detection of Fos-like immunoreactivity (Fos-LI) and high-resolution autoradiographic imaging of 14C-2-deoxyglucose (2-DG) uptake. The stress paradigm investigated was a classic behavioral screen for antidepressant drug activity, the forced swim test. One of the most pronounced effects produced by swim stress was an increase in 2-DG uptake and induction of Fos-LI in a restricted region of the lateral septal nucleus. Specific "limbic" cortical regions, including the medial prefrontal, ventrolateral orbital, and cingulate cortices, also exhibited both increased 2-DG uptake and expression of Fos-LI in response to swim stress. In the hypothalamic paraventricular nucleus of swim-stressed rats, Fos-LI was induced but no change in 2-DG uptake was apparent. Since the specific swim stress protocol used is a behavioral screen for antidepressant drugs, the effects of imipramine on stress-induced alterations in 2-DG uptake and induction of Fos-LI were examined. The stress-induced increase in 2-DG uptake in the lateral septum was blocked by treatment with imipramine, but treatment with imipramine had no effect on induction of Fos-LI in the same region. Neither 2-DG uptake nor Fos-LI expression was altered by imipramine treatment in the cortical regions influenced by swim stress. Administration of imipramine alone under basal conditions produced a robust induction of Fos-LI in the central nucleus of the amygdala and in the dorsal lateral subdivision of the bed nucleus of the stria terminalis. No effect of imipramine treatment on 2-DG uptake was apparent in these latter regions. The results provide insights into topographic patterns of brain activity associated with swim stress and neuroanatomically selective actions of imipramine. The different and complementary information obtained by assessment of Fos-LI and 2-DG uptake illustrates the utility of applying both functional mapping approaches to examine neuroanatomical correlates of behavioral states and drug treatment.


Parallel experimental evolution reveals a novel repressive control of GalP on xylose fermentation in Escherichia coli.
Efficient xylose utilization will facilitate microbial conversion of lignocellulosic sugar mixtures into valuable products. In Escherichia coli, xylose catabolism is controlled by carbon catabolite repression (CCR). However, in E. coli such as the succinate-producing strain KJ122 with disrupted CCR, xylose utilization is still inhibited under fermentative conditions. To probe the underlying genetic mechanisms inhibiting xylose utilization, we evolved KJ122 to enhance its xylose fermentation abilities in parallel and characterized the potential convergent genetic changes shared by multiple independently evolved strains. Whole-genome sequencing revealed that convergent mutations occurred in the galactose regulon during adaptive laboratory evolution potentially decreasing the transcriptional level or the activity of GalP, a galactose permease. We showed that deletion of galP increased xylose utilization in both KJ122 and wild-type E. coli, demonstrating a common repressive role of GalP for xylose fermentation. Concomitantly, induced expression of galP from a plasmid repressed xylose fermentation. Transcriptome analysis using RNA sequencing indicates that galP inactivation increases transcription levels of many catabolic genes for secondary sugars including xylose and arabinose. The repressive role of GalP for fermenting secondary sugars in E. coli suggests that utilization of GalP as a substitute glucose transporter is undesirable for conversion of lignocellulosic sugar mixtures.


[Optimization of prophylaxis of relapses of primary erysipelas with the use of cyclopheron].
The aim of the work was to evaluate efficiency of combined therapy of primary erysipelas with the use of immunomodulator cyclopheron (CP), its influence on the clinical picture of the disease, frequency of relapses, lipid peroxidation (LPO) and dynamics of anti-inflammatory cytokines (IL-1b, TNF-alpha). Some of the 87 patients with uncomplicated primary erysipelas of different localization were followed up for 2 years. Lipid peroxidation and dynamics of anti-inflammatory cytokines were studied in 65 patients. A group of 36 patients were given cyclopheron (Polisan, Russia) in addition to standard treatment including etiotropic, pathogenetic and symptomatic therapy. Cyclopheron was first administered by intramuscular injections and thereafter as tablets. Cyclopheron reduced duration of asthenovegetative syndrome, hyperemia, infiltration and regional lymphadenitis compared with controls, but did not significantly alter duration of fever and local oedema. The drug decreased the frequency of early complications as demonstrated by "absolute risk reduction" to 0.35 [0.19; 0.51]. Plasma levels of malonic dialdehyde, lipid hydroperoxides, and TNF-alpha in the reconvalescence period were lower than in control subjects suggesting optimization of homeostasis and correction of inflammatory processes. It is supposed that efficiency of cyclopheron in patients with primary erysipelas may be due to its immunomodulatory activity that prevents formation of chronic foci of Staphylococcal infections in derma and regional lymph nodes.


