EphA4 promotes cell proliferation and cell adhesion-mediated drug resistance via the AKT pathway in multiple myeloma.
Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion-mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion-mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion-mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.


Structural basis for the regulation of N-acetylglutamate kinase by PII in Arabidopsis thaliana.
PII is a highly conserved regulatory protein found in organisms across the three domains of life. In cyanobacteria and plants, PII relieves the feedback inhibition of the rate-limiting step in arginine biosynthesis catalyzed by N-acetylglutamate kinase (NAGK). To understand the molecular structural basis of enzyme regulation by PII, we have determined a 2.5-A resolution crystal structure of a complex formed between two homotrimers of PII and a single hexamer of NAGK from Arabidopsis thaliana bound to the metabolites N-acetylglutamate, ADP, ATP, and arginine. In PII, the T-loop and Trp(22) at the start of the alpha1-helix, which are both adjacent to the ATP-binding site of PII, contact two beta-strands as well as the ends of two central helices (alphaE and alphaG) in NAGK, the opposing ends of which form major portions of the ATP and N-acetylglutamate substrate-binding sites. The binding of Mg(2+).ATP to PII stabilizes a conformation of the T-loop that favors interactions with both open and closed conformations of NAGK. Interactions between PII and NAGK appear to limit the degree of opening and closing of the active-site cleft in opposition to a domain-separating inhibitory effect exerted by arginine, thus explaining the stimulatory effect of PII on the kinetics of arginine-inhibited NAGK.


Cranberry extract supplementation exerts preventive effects through alleviating Aβ toxicity in Caenorhabditis elegans model of Alzheimer's disease.
Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Aβ toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Aβ toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals.


Diet and cancer. Any progress in the interim?
It has been 5 years since the National Research Council (NRC) Committee on Diet, Nutrition and Cancer published "Interim Dietary Guidelines" for the nutritional prevention of cancer. The term "interim" implies that these recommendations should be regarded as temporary, pending more definitive findings from additional scientific research. This article reviews findings relevant to the connections between diet and cancer that have emerged from nutritional epidemiology subsequent to the 1982 the NRC report. Some recent research has supported the earlier work which served as a basis for the interim recommendations, some has not, and additional hypotheses have emerged. There continues to be evidence, although it is inconsistent, that dietary fat may be an important factor in colon cancer, and that something related to fruits and vegetables, perhaps carotene, may lower the risk of lung cancer. However, the hypothesized relationships between dietary fat and breast cancer and between dietary fiber and colon cancer have been less consistently supported by new findings. Meanwhile, a new hypothesis has emerged relating alcohol intake to breast cancer risk, although many important questions remain regarding the age at which alcohol use may affect risk, and the dose above which risk is increased. The last 5 years seem to have been characterized by only slow progress in our understanding of the relationship between diet and cancer. It is clear that in 1988 we are still very much in the interim. Critical methodologic assessments of the reasons for the discrepancies in findings among the various studies, and meta analytic approaches may be helpful in increasing our understanding of the set of epidemiologic research conducted to date. More important, however, are the many types of studies now underway, including more rigorously designed observational studies and chemo-preventive and dietary-preventive trials. These studies will likely provide more definitive future answers to the questions we still face in the interim.


Membership inference attack on differentially private block coordinate descent.
The extraordinary success of deep learning is made possible due to the availability of crowd-sourced large-scale training datasets. Mostly, these datasets contain personal and confidential information, thus, have great potential of being misused, raising privacy concerns. Consequently, privacy-preserving deep learning has become a primary research interest nowadays. One of the prominent approaches adopted to prevent the leakage of sensitive information about the training data is by implementing differential privacy during training for their differentially private training, which aims to preserve the privacy of deep learning models. Though these models are claimed to be a safeguard against privacy attacks targeting sensitive information, however, least amount of work is found in the literature to practically evaluate their capability by performing a sophisticated attack model on them. Recently, DP-BCD is proposed as an alternative to state-of-the-art DP-SGD, to preserve the privacy of deep-learning models, having low privacy cost and fast convergence speed with highly accurate prediction results. To check its practical capability, in this article, we analytically evaluate the impact of a sophisticated privacy attack called the membership inference attack against it in both black box as well as white box settings. More precisely, we inspect how much information can be inferred from a differentially private deep model's training data. We evaluate our experiments on benchmark datasets using AUC, attacker advantage, precision, recall, and F1-score performance metrics. The experimental results exhibit that DP-BCD keeps its promise to preserve privacy against strong adversaries while providing acceptable model utility compared to state-of-the-art techniques.


[Prevalence of anti-Toxoplasma gondii antibodies in dairy cattle from Sul Fluminense Paraíba Valley, State of Rio de Janeiro].
A survey of toxoplasmosis in cattle from Sul Fluminense Paraiba Valley micro region in the State of Rio de Janeiro was realized, where serum samples were collected from 589 animals of 29 dairy farms located at municipalities of Resende and Rio Claro. Serology was performed by using indirect immune fluorescent test (IFAT), and considering as positive to Toxoplasma gondii titles > or = 64. Results found in both municipalities were 14.8% serum reagents animals. When these results were analyzed by each Municipality, Resende had 15.3% (48 animals of 314) positive animals, and 14.2% (39 animals of 275) was observed at Rio Claro. In the analysis of 58 studied dairy farms was observed that 38 (65.5%) of them having positive cows for anti-T. gondii, being 20 (69.0%) at Resende, and 18 (62.1%) at Rio Claro. With regard to serologic samples found in the IFAT, 79 (13.41%) animals were positives with titles of 64, six (1.02%) with 256, two (0.34%) with 1024, and none of animals had titles > or = 4096.


Tyrosine phosphorylation coupled to IgE receptor-mediated signal transduction and histamine release.
Antigen-induced cross-linking of IgE bound to its receptors at the surface of basophils or mast cells initiates a number of biochemical events culminating in the release of histamine-containing granules. In the present study, we investigated the possible involvement of tyrosine phosphorylation in signaling by the high-affinity IgE receptor (Fc epsilon RI). Cross-linking of Fc epsilon RI in rat basophilic leukemia cells (RBL-2H3) led to the phosphorylation of several proteins on tyrosine, the most prominent having a mass of 72 kDa. Tyrosine phosphorylation was rapid, detectable 1 min after stimulation, and correlated with both the time course and antigen dose for histamine release. Reversal of Fc epsilon RI cross-linking prevented continuation of the degranulation process and resulted in rapid loss of tyrosine phosphorylation. The receptor-mediated tyrosine phosphorylation was still induced in the absence of calcium in the medium. Depletion of protein kinase C with phorbol 12-myristate 13-acetate did not dramatically affect the tyrosine phosphorylation signal or the release of histamine. In contrast, the calcium ionophore A23187 induced histamine release in the absence of a perceptible increase in protein tyrosine phosphorylation. Thus, tyrosine phosphorylation is an early signal following Fc epsilon RI aggregation, independent of the exocytotic process itself. Taken together, our findings functionally link protein phosphorylation on tyrosine residues to Fc epsilon RI-mediated signal transduction leading to histamine release.


FISH, PCR and cytogenetic characterization in a girl with ambiguous genitalia and karyotype mos46,X,iso(Y)(qter-->p11.3::p11.3-->qter)[80]/45,X[17]/46,X,+mar[3].
A cytogenetic study was carried out in a girl with virilized external genitalia, who showed a karyotype containing a Y isochromosome in mosaic form: mos46,X,iso(Y)(qter-->p11.3::p11.3-->qter)[80]/45,X[17]/46,X,+mar[3]. The chromosome aberrations were confirmed by fluorescence in situ hybridization analysis, with both whole chromosome paint Y probe and centromeric X chromosome probe. The molecular analyses by PCR detected the presence of the SRY, DAZ and AMGY genes, confirming the presence of the whole long arm and almost whole short arm of the Y chromosome. We suggest that the structural alteration of the Y chromosome was a new mutation, which occurred in the initial mitotic divisions of the embryo, originally 46,XY. The breakpoints occurred on the distal extremity of the short arm with later fusion of its extremities producing a Y isochromosome. The later numerical alteration occurred as a consequence of chromosomal instability. Although almost all cells (80%) in peripheral blood belonged to the iso(Y) line with a duplicated SRY gene, this did not determine male sexual differentiation in the patient. The result of accurate evaluation provides correct sex assignment and the prevention of the neoplastic degeneration of a dysgenetic gonad.


Diabetes care among veteran women with disability.
The primary objective of this study was to analyze predictors of diabetes care consistent with performance standards among women Veterans Health Administration (VHA) clinic users with disability enrollment status. This is a retrospective cohort study using VHA and Medicare files of VHA clinic users with diabetes. Diabetes care measures consisted of annual testing for hemoglobin A(1c) (HbA(1c)), low-density lipoprotein cholesterol (LDL-C), and poor HbA(1c) (>9%) and LDL-C (> or =130 mg/dL) control in fiscal year 2000. Chi-square tests and logistic regressions were used to assess subgroup differences in diabetes care. Independent variables included demographic characteristics and physical and psychiatric comorbidities. Study population was based on veteran women <65 years of age who used VHA clinics; we identified 2,344 women as having coexisting disability and diabetes and 2,766 women with diabetes and without disability. Among veteran women with diabetes and disability, 65% received > or =1 HbA(1c) test, and 54% received a LDL-C test; 25% and 30% had poor HbA(1c) and LDL-C control, respectively. In logistic regressions, none of the independent variables had significant effects on poor HbA(1c) or LDL-C control, except that African Americans were more likely to have poor HbA(1c) control than whites. Significant age effects were noted in rates of HbA(1c) and LDL testing. Comparison of diabetes care measures between women with and without disability indicated that those with disability were more likely to receive HbA(1c) and LDL-C tests; no significant differences in HbA(1c) and LDL-C control were noted. Disability status of women veterans was not a barrier to diabetes care consistent with performance standards. Our findings suggest that to improve diabetes care, subgroup-specific interventions, rather than a global approach, are warranted.


