Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells.
Polo-like kinase 1 (PLK1), a critical kinase that regulates multiple steps in mitosis, is overexpressed in diverse human cancers; thus many PLK1 inhibitors have been developed as potential cancer therapeutic agents. One of these compounds, the PLK1-specific inhibitor BI2536, has been investigated as a cytotoxic drug in several cancers, including lung cancer; however, the detailed mechanism by which BI2536 induces defects in cell proliferation of non-small cell lung cancer (NSCLC) has not yet been determined. We found that BI2536 treatment resulted in mitotic arrest due to improper formation of the mitotic spindles and mitotic centrosomes. The unattached kinetochores in BI2536-treated NSCLC cells activated the spindle assembly checkpoint (SAC). The prolonged activation of the SAC led to a type of apoptotic cell death referred to as mitotic catastrophe. Finally, BI2536-treated NSCLC cells show a defect in cell proliferation. Overall, these data indicate that PLK1 inhibition via mitotic disruption represents a potential approach for the treatment of NSCLC.


Effect of anaesthetic agents on bile flow and biliary excretion of 131I-cholylglycyltyrosine in the rat.
We have compared in the rat the effects of i.v. anaesthetic agents on bile flow rate and on the biliary excretion of a novel bile acid, 131I-cholylglycyltyrosine (131I-cholylgly.tyr.). Etomidate 1-mg bolus and 2-mg h-1 infusion, Althesin 3-mg bolus and 14.5-mg h-1 infusion and propofol 3.3-mg bolus and 3.3-mg h-1 were given via a tail vein cannula and pentobarbitone 50 mg kg-1 was given by the intraperitoneal route, to groups of six rats. Each animal received only one anaesthetic agent. One hour after cannulation of the common bile duct, 131I-cholylgly.tyr. 5 microCi was injected into the jugular vein and bile was collected every 1 min for 10 min. The mean (SD) percentage cumulative biliary excretion of 131I-cholylgly.tyr. at the end of 10 min was: propofol group 74.1 (5.2)%; Althesin group 82.3 (2.2)%; etomidate group 69.4 (17.6)%; pentobarbitone group 76.4 (3.2)%. Propofol and Althesin were relatively more choleretic, causing bile flow rates twice that produced by pentobarbitone. Only Althesin caused a significant increase in biliary excretion of 131I-cholylgly.tyr. relative to that in rats that received pentobarbitone. Bile flow rates for the respective anaesthetic techniques (microliter min-1/100 g body weight) (mean (SD)) were: propofol group 14.1 (1.8); Althesin group 12.5 (1.7); etomidate 8.5 (1.4); pentobarbitone group 7.3 (1.0). There was a marked metabolic acidosis in all rats except in the propofol group, in which normal acid-base status and oxygenation were observed.


Barriers and facilitators of successful deprescribing as described by older patients living with frailty, their informal carers and clinicians: a qualitative interview study.
To explore the barriers/facilitators to deprescribing in primary care in England from the perspectives of clinicians, patients living with frailty who reside at home, and their informal carers, drawing on the Theoretical Domains Framework to identify behavioural components associated with barriers/facilitators of the process. Exploratory qualitative study. General practice (primary care) in England. 9 patients aged 65+ living with frailty who attended a consultation to reduce or stop a medicine/s. 3 informal carers of patients living with frailty. 14 primary care clinicians including general practitioners, practice pharmacists and advanced nurse practitioners. Qualitative semistructured interviews took place with patients living with frailty, their informal carers and clinicians. Patients (n=9) and informal carers (n=3) were interviewed two times: immediately after deprescribing and 5/6 weeks later. Clinicians (n=14) were interviewed once. In total, 38 interviews were undertaken. Framework analysis was applied to manage and analyse the data. 6 themes associated with facilitators and barriers to deprescribing were generated, respectively, with each supported by between two and three subthemes. Identified facilitators of deprescribing with patients living with frailty included shared decision-making, gradual introduction of the topic, clear communication of the topic to the patient and multidisciplinary working. Identified barriers of deprescribing included consultation constraints, patients' fear of negative consequences and inaccessible terminology and information. This paper offers timely insight into the barriers and facilitators to deprescribing for patients living with frailty within the context of primary care in England. As deprescribing continues to grow in national and international significance, it is important that future deprescribing interventions acknowledge the current barriers and facilitators and their associated behavioural components experienced by clinicians, patients living with frailty and their informal carers to improve the safety and effectiveness of the process.


Rapid detection of genomic imbalances using micro-arrays consisting of pooled BACs covering all human chromosome arms.
A strategy is presented to select, pool and spot human BAC clones on an array in such a way that each spot contains five well performing BAC clones, covering one chromosome arm. A mini-array of 240 spots was prepared representing all human chromosome arms in a 5-fold as well as some controls, and used for comparative genomic hybridization (CGH) of 10 cell lines with aneusomies frequently found in clinical cytogenetics and oncology. Spot-to-spot variation within five replicates was below 6% and all expected abnormalities were detected 100% correctly. Sensitivity was such that replacing one BAC clone in a given spot of five by a BAC clone from another chromosome, thus resulting in a change in ratio of 20%, was reproducibly detected. Incubation time of the mini-array was varied and the fluorescently labelled target DNA was diluted. Typically, aneusomies could be detected using 30 ng of non-amplified random primed labelled DNA amounts in a 4 h hybridization reaction. Potential application of these mini-arrays for genomic profiling of disseminated tumour cells or of blastomeres for preimplantation genetic diagnosis, using specially designed DNA amplification methods, are discussed.