Host chemical footprints induce host sex discrimination ability in egg parasitoids.
Trissolcus egg parasitoids, when perceiving the chemical footprints left on a substrate by pentatomid host bugs, adopt a motivated searching behaviour characterized by longer searching time on patches were signals are present. Once in contact with host chemical footprints, Trissolcus wasps search longer on traces left by associated hosts rather than non-associated species, and, in the former case, they search longer on traces left by females than males. Based on these evidences, we hypothesized that only associated hosts induce the ability to discriminate host sex in wasps. To test this hypothesis we investigated the ability of Trissolcus basalis, T. brochymenae, and Trissolcus sp. to distinguish female from male Nezara viridula, Murgantia histrionica, and Graphosoma semipunctatum footprints. These three pentatomid bugs were selected according to variable association levels. Bioassays were conducted on filter paper sheets, and on Brassica oleracea (broccoli) leaves. The results confirmed our hypothesis showing that wasps spent significantly more time on female rather than male traces left by associated hosts on both substrates. No differences were observed in the presence of traces left by non-associated hosts. The ecological consequences for parasitoid host location behaviour are discussed.


[Coping strategies developed by caregivers of elderly with chronic diseases].
Care for a dependent elderly individual with a chronic disease can be a threat and cause stress. Success in dealing with this situation will depend on coping strategies, defined as processes used in order to control the demands of the individual-environment relationship. In this study the goal was to detect coping strategies used by caregivers for the elderly. A qualitative study was carried out through the analysis of coping discourse and theoretical reference. The sample was comprised of 16 individuals. It was observed that the coping strategies most used by caregivers were centered on emotion, and that caregiving tasks imply many changes in the life of caregivers, who perform them with no aid, with work overload, loss of liberty, and frustration. The greatest stress is related to the lack of help from family members and of shared responsibilities. Stimulating the involvement of the family, educating and giving basic orientation, which may reduce the difficulties of caregiving, could improve these individuals' well-being.


Is grammatical gender considered arbitrary or semantically motivated? Evidence from young adult monolinguals, second language learners, and early bilinguals.
It is generally assumed that speakers of grammatical gender languages consider grammatical gender arbitrary, but this assumption has never been tested. Research shows that the grammatical gender of nouns can affect perceptions of the masculinity or femininity of the noun's referent in speakers of languages with masculine and feminine noun classes. However, bilingualism facilitates the development of lexical arbitrariness awareness, and could therefore affect awareness of grammatical gender arbitrariness. This study then compared three groups of young adult speakers of a grammatical gender language: monolinguals, early bilinguals, and instructed second language learners. Participants evaluated the gender assignments of 25 nouns of entities (animals, abstract concepts, natural kinds, and artefacts), and answered open and closed questions about grammatical gender. Participants considered grammatical gender as semantically motivated and mostly related gender assignments to perceived masculine or feminine connotations of referents. Knowledge of an additional grammatical gender language was linked to increased awareness of the arbitrariness of first language gender assignments in both early bilinguals and later instructed learners. It is argued that grammatical gender awareness deserves further investigation. Knowing more than one grammatical gender language can increase awareness of grammatical gender arbitrariness. Implications are discussed for language teaching and language reform.


Association Between Changes in Splanchnic Hemodynamics and Risk Factors of Portal Venous System Thrombosis After Splenectomy with Periesophagogastric Devascularization.
BACKGROUND The purpose of this study was to investigate splanchnic hemodynamic changes and determine an optimal cutoff value for risk factors of portal venous system thrombosis (PVST) after splenectomy with periesophagogastric devascularization (SPD) in cirrhotic patients with esophageal and gastric variceal bleeding (EGVB) and portal hypertension (PH). MATERIAL AND METHODS Data on patients who underwent SPD were collected retrospectively from January 2013 to December 2017. Color Doppler ultrasound was performed to detect hemodynamic changes of the hepatic artery, splenic artery, splenic vein, and portal vein in included patients (n=60) and healthy volunteers (n=30). Outcomes were compared between preoperative and postoperative biochemical indicators. The cutoff values for hemodynamics were identified using receiver operating characteristic (ROC) curve analysis, and univariate and multivariate analyses of risk factors of PVST were performed. RESULTS In our series, hemodynamic indexes of splenic artery, spleen vein, and portal vein in the study group were significantly higher than that of the control group (P<0.05). Multivariate analysis revealed that the portal vein flow and the internal diameter of the portal vein were significantly correlated with PVST. The ROC analysis revealed that the cutoff points for portal vein flow and internal diameter of the splenic vein and portal vein were ≥1822.32 ml/min, ≥1.37 cm, and ≥1.56 cm, respectively. CONCLUSIONS SPD is an effective treatment in cirrhotic patients with concomitant EGVB and PH by increasing hepatic artery flow and decreasing portal vein flow. High portal vein flow and wider diameters of the portal vein and splenic vein are important markers of PVST.