R-citalopram prevents the neuronal adaptive changes induced by escitalopram.
This study examined the long-term effects of the antidepressant escitalopram on rat serotonin (5-HT) neuronal activity and hippocampal neuroplasticity. In the dorsal raphe nucleus, a 2-week treatment with escitalopram (10 mg/kg/day, subcutaneous) did not modify the firing activity of 5-HT neurons, whereas a cotreatment with R-citalopram (20 mg/kg/day, subcutaneous) decreased it. In the dentate gyrus of dorsal hippocampus, escitalopram increased significantly (57%) the number of de novo cells and this was prevented by a cotreatment with R-citalopram. The present results support the role of the allosteric modulation of the 5-HT transporter in the regulation of the recovery of 5-HT neuronal activity and long-lasting hippocampal cellular plasticity induced by escitalopram, two adaptive changes presumably associated with the antidepressant response.


Music for relaxation: a comparison of musicians and nonmusicians on ratings of selected musical recordings.
The purpose of this study was to determine the kinds of musical selections/CDs to place in a portfolio to be used within a music listening/relaxation program for parents of children in a pediatric hospital. A panel of experts (4 music therapy graduate students and 2 music therapy instructors) listened to a selection of CD recordings (n = 10) which reported to contain music for relaxation. These 10 recordings were chosen based either on words within the title suggestive of sedative/relaxing music, or the literature (booklet) accompanying the CD that contained claims of such therapeutic value. Average number of selections across the 10 recordings was 9.8 with a total of 98 musical selections presented to the panel. A 1 1/2-minute segment from each selection (starting at the beginning of each piece) was played on a stereo CD unit, and time was given to complete a response form following each of the musical selections. The panel was asked to rate the relaxation quality of each piece, and to specify the musical characteristics that enhanced and/or distracted from relaxation. Weekly listening sessions of 40-50 minutes in duration were scheduled across a 10-week time period. Based on the results of the experts, 10 of the 98 musical selections were chosen for presentation to a group of nonmusicians. Again, as with the experts, the nonmusicians listened to 1 1/2-minute segments from each selection and completed a response form similar to the form completed by the panel. Additional questions asked the nonmusicians whether they listened to music for relaxation, and if so, what kind(s) of music they preferred to use for this purpose. Results from the panel of experts and nonmusicians were compiled, and descriptive statistics were used to compare the data. Suggestions were given concerning possible inclusion of musical recordings that may be used in a music listening/ relaxation program for parents of children within a pediatric setting.


Author perception of peer review: impact of review quality and acceptance on satisfaction.
To determine author perception of peer review and association between quality of review and author satisfaction. Survey between May 1999 and October 2000 of 897 corresponding authors of manuscripts under consideration by the Annals of Emergency Medicine and had received final editorial decisions during the study period. A total of 576 authors (64%) returned the survey. Using a 5-point Likert scale, the survey assessed differences in satisfaction between authors whose manuscripts were accepted, reviewed and rejected, and rejected without full review. The association of author satisfaction with editor's assessment of review quality, publication decision, author sex, specialty, and publication experience were also assessed. Overall mean (SD) satisfaction score, indicated by agreement with "My experience with the review process will make me more likely to submit to Annals in the future," was 3.1 (1.0) and was significantly higher among authors of accepted papers (3.7 [0.9]) than among either group of rejected papers (rejected/reviewed, 2.8 [1.0]; rejected/no review, 3.0 [0.9]; P.05). Authors whose manuscripts were reviewed and rejected were the least satisfied with the time to decision (rejected/reviewed, 3.0 [1.2] vs accepted, 3.7 [1.0] and rejected/no review, 3.9 [0.9]; P<.05). Those whose papers were rejected without review were the least satisfied with the letter explaining the editorial decision (rejected/no review, 2.8 [1.2] vs accepted, 4.2 [0.7] and rejected/reviewed, 3.1 [1.2]; P<.05). Among respondents whose manuscripts underwent full review (accepted and rejected/reviewed), overall satisfaction was highly associated with acceptance of the manuscript for publication (odds ratio [OR], 6.12; 95% confidence interval [CI], 3.43-10.91) but not with quality rating of reviews (OR, 1.26; 95% CI, 0.84-1.90). Contributor satisfaction with peer review was modest. Authors of rejected manuscripts were dissatisfied with the time to decision and communication from the editor. Author satisfaction is associated with acceptance but not with review quality.


Accurate Non-Disturbance Population Survey Method of Nesting Colonies in the Reedbed with Georeferenced Aerial Imagery.
High altitude aerial surveys have the potential to improve disturbance-free data collection in wildlife research, but previously, bird species were not recognizable in high-altitude orthophotos. This method of aerial surveying is effective and can be repeated frequently due to its low cost; it also has the additional advantage of being able to monitor the status of protected areas. In the case of waterbirds, due to the low vegetation coverage, aerial remote sensing is an exceptionally effective technique for surveying populations and detecting nests. Aerial surveys made at low altitudes can cause serious stress for birds. The method we developed and employed is unlikely to be detected by either ground-based or nesting birds but is far more reliable compared to the low-resolution imaging methods and to the evaluation of non-georeferenced photo series. The modern sensors and photogrammetric procedures enable the use of the present method worldwide; furthermore, the large-scale ortho image-derived information has become obtainable more frequently. Direct georeferencing makes the field geodetic survey unnecessary. Orthophotos with a 0.7 cm spatial resolution allow us to reliably identify even the individuals of smaller species, and by the use of oblique images, they can be tracked from two or four different directions.


Studying Protein-Protein Interactions at Plasmodesmata by Measuring Förster Resonance Energy Transfer.
Plasmodesmata (PD) provide interconnectivity between plant cells to enable the intercellular transport and communication that is requisite to multicellularity. Being at the interface of the apoplast, plasma membrane (PM), endoplasmic reticulum (ER), and symplast, PD are uniquely positioned to integrate exogenously and endogenously derived signals with plant developmental and physiological responses. The distinct membrane curvature and composition of PD allow them to function as microdomains to facilitate dynamic protein-protein interactions. Förster resonance energy transfer (FRET) combined with fluorescence lifetime imaging microscopy (FLIM) and fluorescence anisotropic decay measurements provides valuable tools to analyze these interactions in vivo and in planta. Here we describe a detailed methodology to perform FRET-FLIM and fluorescence anisotropy measurements to analyze protein-protein interactions at PD in a transient expression system using Nicotiana benthamiana; however this can be adapted to other plant species and subcellular compartments.


Fluctuation of anti-endothelial cell antibody titers in " mixed connective tissue disease.
Antibodies directed against endothelial cell surface antigens have been described in many disorders and have been associated with disease activity. Since the most prominent histopathologic feature in mixed connective tissue disease (MCTD) is the widespread and unique proliferative vascular lesion, our aim was to evaluate the frequency of anti-endothelial cell antibodies (AECA) in this condition. To evaluate the frequency of AECA in this disease and assess its clinical and laboratory associations. Seventy-three sera from 35 patients with MCTD (Kasukawa's criteria), collected during a 7 year period, were tested for immunoglobulins G and M (IgG and IgM) AECA by cellular ELISA, using HUVEC (human umbilical vein endothelial cells). Sera from 37 patients with systemic lupus erythematosus (SLE), 22 with systemic sclerosis (SSc) and 36 sera from normal healthy individuals were used as controls. A cellular ELISA using HeLa cells was also performed as a laboratory control method. IgG-AECA was detected in 77% of MCTD patients, 54% of SLE patients, 36% of SSc patients and 6% of normal controls. In MCTD, IgG-AECA was associated with vasculitic manifestations, disease activity and lymphopenia, and was also a predictor of constant disease activity. Immunosuppressive drugs were shown to reduce IgG-AECA titers. Since antibodies directed to HeLa cell surface were negative, AECA was apparently unrelated to common epitopes present on epithelial cell lines. AECA are present in a large proportion of patients with MCTD and these antibodies decrease after immunosuppressive treatment.


On the importance of carbohydrate-aromatic interactions for the molecular recognition of oligosaccharides by proteins: NMR studies of the structure and binding affinity of AcAMP2-like peptides with non-natural naphthyl and fluoroaromatic residues.
The specific interaction of a variety of modified hevein domains to chitooligosaccharides has been studied by NMR spectroscopy in order to assess the importance of aromatic-carbohydrate interactions for the molecular recognition of neutral sugars. These mutant AcAMP2-like peptides, which have 4-fluoro-phenylalanine, tryptophan, or 2-naphthylalanine at the key interacting positions, have been prepared by solid-phase synthesis. Their three-dimensional structures, when bound to the chitin-derived trisaccharide, have been deduced by NMR spectroscopy. By using DYANA and restrained molecular dynamics simulations with the AMBER 5.0 force field, the three-dimensional structures of the protein-sugar complexes have been obtained. The thermodynamic analysis of the interactions that occur upon complex formation have also been carried out. Regarding binding affinity, the obtained data have permitted the deduction that the larger the aromatic group, the higher the association constant and the binding enthalpy. In all cases, entropy opposes binding. In contrast, deactivation of the aromatic rings by attaching fluorine atoms decreases the binding affinity, with a concomitant decrease in enthalpy. The role of the chemical nature of the aromatic ring for establishing sugar contacts has been thus evaluated.