Idiopathic gastric acid hypersecretion presenting as a diarrheal disorder and mimicking both Zollinger-Ellison syndrome and Crohn's disease.
Many gastric acid hypersecretory states (basal acid output of greater than 15.0 mEq/h) exist for which the etiology is known, such as Zollinger-Ellison syndrome, systemic mastocytosis, antral exclusion, antral predominant Helicobacter pylori gastritis (antral G cell hyperplasia), chronic gastric outlet obstruction, short gut syndrome and basophilic leukemias. However, many hypersecretory patients have no identified etiology for their acid hypersecretion and are designated as idiopathic gastric acid hypersecretors with a basal acid output of greater than 10 mEq/h and a normal serum gastrin level. Because of the gastric acid hypersecretion these patients also commonly have an increased frequency of stools. Idiopathic gastric acid hypersecretion represents a known cause of gastric acid hypersecretion that is far more common than Zollinger-Ellison syndrome and it has a markedly different treatment regimen and natural history. We report a case of a patient with idiopathic gastric acid hypersecretion previously misdiagnosed as having Crohn's disease because of a presenting complaint of diarrhea and mimicking Zollinger-Ellison syndrome because her fasting serum gastrin level was elevated when incorrectly measured in the presence of antisecretory treatment.


Immediate serial recall of words and nonwords: tests of the retrieval-based hypothesis.
In two experiments, the immediate serial recall of lists of words or nonwords was investigated under quiet and articulatory suppression conditions. The results showed better item recall for words but better order recall for nonwords, as measured with proportion of order errors per item recalled. Articulatory suppression hindered the recall of item information for both types of lists and of order information for words. These results are interpreted in light of a retrieval account in which degraded phonological traces must undergo a reconstruction process calling on long-term knowledge of the to-be-remembered items. The minimal long-term representations for nonwords are thought to be responsible for their lower item recall and their better order recall. Under suppression, phonological representations are thought to be minimal, producing trace interpretation problems responsible for the greater number of item and order errors, relative to quiet conditions. The very low performance for nonwords under suppression is attributed to the combination of degraded phonological information and minimal long-term knowledge.


Tunable Luminescent Properties of Tricyanoosmium Nitrido Complexes Bearing a Chelating O^N Ligand.
We have recently reported a strongly luminescent osmium(VI) nitrido complex [OsVI(N)(NO2-L)(CN)3]- [HNO2-L = 2-(2-hydroxy-5-nitrophenyl)benzoxazole]. The excited state of this complex readily activates the strong C-H bonds of alkanes and arenes (Commun. Chem. 2019, 2, 40). In this work, we attempted to tune the excited-state properties of this complex by introducing various substituents on the bidentate L ligand. The series of nitrido complexes were characterized by IR, UV/vis, 1H NMR, and electrospray ionization mass spectrometry. The molecular structures of five of the nitrido compounds have been determined by X-ray crystallography. The photophysical and electrochemical properties of these complexes have been investigated. The luminescence of these nitrido complexes in the solid state, in a CH2Cl2 solution, and in a CH2Cl2 solid matrix at 77 K glassy medium clearly shows that these emissions are due to 3LML'CT [L ligand to Os≡N] phosphorescence. The presence of strongly electron-withdrawing substituents in these complexes enhances the LML'CT emission. Our result demonstrates that the excited-state properties of this novel class of luminescent osmium(VI) nitrido complexes can be fine-tuned by introducing various substituents on the bidentate L ligand.


Acute coronary syndrome in oman: results from the gulf registry of acute coronary events.
Acute coronary syndrome (ACS) is the most common cause of cardiovascular mortality and morbidity in Western countries. International guidelines for diagnosis and treatment have been developed based on randomised clinical trials. However, data from international registries report a lack of association between guideline recommendations and actual clinical practice. Similarly, the Gulf Heart Association initiated a registry called Gulf Registry of Acute Coronary Events (Gulf RACE). This registry was developed to determine the characteristics and management of ACS in the Gulf countries including Oman. Here, we report on the results of the various Gulf RACE registry studies from Oman and compare our results with the main Gulf RACE data as well as other international registries.


Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake.
Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis.


Characterization and comparative genomic analysis of bacteriophages infecting members of the Bacillus cereus group.
The Bacillus cereus group phages infecting B. cereus, B. anthracis, and B. thuringiensis (Bt) have been studied at the molecular level and, recently, at the genomic level to control the pathogens B. cereus and B. anthracis and to prevent phage contamination of the natural insect pesticide Bt. A comparative phylogenetic analysis has revealed three different major phage groups with different morphologies (Myoviridae for group I, Siphoviridae for group II, and Tectiviridae for group III), genome size (group I > group II > group III), and lifestyle (virulent for group I and temperate for group II and III). A subsequent phage genome comparison using a dot plot analysis showed that phages in each group are highly homologous, substantiating the grouping of B. cereus phages. Endolysin is a host lysis protein that contains two conserved domains: a cell-wall-binding domain (CBD) and an enzymatic activity domain (EAD). In B. cereus sensu lato phage group I, four different endolysin groups have been detected, according to combinations of two types of CBD and four types of EAD. Group I phages have two copies of tail lysins and one copy of endolysin, but the functions of the tail lysins are still unknown. In the B. cereus sensu lato phage group II, the B. anthracis phages have been studied and applied for typing and rapid detection of pathogenic host strains. In the B. cereus sensu lato phage group III, the B. thuringiensis phages Bam35 and GIL01 have been studied to understand phage entry and lytic switch regulation mechanisms. In this review, we suggest that further study of the B. cereus group phages would be useful for various phage applications, such as biocontrol, typing, and rapid detection of the pathogens B. cereus and B. anthracis and for the prevention of phage contamination of the natural insect pesticide Bt.


Association between Antidepressants and Fall-Related Injuries among Long-Term Care Residents.
Antidepressants are associated with an increased risk of falls although little is known of the comparative risks of different types of antidepressants or individuals who are at greatest risk for falls. We examined the association between new use of antidepressants and fall-related injuries among older adults in long-term care (LTC). This was a matched, retrospective cohort study involving LTC residents in Ontario, Canada, from 2008 to 2014. New users of antidepressants were matched to non-users of antidepressants. The primary outcome was any fall resulting in an emergency department (ED) visit or hospitalization within 90 days after exposure. Secondary outcomes included hip fractures, wrist fractures, and falls reported in LTC. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval associated with antidepressants and outcomes. New users of any antidepressant had an increased risk of ED visits or hospitalization for falls within 90 days when compared with individuals not receiving antidepressants (5.2% versus 2.8%; adjusted OR: 1.9, 95% CI: 1.7-2.2). Antidepressants were also associated with an increased risk of all secondary outcomes. The increased risk of fall-related injuries was evident among selective-serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, trazodone, and across multiple patient subgroups. New use of antidepressants is associated with significantly increased risk of falls and fall-related injuries among LTC residents across different patient subgroups and antidepressant classes. The potential risk of fall-related outcomes should be carefully considered when initiating antidepressants among older adults in LTC.


Autocrine stimulation of Nb2 cell proliferation by secreted, but not intracellular, prolactin.
We have introduced expression constructs for mouse PRL (mPRL) or a nonsecreted form of mPRL into the PRL-responsive Nb2 rat lymphoma cell line. Cell lines resulting from transfection of Nb2 cells with the wild type mPRL construct synthesize and secrete mPRL. These cells are able to grow independently of added lactogens, and conditioned media and cell extracts from these cultures stimulate the growth of Nb2 cells. In contrast, cells synthesizing the nonsecreted mPRL do not proliferate in the absence of added lactogenic hormones, and conditioned media from these cell cultures do not have PRL-like activity in the Nb2 cell growth assay. PRL protein is detected in these nonsecreting cell lines; however, extracts from these lines are generally unable to stimulate Nb2 cell proliferation. These results indicate that cells can respond in an autocrine fashion to PRL, but that an intracellular form of PRL is unable to activate Nb2 cell growth.