Latino sexual and gender identity minorities promoting sexual health within their social networks: process evaluation findings from a lay health advisor intervention.
The HOLA intervention was a lay health advisor intervention designed to reduce the disproportionate HIV burden borne by Latino sexual and gender identity minorities (gay, bisexual, and other men who have sex with men, and transgender persons) living in the United States. Process evaluation data were collected for over a year of intervention implementation from 11 trained Latino male and transgender lay health advisors (Navegantes) to document the activities each Navegante conducted to promote condom use and HIV testing among his or her eight social network members enrolled in the study. Over 13 months, the Navegantes reported conducting 1,820 activities. The most common activity was condom distribution. Navegantes had extensive reach beyond their enrolled social network members, and they engaged in health promotion activities beyond social network members enrolled in the study. There were significant differences between the types of activities conducted by Navegantes depending on who was present. Results suggest that lay health advisor interventions reach large number of at-risk community members and may benefit populations disproportionately affected by HIV.


D1 and D2 dopamine receptors in perinatal and adult basal ganglia.
There is reason to believe that dopamine is important in developmental programs of the basal ganglia, brain nuclei implicated in motor and cognitive processing. Dopamine exerts effects through dopamine receptors, which are predominantly of the D1 and D2 subtypes in the basal ganglia. Cocaine acts as a stimulant of dopamine receptors and may cause long-term abnormalities in children exposed in utero. Dopamine receptor (primarily D1) stimulation has been linked to gene regulation. Therefore, D1 and D2 receptor densities in perinatal and adult striatum and globus pallidus were examined using quantitative autoradiography. The most striking finding was that pallidal D1 receptor densities were 7-15 times greater in the perinatal cases than in the adult. Pallidal D2 receptor densities were similar at both ages. In both the adult and perinatal striatum, D2 receptor densities were greater in the putamen than in the caudate, and both D1 and D2 receptor densities were modestly enriched in caudate striosomes compared with the matrix. In both caudate and putamen, perinatal D1 receptor levels were within the adult range, whereas D2 receptor levels were only 50% of adult values. The development of D1 and D2 receptors appears to vary across the major subdivisions of the human basal ganglia. The facts that we found such extremely high levels of D1 receptors in the perinatal pallidum, and that D1 receptor activation influences gene regulation, suggest that the globus pallidus could be particularly susceptible to long-term changes with perinatal exposure to cocaine and other D1 receptor agonists or antagonists.


Methodological aspects on cytochemical DNA assessment of adenocarcinoma of the endometrium by means of image and flow cytometry using conventionally formalin-fixed and paraffin-embedded specimens.
Sometimes widely diverging results have been reported as regards the nuclear DNA ploidy pattern of adenocarcinomas of the endometrium. Since such discrepancies might be due to differences in the techniques applied, it seemed worthwhile to investigate this possibility in conventional uterine curetted specimens. In order to obtain a high incidence of tumours with cancer cell nuclei showing "aneuploid" DNA distribution pattern, a selection was made, so that only those adenocarcinomas that had led to a fetal outcome of the neoplastic disease were examined. The results of two image cytometric (ICM) techniques for cytochemical nuclear DNA assessments were compared. One was direct photographic cytometric measurements on Feulgen-stained sections; the other was densitometric assessments on isolated tumour cell nuclei of deparaffinised and disintegrated specimens. In 39 cases out of 43 the DNA ploidy pattern was the same by means of the two techniques. However, about half the numbers of the specimens (40 out of 83) were lost during the deparaffinisation and disintegration procedure. As far as could be found from a limited study on 20 (out of the 43) selected cases, these losses of specimens became even greater when the flow-cytometric (FCM) technique was applied on the deparaffinised specimens; about one third of these specimens were not possible to evaluate. In addition, in those where assessments by means of FCM could be made, the DNA ploidy pattern obtained differed from that of the two ICM techniques in not less than 80% of the cases. Broad peaks and high amounts of counts in the background in the DNA histograms indicated that most of the DNA assessments made by means of FCM on archival material of the present kind of curetted specimens of endometrial adenocarcinomas gave no reliable results. Consequently, differences in the techniques applied in cytochemical assessments of the nuclear DNA distribution pattern in endometrial carcinomas can explain the more or less controversial results reported from different laboratories.


Functional effects of human milk oligosaccharides (HMOs).
Human milk oligosaccharides (HMOs) are the third most important solid component in human milk and act in tandem with other bioactive components. Individual HMO levels and distribution vary greatly between mothers by multiple variables, such as secretor status, race, geographic region, environmental conditions, season, maternal diet, and weight, gestational age and mode of delivery. HMOs improve the gastrointestinal barrier and also promote a bifidobacterium-rich gut microbiome, which protects against infection, strengthens the epithelial barrier, and creates immunomodulatory metabolites. HMOs fulfil a variety of physiologic functions including potential support to the immune system, brain development, and cognitive function. Supplementing infant formula with HMOs is safe and promotes a healthy development of the infant revealing benefits for microbiota composition and infection prevention. Because of limited data comparing the effect of non-human oligosaccharides to HMOs, it is not known if HMOs offer an additional clinical benefit over non-human oligosaccharides. Better knowledge of the factors influencing HMO composition and their functions will help to understand their short- and long-term benefits.


Transcatheter closure of ischemic and post-traumatic ventricular septal ruptures.
Post-traumatic ventricular septal defects (VSD) can occur after acute MI or iatrogenically after invasive surgical procedures. Emergency surgery is associated with high perioperative mortality and postsurgical shunt in up to 20% of patients. Transcatheter closure (TCC) of post MI VSD may be an alternative that avoids the high risk of surgery. We report a lower mortality and morbidity than surgical closure in the post infarction VSD's even with a short interval between defect occurrence and percutaneous device placement. Furthermore, in patients with a failed or suboptimal surgical result adjunctive percutaneous closure may be beneficial and offers an alternative to redo VSD repair. Finally, in patients who suffer an unexpected traumatic VSD post surgical procedure, percutaneous closure offers an alternative with excellent results.


[Prophylaxis and treatment of viral infections. Part I--infections caused by DNA viruses].
The amount of antiviral drugs have increased recently. Many viruses treated as a mild pathogens has turned out to cause different complications and severe diseaseses in elderly people and immunocomprised patients. The authors have made an attempt of presenting on the basis of scientific reports the principles of antiviral prophylaxis and treatment. The first part is focused on infections caused by DNA viruses.


P048 Metastatic Crohn's Disease Debuting with Severe Oral Manifestation and Vulvar Involvement - A Diagnostic Challenge.
Background: Metastatic Crohn's disease (MCD) is an unusual cutaneous manifestation in Crohn's disease (CD), and concomitant oral and vulvar involvement is even more unusual. It can debut with cavity lesions oral such as canker sores, ulcers, lip edema, granulomatosis, dry mouth, abscesses in the salivary ducts, erythema, gingivitis, glossitis, among others, however, simultaneous compromise with several oral lesions and so severe with loss of multiple pieces dental is very rare. Patient in the fourth decade of life with a family history of autoimmunity who debuts with severe oral manifestations with a requirement for extraction of 14 teeth, severe gingivitis, smooth tongue and glossitis, aphthous stomatitis, ulcers, lip edema and angular cheilitis, without clear cause, and in management by the oral pathology group. Associated with this, there was vulvo-perineal compromise with ulcerated, inflammatory, erythematous and infiltrated lesions. It was initially suspected of Behçet's disease, HLA B51 was performed, it was negative, also, negative pathergy test, and no other suggestive systemic findings. A vulvar biopsy was performed with marked edema of the dermis, dilated lymphatics with perivascular and interstitial lymphoplasmacytic infiltrate and noncaseating granulomas, negative for microorganisms. At this level, it was compatible with MCD, without presence of gastrointestinal symptoms and calprotectin levels in stool in normal range. High and low endoscopic studies and capsule endoscopy were performed in small intestine, without alterations, it was managed by dermatology with topical steroids and by dentistry with dental implants. It was considered patient with inflammatory bowel disease (IBD) type CD with severe extraintestinal manifestations (EIM), although it did not present compromise intestinal treatment, it was decided to start treatment with anti-TNF initially with adalimumab developing paradoxical psoriasis, later treatment with infliximab, again with presentation of severe paradoxical psoriasis, for which it was suspended. Cyclosporine was also used as an immunomodulator, presenting intolerable tachycardia. 18 months after these symptoms, she presented episcleritis of the left eye and begins with colicky abdominal pain and average diarrheal stools 5-a-day, it was performed high and low endoscopic studies without alterations and new capsule endoscopic of small intestine documenting Crohn's enteritis involving the duodenum, jejunum and ileum, considering a patient with IBD type CD, with EIM with vulvo-perineal compromise, severe oral involvement and episcleritis. Currently is under management with azathioprine and Ustekinumab, with clinical improvement significant. MCD represents a diagnostic challenge, it can debut without gastrointestinal involvement, and its clinical and histopathological findings simulate other entities. A timely diagnosis is required to seek early benefit in the patient.


Strong anisotropy of projected 3d moments in epitaxial CrO2 films.
Soft x-ray magnetic circular dichroism (XMCD) spectra have been investigated for different crystallographic projections of CrO2. Strong anisotropic orbital Cr 3d contributions and a change of sign of the XMCD signal is observed and attributed to t(2g) majority states near the Fermi level. Additionally, moment analysis exhibits anisotropic behavior in the projected spin contributions of CrO2 assigned to a strong magnetic dipole term T(z), consistent with an intrinsic magnetic easy axis behavior along the CrO2 [001] axis. A reduced projected isotropic Cr 3d spin moment has been interpreted in terms of hybridization with oxygen.