Evidence accumulation and the moment of recognition: dissociating perceptual recognition processes using fMRI.
Decision making can be conceptualized as the culmination of an integrative process in which evidence supporting different response options accumulates gradually over time. We used functional magnetic resonance imaging to investigate brain activity leading up to and during decisions about perceptual object identity. Pictures were revealed gradually and subjects signaled the time of recognition (T(R)) with a button press. We examined the time course of T(R)-dependent activity to determine how brain regions tracked the timing of recognition. In several occipital regions, activity increased primarily as stimulus information increased, suggesting a role in lower-level sensory processing. In inferior temporal, frontal, and parietal regions, a gradual buildup in activity peaking in correspondence with T(R) suggested that these regions participated in the accumulation of evidence supporting object identity. In medial frontal cortex, anterior insula/frontal operculum, and thalamus, activity remained near baseline until T(R), suggesting a relation to the moment of recognition or the decision itself. The findings dissociate neural processes that function in concert during perceptual recognition decisions.


Genetic analysis of Bacillus anthracis Sap S-layer protein crystallization domain.
Bacillus anthracis, the aetiological agent of anthrax, synthesizes two surface-layer (S-layer) proteins. S-layers are two-dimensional crystalline arrays that completely cover bacteria. In rich medium, the B. anthracis S-layer consists of Sap during the exponential growth phase. Sap is a modular protein composed of an SLH (S-layer homology)-anchoring domain followed by a putative crystallization domain (Sap c). A projection map of the two-dimensional Sap array has been established on deflated bacteria. In this work, the authors used two approaches to investigate whether Sap c is the crystallization domain. The purified Sap c polypeptide (604 aa) was sufficient to form a crystalline structure, as illustrated by electron microscopy. Consistent with this result, the entire Sap c domain promoted auto-interaction in a bacterial two-hybrid screen developed for the present study. The screen was derived from a system that takes advantage of the Bordetella pertussis cyclase subdomain structure to enable one to identify peptides that interact. A screening strategy was then employed to study Sap c subdomains that mediate interaction. A random library, derived from the Sap c domain, was constructed and screened. The selected polypeptides interacting with the complete Sap c were all larger (155 aa and above) than the mean size of the randomly cloned peptides (approx. 60 residues). This result suggests that, in contrast with observations for other interactions studied with this two-hybrid system, large fragments were required to ensure efficient interaction. It was noteworthy that only one polypeptide, which spanned aa 148-358, was able to interact with less than the complete Sap c, in fact, with itself.


The use of neuronavigation and intraoperative imaging systems in the surgical treatment of orbital tumors.
We aimed to show the effects of neuronavigation and intraoperative imaging systems on the surgical outcomes of orbital tumors. Seventeen patients who underwent surgical treatment for orbital tumors by transcranial and transnasal approaches between 2008 and 2013 were analyzed retrospectively. Twelve of them were male and 5 were female. The mean age was 41.6 years. Neuronavigation systems were used in all cases. Four patients were operated using intraoperative imaging systems. The transcranial approach was used in 9 (53%) patients, endoscopic medial orbital approach in 4 (23.5%), endoscopic inferolateral approach in 1 (6%), cranioorbitozygomatic approach in 1, lateral approach in 1, and the combined (medial endoscopic and lateral) approach in 1 patients. Total resection was achieved in 5 patients, gross total excision in 2, subtotal in 9 and partial in 1 patients. Modern technology has made a significant contribution to the treatment of orbital tumors. Although technological equipments facilitate the excision of tumors, the level of resection is mainly determined by the nature of tumor and adhesion to the adjacent neurovascular structures. It should not be forgotten that advanced technology never replaces a good anatomical knowledge and surgical experience, but has a complementary role.


Contrast-enhanced magnetic resonance angiography for diagnosis of portosystemic shunts in 10 dogs.
Computed tomography angiography, sonography, scintigraphy, and portography can be used to evaluate the portal vasculature to evaluate for a portosystemic shunt (PSS). Time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced MRA (CE-MRA) are other potentially useful techniques. The aim of this study was to evaluate CE-MRA in 10 dogs suspected of having a PSS. Noncontrast MR images of the abdomen were obtained using a Siemens Symphony MR-scanner (1.5 T) and a T1-weighted FLASH-3D sequence with a very short scan time (about 20 s). After injection of contrast medium, the initial sequence was repeated five times. The sequence with the best contrast medium filling of the portal vasculature was selected subjectively, subtracted from the initial survey image series, and a maximum intensity projection (MIP) of the subtraction data, in multiple views, was created. The cross-sectional and MIP images were evaluated for abnormal portosystemic vasculature. A single PSS was identified and confirmed at surgery in all dogs. A portocaval shunt was found in five dogs, a portophrenic shunt in three dogs, a portoazygos shunt in one, and a central divisional intrahepatic shunt in one other dog. Based on our results, CE-MRA is a useful tool for imaging abdominal and portal vasculature and for the diagnosis of a PSS.


Results of long-term follow-up in patients undergoing anterior screw fixation for type II and rostral type III odontoid fractures.
Retrospective analysis of the fusion rate of a group of 38 patients having undergone anterior screw fixation for type II and "shallow" type III odontoid fractures. OBJECTIVE.: To determine primarily the long-term fusion rate after anterior screw fixation and to study the clinical characteristics of patients that have a statistically significant or nonsignificant influence on successful outcome. Long-term outcome of anterior screw fixation for odontoid fractures has been evaluated in very few studies. This information should be critical for further establishing this technique as a major therapeutic strategy for these cases. Thirty-eight patients, 25 males and 13 females (with mean age 48.4 +/- 0.4 years), with type II and rostral type III odontoid fractures, underwent anterior cannulated screw fixation during a 62-month period. Radiologic examination of the cervical spine with plain radiographs was performed at 6 weeks, and 2, 6, 12, and 24 months, while computerized tomography of the upper cervical spine (C1-C3) was obtained at 6 months after surgery. Follow-up was available for 31 patients, and the follow-up time ranged from 39 to 87 months (mean 58.4). Radiographic evaluation of the follow-up group showed satisfactory bony fusion and no evidence of abnormal movement at the fracture site in 27 (87.1%) patients. Pseudarthrosis developed in 4 (12.9%) patients; however, 3 (9.6%) of them without instability and 1 (3.2%) with instability. One (3.2%) patient had an instrumentation failure without instability. In our series, anterior odontoid screw fixation comprised a safe therapeutic modality with high stability and low mechanical failure rates during short-term and long-term follow-up.


Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening.
The introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed. In this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening. In a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease. This automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme. Work was funded by the MRC Imperial Confidence in Concept Scheme, Imperial College Healthcare Charity, British Society for Colposcopy and Cervical Pathology, National Research Development and Innovation Office of Hungary, Waters corporation and NIHR BRC.


Hydrogen improves cell viability partly through inhibition of autophagy and activation of PI3K/Akt/GSK3β signal pathway in a microvascular endothelial cell model of traumatic brain injury.
Objective:Traumatic brain injury (TBI) is one of the most serious public health problems in the world. Hydrogen (H2), a flammable, colorless, and odorless gas, has been observed to have preventive and therapeutic effects on brain trauma and other neurological disorders, but its exact mechanism has not been fully clarified.Methods: To further study the mechanism underlying the role of hydrogen gas in alleviating BBB damage after TBI, we performed the scratch injury model on cultured brain microvascular endothelial cells (bEnd.3), which formed the microvascular endothelial barrier - an integral part of the highly specialized BBB.Results: In the case of TBI, hydrogen was able to improve the decline of cell viability induced by TBI. More importantly, inhibition of PI3 K/Akt/GSK3β signal pathway or activation of autophagy reduced the protective effect of hydrogen on cell viability, indicating that such protective effect was regulated by PI3 K/Akt/GSK3β signal pathway and was related to the inhibition of autophagy.Conclusion: So we concluded that hydrogen improved the cell viability in a microvascular endothelial cell model of TBI partly through inhibition of autophagy, and inhibitory effect of hydrogen on autophagy was exerted by activating PI3 K/Akt/GSK3β signal pathway. These findings enriched our knowledge about the mechanism of hydrogen therapy against TBI.


The association between sequential changes in serum antineuronal antibodies and neuropsychiatric systemic lupus erythematosus.
To determine the significance of changes in serum antineuronal antibody levels in systemic lupus erythematosus, 9 patients who had a rise and 11 patients who had a fall in neuronal antibody titre over a mean duration of 2.1 years (range 0.25-5.2) were identified. These changes were examined in the light of concurrent changes in other serological variables, overall disease activity, neuropsychiatric disease and neuropsychological tests. Changes in antineuronal antibodies were frequently associated with concurrent changes in anti-DNA antibodies and overall disease activity. When neuropsychiatric disease or cognitive dysfunction were present, their course showed a close correlation with changes in antineuronal antibody levels. The results support the association between antineuronal antibodies and neuropsychiatric-systemic lupus erythematosus, but suggest that their measurement will provide useful information of disease status in only a subpopulation of patients.