Effects of Commercial Exergames and Conventional Exercises on Improving Executive Functions in Children and Adolescents: Meta-Analysis of Randomized Controlled Trials.
Exergames are promising exercise tools for improving health. To the best of our knowledge, no systematic review has compared the effects of commercial exergames and conventional exercises on improving executive functions (EFs) in children and adolescents. This study aimed to investigate the effects of commercial exergames and conventional exercises on improving EFs in children and adolescents. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, 5 randomized controlled trial (RCT) databases (PubMed, Web of Science, Scopus, PsycINFO, and SPORTDiscus) were searched from their inception to July 7, 2022, to identify relevant RCTs. The Cochrane Collaboration tool was used to evaluate the risk of bias for each study. GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) was used to evaluate the overall quality of evidence. In total, 8 RCTs including 435 children and adolescents were included in the analysis. Commercial exergames had no significant benefit on overall EFs compared to conventional exercises (Hedges g=1.464, 95% CI -0.352 to 3.280; P=.06). For core EFs, there was no evidence to suggest that commercial exergames are more beneficial for improving cognitive flexibility (g=0.906, 95% CI -0.274 to 2.086; P=.13), inhibitory control (g=1.323, 95% CI -0.398 to 3.044; P=.13), or working memory (g=2.420, 95% CI -1.199 to 6.038; P=.19) than conventional exercises. We rated the evidence for overall EFs, cognitive flexibility, inhibitory control, and working memory as being of very low quality due to inconsistency (large heterogeneity) and imprecision (low number of people). Additionally, no effects of the intervention were observed in the acute and chronic groups. We do not have strong evidence to support the benefit of commercial exergaming on EFs because we did not observe a Hedges g close to 0 with tight CIs. Further research is needed to confirm this hypothesis. PROSPERO CRD42022324111; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=324111.


The Aachen Mobility and Balance Index to measure physiological falls risk: a comparison with the Tinetti POMA Scale.
The most commonly used mobility assessments for screening risk of falls among older adults are rating scales such as the Tinetti performance oriented mobility assessment (POMA). However, its correlation with falls is not always predictable and disadvantages of the scale include difficulty to assess many of the items on a 3-point scale and poor specificity. The purpose of this study was to describe the ability of the new Aachen Mobility and Balance Index (AMBI) to discriminate between subjects with a fall history and subjects without such events in comparison to the Tinetti POMA Scale. For this prospective cohort study, 24 participants in the study group and 10 in the control group were selected from a population of patients in our hospital who had met the stringent inclusion criteria. Both groups completed the Tinetti POMA Scale (gait and balance component) and the AMBI (tandem stance, tandem walk, ten-meter-walk-test, sit-to-stand with five repetitions, 360° turns, timed-up-and-go-test and measurement of the dominant hand grip strength). A history of falls and hospitalization in the past year were evaluated retrospectively. The relationships among the mobility tests were examined with Bland-Altmananalysis. Receiver-operated characteristics curves, sensitivity and specificity were calculated. The study showed a strong negative correlation between the AMBI (17 points max., highest fall risk) and Tinetti POMA Scale (28 points max., lowest fall risk; r = -0.78, p < 0.001) with an excellent discrimination between community-dwelling older people and a younger control group. However, there were no differences in any of the mobility and balance measurements between participants with and without a fall history with equal characteristics in test comparison (AMBI vs. Tinetti POMA Scale: AUC 0.570 vs. 0.598; p = 0.762). The Tinetti POMA Scale (cut-off <20 points) showed a sensitivity of 0.45 and a specificity of 0.69, the AMBI a sensitivity of 0.64 and a specificity of 0.46 (cut-off >5 points). The AMBI comprises mobility and balance tasks with increasing difficulty as well as a measurement of the dominant hand-grip strength. Its ability to identify fallers was comparable to the Tinetti POMA Scale. However, both measurement sets showed shortcomings in discrimination between fallers and non-fallers based on a self-reported retrospective falls-status.


α-Synuclein Alters Toll-Like Receptor Expression.
Parkinson's disease, an age-related neurodegenerative disorder, is characterized by the loss of dopamine neurons in the substantia nigra, the accumulation of α-synuclein in Lewy bodies and neurites, and neuroinflammation. While the exact etiology of sporadic Parkinson's disease remains elusive, a growing body of evidence suggests that misfolded α-synuclein promotes inflammation and oxidative stress resulting in neurodegeneration. α-Synuclein has been directly linked to microglial activation in vitro and increased numbers of activated microglia have been reported in an α-synuclein overexpressing mouse model prior to neuronal loss. However, the mechanism by which α-synuclein incites microglial activation has not been fully described. Microglial activation is governed in part, by pattern recognition receptors that detect foreign material and additionally recognize changes in homeostatic cellular conditions. Upon proinflammatory pathway initiation, activated microglia contribute to oxidative stress through release of cytokines, nitric oxide, and other reactive oxygen species, which may adversely impact adjacent neurons. Here we show that microglia are directly activated by α-synuclein in a classical activation pathway that includes alterations in the expression of toll-like receptors. These data suggest that α-synuclein can act as a danger-associated molecular pattern.


Quantitative in vitro assessment of phototoxicity using a human skin model, Skin2.
The ability to accurately predict the phototoxic potential of personal and skin care products remains a key element in assessing the safety of premarketed products. To find a reliable in vitro alternative test for photoirritancy, the European Commission and the European Cosmetic Association are conducting a 3-year, European validation study. Based on the results of this study, an in vitro photoirritancy method will be selected for incorporation into new international guidelines for photoirritancy testing. As a part of this study, Skin2, a cultured human skin system, was used to evaluate the phototoxic potential of chemicals with known photoirritative properties. The Skin2 ZK1351, a 3-dimensional co-culture system, consists of dermal fibroblasts and a multilayered epidermis comprising differentiated keratinocytes. This product line has previously been used to evaluate the irritative potential of topically applied ingredients and products. In this study, various concentrations of the test chemicals were applied to the epidermal side of the Skin2 tissue for contact times of 1 h or 24 h and then the tissue was exposed to 2.9 J/cm2 of ultraviolet A (UVA) radiation. Treated but nonirradiated tissues were also assayed to predict the cytotoxic potential of the test chemicals, which could mask the phototoxic reaction. After exposure, the tissue substrates were rinsed free of test chemicals and allowed to recover for 24 h. Following this incubation, the MTT reduction assay was used to assess cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)


Contributory factors to traffic crashes at signalized intersections in Hong Kong.
Efficient geometric design and signal timing not only improve operational performance at signalized intersections by expanding capacity and reducing traffic delays, but also result in an appreciable reduction in traffic conflicts, and thus better road safety. Information on the incidence of crashes, traffic flow, geometric design, road environment, and traffic control at 262 signalized intersections in Hong Kong during 2002 and 2003 are incorporated into a crash prediction model. Poisson regression and negative binomial regression are used to quantify the influence of possible contributory factors on the incidence of killed and severe injury (KSI) crashes and slight injury crashes, respectively, while possible interventions by traffic flow are controlled. The results for the incidence of slight injury crashes reveal that the road environment, degree of curvature, and presence of tram stops are significant factors, and that traffic volume has a diminishing effect on the crash risk. The presence of tram stops, number of pedestrian streams, road environment, proportion of commercial vehicles, average lane width, and degree of curvature increase the risk of KSI crashes, but the effect of traffic volume is negligible.


[Hepatitis B and C virus infection and liver dysfunction in patients receiving chemotherapy].
Liver dysfunction and reactivation of hepatitis virus are well-described complications in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. However, there has been just few reports on such complications and on the preemptive use of lamivudine in Korea. The aims of this study were to determine the prevalence of hepatitis B and C virus infection and the incidence of liver dysfunction in patients with malignancies who receive chemotherapy, to determine the reactivation rate of hepatitis B virus (HBV) in those patients, to evaluate the effect of preemptive use of lamivudine in patients with HBV infection. Among 1,477 patients who received chemotherapy due to various malignancies from January 2000 to June 2005, 668 patients with incomplete viral studies or hepatitis related malignancy were excluded. A retrospective study was conducted by reviewing the medical records of remaining 809 patients. The overall prevalence rate of hepatitis B or C virus in patients receiving chemotherapy was 6.55% (53/809). The incidences of liver dysfunction was not significantly different between hepatitis virus positive group and negative group. Reactivation rate of hepatitis B or C virus after chemotherapy was 15% (6/40). In all patients who received lamivudine therapy, aspartate aminotransferase and alanine aminotransferase level were normalized and HBV DNA negativity achieved. The existence of hepatitis virus in patients receiving chemotherapy did not significantly influence the development of severe liver dysfunction, owing probably to the lamivudine therapy. Further prospective studies are required to ascertain the reactivation of hepatitis virus in patients receiving chemotherapy and the need for prophylactic lamivudine therapy in HBV positive patients.


Water permeability of thin lipid membranes.
The osmotic permeability coefficient, P(f), and the tagged water permeability coefficient, P(d), were determined for thin (<100 A) lipid membranes formed from ox brain lipids plus DL-alpha-tocopherol; their value of approximately 1 x 10(-3) cm/sec is within the range reported for plasma membranes. It was established that P(f) = P(d). Other reports that P(f) > P(d) can be attributed to the presence of unstirred layers in the experimental determination of P(d). Thus, there is no evidence for the existence of aqueous pores in these thin phospholipid membranes. The adsorption onto the membrane of a protein that lowers its electrical resistance by a factor of 10(3) was found not to affect its water permeability; however, glucose and sucrose were found to interact with the membrane to modify P(f). Possible mechanisms of water transport across these films are discussed, together with the implications of data obtained on these structures for plasma membranes.


Mathematically gifted male adolescents activate a unique brain network during mental rotation.
Mental rotation involves the creation and manipulation of internal images, with the later being particularly useful cognitive capacities when applied to high-level mathematical thinking and reasoning. Many neuroimaging studies have demonstrated mental rotation to be mediated primarily by the parietal lobes, particularly on the right side. Here, we use fMRI to show for the first time that when performing 3-dimensional mental rotations, mathematically gifted male adolescents engage a qualitatively different brain network than those of average math ability, one that involves bilateral activation of the parietal lobes and frontal cortex, along with heightened activation of the anterior cingulate. Reliance on the processing characteristics of this uniquely bilateral system and the interplay of these anterior/posterior regions may be contributors to their mathematical precocity.


Gender and theory of mind in preschoolers' group effort: evidence for timing differences behind children's earliest social loafing.
This study explored mental state reasoning within the context of group effort and possible differences in development between boys and girls. Preschool children (59 girls, 47 boys) were assessed for theory of mind (ToM) ability using classic false belief tests. Children participated in group effort conditions that alternated from one condition, where individual effort was transparent and obvious, to one where individual effort remained anonymous. The aim was to investigate if emergent mental state reasoning, after controlling for age, was associated with the well-known phenomenon of reduced effort in group tasks ("social loafing"). Girls had slightly higher ToM scores and social loafing than boys. Hierarchical regression, controlling for age, indicated that understanding of others' false beliefs uniquely predicted social loafing and interacted weakly with gender status.


Exhaustion of the CD8+ T Cell Compartment in Patients with Mutations in Phosphoinositide 3-Kinase Delta.
Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them with healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable with HIV patients with decreased naive CD4+ and CD8+ T cells and increased effector CD8+ T cells. Like in HIV+ patients, expression of activation markers and inhibitory receptors CD160, CD244, and programmed death receptor (PD)-1 on CD8+ T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8+ T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8+ T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8+ T cells from APDS patients enhanced in vitro proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8+ T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV.


Antenatal survey of women's birthing choices in Qatar.
Objectives Attitudes towards labour care and women's choices for their preferred mode of delivery are documented in studies from the around the world, however less is known about women's birth choices in the Middle East. This study was designed with the aim of exploring beliefs and attitudes in this region. Methods Voluntary participation in an ethics-approved survey was offered to pregnant women attending the antenatal clinic at Sidra Medicine from August 2018 to January 2019 with no exclusion criteria. Results Of the 346 respondents, 58.1% were Arabic and the remainder expatriates. This group composition allowed comparison between women native and non-native to the Gulf region. Arabic and non-Arabic women differed significantly in previous birth experiences: the Arabs had had more doctor-led deliveries (45 vs. 34%), epidurals (56.6 vs. 45%) and episiotomies (65.7 vs. 54%). 70.2% of the respondents chose a normal delivery as their preferred birth mode though a smaller majority of the Arabic subgroup did (63.2 %). 60.4% preferred delivery by doctors and longer hospital stays (47.6), more so Arabic participants (64.7 and 68.6 %). Significantly less Arabs, would choose husbands as birth partners (51.2 vs. 86.2%) and more expressed a gender preference for doctors. Other group choices are presented. Conclusions Though women in this region made comparable choices about mode of delivery as their Western counterparts, they demonstrated an expectation of a culturally distinct and more medicalized approach to care in labour. The findings highlight the need for further studies to inform regional obstetric care and health education interventions as well as tailoring maternity care services.


Marijuana use and mortality following orthopedic surgical procedures.
Background: The association between marijuana use and surgical procedures is a matter of increasing societal relevance that has not been well studied in the literature. The primary aim of this study is to evaluate the relationship between marijuana use and in-hospital mortality, as well as to assess associated comorbidities in patients undergoing commonly billed orthopedic surgeries. Methods: The National Inpatient Sample (NIS) database from 2010 to 2014 was used to determine the odds ratios for the associations between marijuana use and in-hospital mortality, heart failure (HF), stroke, and cardiac disease (CD) in patients undergoing 5 common orthopedic procedures: total hip (THA), total knee (TKA), and total shoulder (TSA) arthroplasties, spinal fusion, and traumatic femur fracture fixation. Results: Of 9,561,963 patients who underwent one of the 5 selected procedures in the 4-year period, 26,416 (0.28%) were identified with a diagnosis of marijuana use disorder. In hip and knee arthroplasty patients, marijuana use was associated with decreased odds of mortality compared with no marijuana use (P < .0001) and increased odds of HF (P = .018), stroke (P = .0068), and CD (P = .0123). Traumatic femur fixation patients had the highest prevalence of marijuana use (0.70%), which was associated with decreased odds of mortality (P = .0483), HF (P = .0076), and CD (P = .0003). For spinal fusions, marijuana use was associated with increased odds of stroke (P < .0001) and CD (P < .0001). Marijuana use in patients undergoing total shoulder arthroplasty was associated with decreased odds of mortality (P < .001) and stroke (P < .001). Conclusions: In this study, marijuana use was associated with decreased mortality in patients undergoing THA, TKA, TSA, and traumatic femur fixation, although the significance of these findings remains unclear. More research is needed to provide insight into these associations in a growing surgical population.


GJB2 mutations in the Swiss hearing impaired.
Mutations in the GJB2 gene encoding connexin 26 (Cx26) protein are a major cause for nonsyndromic autosomal recessive and sporadic deafness. However, its contribution to hearing impairment in Switzerland remains undefined. To determine the frequency and type of GJB2 mutations in the Swiss hearing-impaired population diagnosed under the age of 2 yr and at 2 yr and older and to assess the effectiveness of denaturing high-performance liquid chromatography (DHPLC) in screening for mutation in GJB2. Thirty-four patients with hearing impairment underwent mutation screening of the single coding exon of GJB2 with DHPLC followed by bidirectional sequencing to identify sequence alterations. GJB2 mutations were more common in children diagnosed with hearing impairment under the age of 2 yr compared to the group 2 yr and older. In patients under age 2 yr, 9 of 20 (45%) harbored 13 GJB2 mutations including a common 313del14nt mutation; four of these patients were homozygous or compound heterozygous for GJB2 mutations. In contrast, 2 of 14 patients in the 2 yr and older group (14%) had a single mutation in GJB2. The 35delG mutation was exclusively found in 5 patients under the age of 2 yr. DHPLC for mutation screening was 100% sensitive and 83% specific for detecting sequence alterations in GJB2. In Switzerland, GJB2 mutations are a major cause of nonsyndromic hearing impairment in children under the age of 2. Similar to other populations, GJB2 mutations are uncommon in the affected Swiss patients identified after 2 yr. Although 35delG mutation is common in the hearing-impaired children under the age of 2, it was absent in patients diagnosed with hearing impairment after the age of 2. DHPLC is a highly sensitive tool for detection of GJB2 mutations.


Effect of Ethylcellulose on the Rheology and Mechanical Heterogeneity of Asphaltene Films at the Oil-Water Interface.
Asphaltenes are surface-active molecules that exist naturally in crude oil. They adsorb at the water-oil interface and form viscoelastic interfacial films that stabilize emulsion droplets, making water-oil separation extremely challenging. There is, thus, a need for chemical demulsifiers to disrupt the interfacial asphaltene films, and, thereby, facilitate water-oil separation. Here, we examine ethylcellulose (EC) as a model demulsifier and measure its impact on the interfacial properties of asphaltene films using interfacial shear microrheology. When EC is mixed with an oil and asphaltene solution, it retards the interfacial stiffening that occurs between the oil phase in contact with a water phase. Moreover, EC introduces relatively weak regions within the film. When EC is introduced to a pre-existing asphaltene film, the stiffness of the films decreases abruptly and significantly. Direct visualization of interfacial dynamics further reveals that EC acts inhomogeneously, and that relatively soft regions in the initial film are seen to expand. This mechanism likely impacts emulsion destabilization and provides new insight to the process of demulsification.


Identification of a Profile of Neutrophil-Derived Granule Proteins in the Surface of Gold Nanoparticles after Their Interaction with Human Breast Cancer Sera.
It is well known that the interaction of a nanomaterial with a biological fluid leads to the formation of a protein corona (PC) surrounding the nanomaterial. Using standard blood analyses, alterations in protein patterns are difficult to detect. PC acts as a "nano-concentrator" of serum proteins with affinity for nanoparticles' surface. Consequently, characterization of PC could allow detection of otherwise undetectable changes in protein concentration at an early stage of a disease, such as breast cancer (BC). Here, we employed gold nanoparticles (AuNPsdiameter: 10.02 ± 0.91 nm) as an enrichment platform to analyze the human serum proteome of BC patients (n = 42) and healthy controls (n = 42). Importantly, the analysis of the PC formed around AuNPs after their interaction with serum samples of BC patients showed a profile of proteins that could differentiate breast cancer patients from healthy controls. These proteins developed a significant role in the immune and/or innate immune system, some of them being neutrophil-derived granule proteins. The analysis of the PC also revealed serum proteome alterations at the subtype level.


Intracholecystic Papillary Neoplasm Localized to the Cystic Duct: A Case Report.
Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a premalignant lesion. An ICPN arising from the cystic duct is rare. A woman in her 60s exhibited dilatation of the common bile duct on computed tomography (CT) performed for screening of respiratory disease. The CT revealed an enhancing mass, 3.3 cm in diameter, in the cystic duct. Endoscopic ultrasonography showed a well-demarcated, hyperechoic mass in the dilated cystic duct. Endoscopic retrograde cholangiography showed that the common bile duct was slightly retracted by the dilated cystic duct. Cytological analysis of the bile juice did not show any evidence of malignancy. She was diagnosed with a cystic bile duct tumor suggestive of ICPN. Cholecystectomy, resection of the extrahepatic bile duct, and lymph node dissection were performed. Macroscopically, the papillary-proliferated tumor was localized to the cystic duct. No critical lesions were evident in the common bile duct. Histologically, the tumor in the cystic duct showed intraluminal growth with a papillary configuration without malignancy. Based on these findings, the tumor was diagnosed as an ICPN. We encountered a rare case of ICPN localized to the cystic duct of the gallbladder.


Uterine adenocarcinoma with generalised metastasis in a bottlenose dolphin Tursiops truncatus from northern Patagonia, Argentina.
An endometrial adenocarcinoma with areas of squamous differentiation and generalised metastasis was observed in a bottlenose dolphin Tursiops truncatus stranded in northern Patagonia in July 1997. This is the second report of a uterine adenocarcinoma in a free-living cetacean and the first in a Delphinidae. This neoplasm likely compromised reproduction for several years. In addition, the dolphin presented tattoo-like skin lesions and its digestive tract was infested by Anisakis simplex, Pseudoterranova sp., Braunina cordiformis and Corynosoma australe.


Dietary pectin, but not cellulose, influences Heligmosomoides polygyrus (Nematoda) reproduction and intestinal morphology in the mouse.
Dietary texture has been reported to influence parasite establishment and survival, but to what degree this relationship is modified by either the type or quantity of dietary fibre is unknown. Using a 2 x 4 factorial design, we explored the relationship between fibre type (soluble pectin vs insoluble = cellulose) and fibre quantity (0, 5, 10 and 20% by dry weight) on parasitic outcomes in BALB/c mice infected with 100 Heligmosomoides polygyrus (Nematoda) larvae. Pectin, but not cellulose, exerted a significant effect on parasite egg production. Following in vitro culture of female worms, increasing levels of dietary pectin were associated with increasing release of eggs. Yet this pattern was not observed in vivo, where per capita egg production peaked at the 10% pectin concentration, but was very low in mice fed 20% pectin. Parasite establishment was elevated in mice fed 20% pectin, but was unaffected by cellulose concentration. Neither type nor quantity of fibre affected H. polygyrus survival or spatial distribution along the gastrointestinal tract. To what degree differences in parasite establishment and reproduction could be attributed to the marked effects of pectin on gut morphology (increased intestinal length, villus length, mucosa thickness and villus/crypt ratio) requires further exploration. Our data indicate that cellulose is preferable to pectin as the source of fibre for experimental diets as cellulose did not affect H. polygyrus establishment, reproduction or survival during a 4-week primary infection.


Demonstration of rotavirus and rotavirus-like virus in the intestinal contents of diarrheic pheasant chicks.
Intestinal content samples from four flocks of pheasant chicks experiencing diarrhea and increased mortality were evaluated using immune electron microscopy and genome electropherotyping techniques. Enteric viruses serologically and electropherotypically indistinguishable from turkey rotaviruses and turkey rotavirus-like viruses (RVLVs) were detected. Rotavirus-only infections, RVLV-only infections, and simultaneous rotavirus and RVLV infections were demonstrated in these flocks.


Combined therapy with topotecan and gemcitabine in patients with inoperable or metastatic non-small cell lung cancer.
We conducted a phase I/II trial of topotecan combined with gemcitabine in patients with metastatic or unresectable non-small cell lung cancer (NSCLC) based on preclinical data showing in vitro synergy against an established lung adenocarcinoma cell line. The aim was to determine the maximally tolerated dose (MTD) of topotecan when the gemcitabine dose is held constant, as well the dose limiting toxicity (DLTs) of this combination in NSCLC patients. Twenty-four patients with stage IIIB or IV NSCLC were treated weekly times 3 with a week break with gemcitabine (1250 mg/m2 over 30 minutes) and topotecan (30 minutes) at varying doses. The starting dose of topotecan was 1.0 mg/m2 and doses were escalated in 0.25-mg/m2 increments until the MTD was achieved. The MTD of gemcitabine/topotecan was 1250 mg/m2 of gemcitabine and 2.00 mg/m2 of topotecan (level 5). Neutropenia was the DLT. Few nonhematologic toxicities were observed. There were 5 (21%) partial responses among 24 patients. The median survival was 22 weeks. Two patients have had prolonged (> 2 year) survival. The combination of gemcitabine and topotecan seems to be active against NSCLC with acceptable hematologic toxicity and minimal nonhematologic toxicity. The recommended dose for further study is 1250 mg/m2 of gemcitabine (days 1, 8, 15) and 2.0 mg/m2 of topotecan (days 1, 8, 15) administered every 28 days.


Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.
Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells. We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action. CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells. CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks.


[Measurements of vancomycin concentrations in the blood - a method of personalization the antibiotic therapy in patients with chronic kidney disease].
Therapeutic Drug Monitoring is a recognized method of personalizing treatment, having particular application in patients with chronic kidney disease who have frequent infections, requiring administration of vancomycin. International guidelines indicate the need to adjust the dose of the drug to the state of renal function. The recommended therapeutic ranges of minimum and maximum levels should be achieved in order to increase the effectiveness and safety of treatment. The aim of this study was to evaluate the usefulness of measuring the concentration of vancomycin in patients with chronic kidney disease due to bacterial infection. The study included 96 adult patients with chronic kidney disease of varying severity treated with vancomycin Patients were divided into 3 groups: treated by haemodialysis (hd), after renal transplantations (ktx), do not require renal replacement therapy (nef). In subjects were examined the minimum and maximum concentrations of vancomycin in steady-state and were compared with recommended therapeutic ranges. Statistically significant decrease of inflammatory markers was observed only in patients treated with dialysis. In the other groups not significant changes in values of inflammatory parameters were confirmed. Trough concentrations of vancomycin marked in patients were consistent with the recommendation of EUCAST, but exceeded the value recommended by the manufacturers of the drug. Considering absolute values of the minimum concentrations, only about 50% of patients achieved the therapeutic range (58% for recommendation EUCAST and 36% for the manufacturer's instructions). Peak concentration values indicated in dialyzed patients were below the prescribed range of 20-50 mg/l and averaged 17.7 mg / l. In the other subgroups they were correct. The rating of the absolute values of the peak concentrations of vancomycin also showed that only 46% (64% in the ktx, 30% - hd and 53% - nef) was within the recommended range, while 50% were classified as concentrations of sub-therapeutic (36% in the ktx, 42% of the nef group and 65% in hd). Vancomycin concentrations measured in patients with chronic kidney disease, both minimum and maximum, were not fully comply with the recommended therapeutic ranges, despite the use of doses determined based on a calculation of glomerular filtration rate. This points to the need for particularly careful monitoring of therapy and analysis of antibiotic concentrations to improve the effectiveness and reduce the incidence of undesirable consequences of treatment.


Curious structure in "canonical" alanine-based peptides.
We have performed all atom simulations of blocked peptides of the form (AAXAA)3, where X = Gln, Asn, Glu, Asp, Arg, and Lys with explicit water molecules to examine the interactions between side chains spaced i,i-5 in the sequence. Although side chains in this i,i-5 arrangement are commonly believed to be noninteracting, we have observed the formation of unusual i,i-5 main chain hydrogen bonding in such sequences with positively charged residues (Lys) as well as polar uncharged groups (Gln). Our results are consistent with the unusual percentage of hydrogen bonding curves produced by amide exchange measurements on the well-studied sequence acetyl-(AAQAA)3-amide in water (Shalongo, W., Dugad, L., Stellwagen, E. J. Am. Chem. Soc. 116:8288-8293, 1994). Analysis of our simulations indicated that the glutamine side chain showed the greatest propensity to support pi helix formation and that the i,i-5 intramolecular hydrogen bonds were stabilized by water-bridging side chain interactions. This intermittent formation of the unusual pi helix structure was observed for up to 23% of the total simulation time in some residues in (AAQAA)3. Control studies on peptides with glutamine side chains spaced i,i-3, i,i-4 and i,i-6 did not reveal similar unique structures, providing stronger evidence for the unique role side chain interactions with i,i-5 spacing.


Novel mechanism of metabolic co-regulation coordinates the biosynthesis of secondary metabolites in Pseudomonas protegens.
Metabolic co-regulation between biosynthetic pathways for secondary metabolites is common in microbes and can play an important role in microbial interactions. Here, we describe a novel mechanism of metabolic co-regulation in which an intermediate in one pathway is converted into signals that activate a second pathway. Our study focused on the co-regulation of 2,4-diacetylphloroglucinol (DAPG) and pyoluteorin, two antimicrobial metabolites produced by the soil bacterium Pseudomonas protegens. We show that an intermediate in DAPG biosynthesis, phloroglucinol, is transformed by a halogenase encoded in the pyoluteorin gene cluster into mono- and di-chlorinated phloroglucinols. The chlorinated phloroglucinols function as intra- and inter-cellular signals that induce the expression of pyoluteorin biosynthetic genes, pyoluteorin production, and pyoluteorin-mediated inhibition of the plant-pathogenic bacterium Erwinia amylovora. This metabolic co-regulation provides a strategy for P. protegens to optimize the deployment of secondary metabolites with distinct roles in cooperative and competitive microbial interactions.


The influence of family's participation in recreational sports on its resilience and communication facilitation.
This study aims to define the influence of the motive and degree of family's participation in recreational sports on its resilience and communication facilitation. Of members of sports centers in Seoul and Gyeonggi areas, 202 people who participated in recreational sports together with their family members were sampled as the population. Input data were computerized for analysis, using PASW 22.0 and AMOS 18.0 programs. Data statistical processing methods of reliability analysis and structural equation modeling were used, and the results are outlined as follows. Motive for family's participation in recreational sports did not influence family resilience and communication facilitation. However, the degree of family's participation in recreational sports influenced family resilience and communication facilitation. Degree of family's participation in recreational sports did not directly influence communication facilitation, but boosted family resilience, further facilitating family communication. In other words, family resilience is an important parameter between recreational sports and communication facilitation.


Rac1 is required for matrix metalloproteinase 13 production by chondrocytes in response to fibronectin fragments.
Matrix fragments, including fibronectin (FN) fragments, accumulate during the development of osteoarthritis (OA), stimulating the production of chondrocyte matrix metalloproteinase (MMP). The objective of this study was to determine the role of the small GTPase Rac1 in chondrocyte signaling stimulated by FN fragments, which results in MMP-13 production. Normal human cartilage was obtained from tissue donors and OA cartilage from knee arthroplasty specimens. Rac1 activity was modulated with a chemical inhibitor, by knockdown with small interfering RNA (siRNA), or with constitutively active Rac or dominant-negative Rac adenovirus. Cells were treated with FN fragments, with or without epidermal growth factor (EGF) or transforming growth factor α (TGFα), which are known activators of Rac. Rac1 activity was measured with a colorimetric activity enzyme-linked immunosorbent assay, a pulldown assay, and immunostaining with a monoclonal antibody against active Rac. Chemical inhibition of Rac1, as well as knockdown by siRNA and expression of dominant-negative Rac, blocked FN fragment-stimulated MMP-13 production, while expression of constitutively active Rac increased MMP-13 production. Inhibition of Rho-associated kinase had no effect. EGF and TGFα, but not FN fragments, increased Rac1 activity and promoted the increase in MMP-13 above that achieved by stimulation with FN fragments alone. Active Rac was detected in OA cartilage by immunostaining. Rac1 is required for FN fragment-induced signaling that results in increased MMP-13 production. EGF receptor ligands, which activate Rac, can promote this effect. The presence of active Rac in OA cartilage and the ability of Rac to stimulate MMP-13 production suggest that it could play a role in the cartilage matrix destruction seen in OA.


Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine.
The antiviral lamivudine is cleared predominantly by the kidney with a relevant contribution of renal tubular secretion. It is not clear which drug transporters mediate lamivudine renal secretion. Our aim was to investigate lamivudine as substrate of the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins MATE1 and MATE2-K. Uptake experiments were performed in OCT2, MATE1, or MATE2-K single-transfected human embryonic kidney 293 (HEK) cells. Transcellular transport experiments were performed in OCT2 and/or MATE1 single- or double-transfected Madin-Darby canine kidney II (MDCK) cells grown on transwell filters. Lamivudine uptake was significantly increased in HEK-OCT2, HEK-MATE1, and HEK-MATE2-K cells compared to control cells. In transcellular experiments, OCT2 located in the basolateral membrane had no effect on transcellular lamivudine transport. MATE1 located in the apical membrane decreased intracellular concentrations and increased transcellular transport of lamivudine from the basal to the apical compartment. MATE1- or MATE2-K-mediated transport was increased by an oppositely directed pH gradient. Several simultaneously administered drugs inhibited OCT2- or MATE2-K-mediated lamivudine uptake. The strongest inhibitors were carvedilol for OCT2 and trimethoprim for MATE2-K (inhibition by 96.3 and 83.7% at 15 μM, respectively, p<0.001). Trimethoprim inhibited OCT2- and MATE2-K-mediated lamivudine uptake with IC₅₀ values of 13.2 and 0.66 μM, respectively. Transcellular lamivudine transport in OCT2-MATE1 double-transfected cells was inhibited by trimethoprim with an IC₅₀ value of 6.9 μM. Lamivudine is a substrate of renal drug transporters OCT2, MATE1, and MATE2-K. Concomitant administration of drugs that inhibit these transporters could decrease renal clearance of lamivudine.


Preserved cardiac performance with reduced left ventricular mass in conscious exercising spontaneously hypertensive rats.
To investigate whether cardiovascular performance can be modified beneficially with left ventricular hypertrophy reversal and whether the associated sudden afterload increases may adversely affect overall cardiac performance. We studied cardiovascular performance with thermodilution techniques at rest and during maximal treadmill exercise after 3 weeks' treatment with the angiotensin converting enzyme inhibitor quinapril (3 mg/kg per day) in 19 male spontaneously hypertensive rats (SHR) aged 20 weeks. Left ventricular mass was reduced significantly, without impairment of exercise performance, demonstrating that left ventricular hypertrophy reversal benefited or at least did not hinder cardiovascular adaptation to physiologic exercise in the SHR. Moreover, decreasing the afterload did not further improve the performance after the reversal of left ventricular hypertrophy.


[Avascular necrosis of the femoral head:correlation of imaging and pathological findings].
To investigate the relationship between imaging and pathological findings of avascular necrotic of the femoral head (ANFH). A comparison among of conventional radiography, computerized tomography (CT), magnetic resonance imaging (MRI), gross section and pathological examinations was performed in 20 femoral heads in 15 patients undergoing total hip replacement for established ANFH. ANFH involved the anterosuperior aspect of femoral head in all hips. Necrotic femoral heads consisted of cartilage, necrotic area, reactive repaired area and extralesional area. The reactive repaired area surrounded necrotic area. Imaging findings: 1) on conventional radiography and CT, as compared with the extralesional area, the necrotic area appeared to be of an equal density (11), a lower density (7) and a higher density (2) On MRI, the necrotic areas revealed adipose intensity (3), blood like intensity (1), aquatic intensity (2), fibrous intensity (9) and non-homogeneous intensity (5); 2) the reactive repaired area separated the necrotic and extralesional areas. Both on plain radiography and CT, the reactive repaired area showed a sclerotic band surrounding the necrotic area and a hypo-density inner line adjacent to sclerotic band was seen in 11 femoral heads on CT and 7 on conventional radiography. A band of low signal in the proliferative zone was seen on MRI in all hips and a rim of high signal intensity inside the low-signal margin (double-line sign) was seen in 3 hips on T2W images. Conventional radiography, CT and MRI can display the grossly discernable necrotic, reactive repaired and extralesional areas accurately. Characteristic imaging findings are observed in the reactive repaired area.


Factors influencing the self-perceived competencies in spiritual care of nurses in the long-term care facilities.
To identify key factors influencing institutional nurses' self-perceived competencies in spiritual care. In the past decade, interest in spiritual care has been increasing; however, in long-term care facilities, limited knowledge is available about nurses' competencies in spiritual care. The cross-sectional study was conducted with 202 nurses in 11 long-term care facilities. Data were collected in a survey using the Spirituality and Spiritual Care Rating Scale, the Nurse Spiritual Care Therapeutics Scale, the Spiritual Care Competence Scale and demographic questions. Data were analysed using stepwise linear regression. Study findings revealed that nurses' perceptions of spirituality and spiritual care, frequency of spiritual care provision and self-satisfaction with the spiritual care given all significantly predicted overall spiritual care competence, which together explain 58% of the total variance. Improving nurses' perceptions of spirituality and spiritual care and encouraging the performance of spiritual care may be an effective pathway to enhance the spiritual care competence of institutional nurses. Additional continuing education on spiritual care topics and the establishment of clear guidance and support from institutional administrators are required to enable nurses to deal with spiritual issues as they arise and improve the quality of holistic care.


Effect of water-soluble carbohydrate content in orchardgrass pasture on grazing time and rumen fermentation in dairy cows.
Two experiments were conducted to clarify the effect of water-soluble carbohydrate (WSC) content in orchardgrass pasture on the diurnal distribution of grazing time. Six ruminally cannulated, non-lactating dairy cows were grazed on either of two pastures with different orchardgrass cultivars containing low WSC (LWSC; cultivar: 'Hokkai 28') or high WSC (HWSC; cultivar: 'Harunemidori'). The cows were grazed in morning and evening sessions in experiment 1, whereas the cows were grazed throughout the day in experiment 2. In experiment 1, grazing time of the cows on HWSC was longer than that of the cows on LWSC (P < 0.01). This difference was larger in the morning session than in the evening session (pasture × grazing session: P < 0.05). Effects on herbage intake were similar to those on grazing time. In experiment 2, daily total grazing time was longer for the cows on HWSC than for those on LWSC (P < 0.05). The cows on HWSC spent a longer time grazing than those on LWSC in the morning between 03.00 and 09.00 hours (P < 0.01). The results indicated that prolonged grazing time in the period between dawn and early morning could increase daily herbage intake in cows grazed on pastures of orchardgrass cultivars with high-WSC content.


Effects of nuclear factor-kappaB small interfering RNA on posterior capsule opacification.
The effects of small interfering (si)RNA of nuclear factor kappa B (NF-kappaB) on the development of posterior capsule opacification (PCO) were investigated both in vitro and in vivo in rabbits. After application of p105 NF-kappaB siRNA to lens epithelial cells (LECs), Western blot analyses were performed to detect p105 and p50 NF-kappaB and a scratch assay was used to determine cell migration. In the capsular bag model, immunocytochemistry was performed to determine expression of p50 NF-kappaB and Western blot analyses for the presence of epithelial-to-mesenchymal transition (EMT) markers. Two sequences of p105 NF-kappaB siRNA were used in cataract surgery in 15 New Zealand White rabbits. PCO grading was conducted by slit lamp biomicroscopy and a computer-based PCO grading program. One month after surgery, the eyes of the rabbits were enucleated, and sections were prepared for examination of the posterior capsule and other ocular tissues by light microscopy. Application of p105 NF-kappaB siRNA to LECs decreased p105 NF-kappaB and p50 NF-kappaB expression, and migration of LECs was shown to be inhibited on the scratch assay. In the capsular bag model, the LEC count was significantly decreased, and immunocytochemistry showed reduced p50 NF-kappaB expression on the posterior capsule. EMT markers were significantly decreased after application of p105 NF-kappaB siRNA in the capsular bag model. In the in vivo study in rabbits, p105 NF-kappaB siRNA effectively decreased PCO, as determined by both slit lamp examination and the PCO grading program. NF-kappaB seems to be related to migration and proliferation of LECs. NF-kappaB siRNA was effective in inhibiting the migration and proliferation of LECs in vitro and decreased PCO formation after cataract surgery in an in vivo rabbit model.


Amplification of different ColE1 plasmids in an Escherichia coli relA strain.
Amino acid starved cells of an E. coli relA strain accumulate a large amount of pBR322 plasmid DNA. In this study ColE1 related plasmids of different copy number and size including a high copy number plasmid mutant of pBR322 were amplified in a relA strain of E. coli K-12 under amino acid limitation in order to determine the upper plasmid level in amino acid starved cells. In all cases we measured a 4 to 6 fold increase of the plasmid copy number in comparison to log-phase cells independent of the size, the number of origins per plasmid molecule or the copy number in log-phase cells. The plasmid copy number in amino acid starved cells varies from about 200 (pBR322-dimer) to about 2000 (high copy number plasmid pERIII-BPL4, see Boros et al. 1986). Rop+ and rop- plasmids show the same amplification rate under the used conditions.


Current evidence for endovascular therapy in stroke and remaining uncertainties.
Class 1 level A evidence now supports endovascular thrombectomy as best practice in the management of large vessel occlusion acute ischaemic stroke. However, significant questions pertaining to initial imaging, radiological assessment, patient selection and therapeutic limits remain unanswered. A specific cohort of patients who benefit from endovascular thrombectomy has been established, although current uncertainties regarding selection of those not meeting top-tier evidence criteria may potentially deny certain patients the benefit of intervention. This is of particular relevance in patients presenting in a delayed manner. Whilst superior outcomes are achieved with reduced time to endovascular reperfusion, denying patients intervention based on symptom duration alone may not be appropriate. Advanced understanding of ischaemic stroke pathophysiology supports an individualized approach to patient evaluation, given variance in the rate of ischaemic core progression and the extent of salvageable penumbra. Physiological imaging techniques may therefore be utilized to better inform patient selection for endovascular thrombectomy and evidence suggests that a transition from time-based to tissue-based therapeutic thresholds may be of greater value. Multiple ongoing randomized controlled trials aim to further define the benefit of endovascular thrombectomy and it is hoped that these results will advance, and possibly broaden, patient selection criteria to ensure that maximum benefit from the intervention may be achieved.


Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.
Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport.


Long term effects of thorium dioxide (thorotrast) administration on human liver. Ultrastructural localization of thorium dioxide in human liver by analytical electron microscopy.
The ultrastructual localization of thorium dioxide was examined in liver biopsy specimens from two patients injected more than 30 years before with thorotrast. An energy dispersive X-ray microanalysis spectrometer (Kevex 5100) was used to identify thorium in the liver tissue. By electron microscopy, most of the thorium particles were found in the cells of the reticuloendothelial system, such as macrophages of the portal triad and Kupffer cells in the hepatic sinusoid. Thorium dioxide particles were mainly located within the phagosomes, but larger aggregates existed in the cytoplasma with no visible limiting membrane. In addition, the deposition of thorium granules in a few hepatocytes was also confirmed by electron microscopy. This fact indicates that two main pathways of elimination are still functioning in the late period, but the hepatocytic pathway appears to be less effective than the reticuloendothelial system.


Translating gene drive science to promote linguistic diversity in community and stakeholder engagement.
Information about genetic engineering (GE) for vector control in the United States is disseminated primarily in English, though non-English speakers are equally, and in some geographic regions even more affected by such technologies. Non-English-speaking publics should have equal access to such information, which is especially critical when the technology in question may impact whole communities. We convened an interdisciplinary workgroup to translate previously developed narrated slideshows on gene drive mosquitoes from English into Spanish, reviewing each iteration for scientific accuracy and accessibility to laypeople. Using the finalised stimuli, we conducted five online, chat-based focus groups with Spanish-speaking adults from California. Overall, participants expressed interest in the topic and were able to summarise the information presented in their own words. Importantly, participants asked for clarification and expressed scepticism about the information presented, indicating critical engagement with the material. Through collaboration with Spanish-speaking scientists engaged in the development of GE methods of vector control, we translated highly technical scientific information into Spanish that successfully engaged Spanish-speaking participants in conversations about this topic. In this manuscript, we document the feasibility of consulting Spanish-speaking publics about a complex emerging technology by drawing on the linguistic diversity of the scientific teams developing the technology.


Quality of cancer survivorship care in the military health system (TRICARE).
Following the acute phase of treatment, national guidelines recommend cancer survivors have routine contact with health care providers and undergo basic ancillary testing while avoiding high-cost imaging (HCI). We conducted this study to determine how frequently breast, prostate, and colorectal cancer survivors received recommended follow-up care and HCI tests during the survivorship period. Using administrative data from TRICARE beneficiaries, we identified a cohort of patients who were treated for breast, prostate, or colorectal cancer between October 2005 and March 2007. These patients were then followed through September 2010. During the 3 years after initial treatment, we determined how frequently survivors received all minimum recommended survivorship care as defined by national guidelines and underwent HCI tests and if these outcomes varied by geographic region. Overall, 3148 patients underwent treatment for breast (n = 1630), prostate (n = 1173), or colorectal (n = 345) cancer. Sixty-five percent received all minimum recommended care over 3 years (breast = 74.1%, prostate = 65.3%, colorectal = 25.5%). During the 3-year period, 74.1% of breast cancer survivors received a mammogram each year, whereas 69.1% of colorectal cancer survivors had at least 1 colonoscopy. Sixty-four percent had at least 1 HCI study during the 3-year period (positron emission tomography = 10.9%, computer tomography = 48.8%, magnetic resonance imaging = 36.6%) at a cost of $3.5 million. Substantial state-level variation was noted for both outcomes. Some cancer survivors do not receive recommended care following initial treatment while frequently undergoing HCI. The existing geographic variation in quality and imaging utilization suggests that improvements to cancer survivorship care are possible.


Logic-gate devices based on printed polymer semiconducting nanostripes.
The applications of organic semiconductors in complex circuitry such as printed CMOS-like logic circuits demand miniaturization of the active structures to the submicrometric and nanoscale level while enhancing or at least preserving the charge transport properties upon processing. Here, we addressed this issue by using a wet lithographic technique, which exploits and enhances the molecular order in polymers by spatial confinement, to fabricate ambipolar organic field effect transistors and inverter circuits based on nanostructured single component ambipolar polymeric semiconductor. In our devices, the current flows through a precisely defined array of nanostripes made of a highly ordered diketopyrrolopyrrole-benzothiadiazole copolymer with high charge carrier mobility (1.45 cm(2) V(-1) s(-1) for electrons and 0.70 cm(2) V(-1) s(-1) for holes). Finally, we demonstrated the functionality of the ambipolar nanostripe transistors by assembling them into an inverter circuit that exhibits a gain (105) comparable to inverters based on single crystal semiconductors.


Excitotoxic mechanisms in hypoglycaemic hippocampal injury.
Light and electron microscopy were used to study the effect of hypoglycaemia on selectively vulnerable neurons of rat hippocampus with and without pharmacologic blockade of the N-methyl-D-aspartate (NMDA)-preferring receptor with 2-amino-7-phosphonoheptanoic acid (AP-7). In control hypoglycaemic hippocampi, dark cell change occurs predominantly in dentate granule cells. The topography and ultrastructural appearance of these changes is distinct from that produced by ischaemia or status epilepticus. In hypoglycaemia, mitochondrial calcium accumulation characteristic of ischaemia or status epilepticus is not seen. NMDA receptor blockade markedly attenuates the hypoglycaemic cell injury. Similar attenuation of ischaemic and epileptic brain damage by NMDA receptor blockade suggest that excessive neuronal excitation is a common mechanism of injury in each of the three conditions.


Randomized trial of two e-learning programs for oral health students on secondary prevention of eating disorders.
The purpose of this study was to test whether an interactive, web-based training program is more effective than an existing, flat-text, e-learning program at improving oral health students' knowledge, motivation, and self-efficacy to address signs of disordered eating behaviors with patients. Eighteen oral health classes of dental and dental hygiene students were randomized to either the Intervention (interactive program; n=259) or Alternative (existing program; n=58) conditions. Hierarchical linear modeling assessed for posttest differences between groups while controlling for baseline measures. Improvement among Intervention participants was superior to those who completed the Alternative program for three of the six outcomes: benefits/barriers, self-efficacy, and skills-based knowledge (effect sizes ranging from 0.43 to 0.87). This study thus suggests that interactive training programs may be better than flat-text e-learning programs for improving the skills-based knowledge and self-efficacy necessary for behavior change.


Intensive insulin therapy to maintain normoglycemia after cardiac surgery.
Drugs used in the perioperative period could have an effect on survival as recently pointed out by an international consensus conference on the reduction in mortality in cardiac anesthesia and intensive care. Insulin infusion to achieve a strict glycemic control is the best example of how an ancillary (i.e. non-surgical) drug/technique/strategy might influence survival rates in patients undergoing cardiac surgery. The author of this "expert opinion" presents her insights into the use of insulin in this setting and suggest that based on available evidence based medicine, insulin infusion, titrated to "normoglycemia" is a complex intervention, that not only requires the simple administration of a "drug", the hormone insulin, but also needs tools and skills to accurately measure and control blood glucose to achieve normoglycemia while avoiding hypoglycemia and large glucose fluctuations.