Development and applications of transgenesis in the yellow fever mosquito, Aedes aegypti.
Transgenesis technology has been developed for the yellow fever mosquito, Aedes aegypti. Successful integration of exogenous DNA into the germline of this mosquito has been achieved with the class II transposable elements, Hermes, mariner and piggyBac. A number of marker genes, including the cinnabar(+) gene of Drosophila melanogaster, and fluorescent protein genes, can be used to monitor the insertion of these elements. The availability of multiple elements and marker genes provides a powerful set of tools to investigate basic biological properties of this vector insect, as well as the materials for developing novel, genetics-based, control strategies for the transmission of disease.


Lithium as an Alternative Option in Graves Thyrotoxicosis.
A 67-year-old woman was admitted with signs and symptoms of Graves thyrotoxicosis. Biochemistry results were as follows: TSH was undetectable; FT4 was >6.99 ng/dL (0.7-1.8); FT3 was 18 pg/mL (3-5); TSI was 658% (0-139). Thyroid uptake and scan showed diffusely increased tracer uptake in the thyroid gland. The patient was started on methimazole 40 mg BID, but her LFTs elevated precipitously with features of fulminant hepatitis. Methimazole was determined to be the cause and was stopped. After weighing pros and cons, lithium was initiated to treat her persistent thyrotoxicosis. Lithium 300 mg was given daily with a goal to maintain between 0.4 and 0.6. High dose Hydrocortisone and propranolol were also administered concomitantly. Free thyroid hormone levels decreased and the patient reached a biochemical and clinical euthyroid state in about 8 days. Though definitive RAI was planned, the patient has been maintained on lithium for more than a month to control her hyperthyroidism. Trial removal of lithium results in reemergence of thyrotoxicosis within 24 hours. Patient was maintained on low dose lithium treatment with lithium level just below therapeutic range which was sufficient to maintain euthyroid state for more than a month. There were no signs of lithium toxicity within this time period. Conclusion. Lithium has a unique physiologic profile and can be used to treat thyrotoxicosis when thionamides cannot be used while awaiting elective radioablation. Lithium levels need to be monitored; however, levels even at subtherapeutic range may be sufficient to treat thyrotoxicosis.


Assessing the Recovery Assessment Scale Across Time.
The Recovery Assessment Scale (RAS) is one of the most used recovery measures in recovery-oriented practice evaluation of people with mental health conditions. Although its psychometric properties have been extensively studied, one critical piece of information that is missing from the literature is evidence of its longitudinal factorial invariance-that is, whether the RAS measures the same recovery construct across time. The authors empirically tested the longitudinal factorial invariance assumption for the RAS. Structural equation modeling was used to test the longitudinal factorial invariance of the RAS with data longitudinally obtained at three time points from 167 people with severe mental illness. The longitudinal factorial invariance assumption was supported (i.e., configural, metric, partial scalar, factor variance and covariance invariance). This study found empirical evidence that the RAS can measure the same recovery construct over time and thus meets one of the important prerequisites for longitudinal assessment.


Randomized, controlled trial of the effect of e-feedback on knowledge about radiotherapy of breast cancer patients in Finland.
The growing number of women with breast cancer and their unmet knowledge expectations of radiotherapy pose a challenge to develop effective electronic patient education. Development efforts should be focused on e-feedback on knowledge because of its positive effects. In this study, we evaluated how an e-feedback knowledge intervention (e-Re-Know) before first radiotherapy improves breast cancer patients' knowledge of radiotherapy and identified the associations with patients' characteristics. Women with breast cancer (n = 128) were randomized prior to the radiotherapy period either to the intervention group or control group. The outcome measured three months after the radiotherapy period was knowledge level of radiotherapy. The increase in knowledge level was higher in the intervention group after adjustment for baseline knowledge level, and a significantly higher increase in knowledge level was seen in one subdomain, side-effect self-care, compared to the control group. The results of this study indicate that the e-Re-Know can be used in patient education to support empowerment. Future research should target new applications of e-Re-Know available on the Internet for those interested in the subject.


Comparison of implanted fiducial markers and self-expandable metallic stents for pancreatic image guided radiation therapy localization.
The delivery of high-quality radiation therapy to pancreatic adenocarcinoma requires accurate localization. Radiopaque implanted fiducial markers (IFM) and self-expandable metallic stents (SEMS) have both been proposed as means of achieving accurate localization in image guided radiation therapy (IGRT). The suitability of IFM and SEMS for localization were evaluated in this study based on geometric and dosimetric surrogates. In a retrospective study of 54 patients with pancreatic cancer who underwent tumor-directed IGRT, 9 were identified as having both IFM and SEMS. For each patient, cone beam computed tomography (CT) scans from each of 6 weeks of treatment were selected for review and comparison with the simulation CT. The centroids of both the IFM and SEMS on each cone beam CT were aligned with those on the planning CT to quantify geometric differences between IFM- and SEMS-based localization. This difference was used to mark the isocenter displacement from the original IFM-localized treatment plan to evaluate the dosimetric implications of SEMS localization. IFM were used as the localization standard given their intratumoral location, and the stability of IFM was evaluated by variability of intrafiducial distance. The original treatment plan was computed on the planning CT at the isocenter shifted by the determined displacement, and dose-volume histograms were calculated for the target volume and organs at risk. The average displacement for SEMS localization over all fractions in all patients was 7.7 mm. Planning target volume coverage by 90% of prescription dose was significantly reduced (mean, 11.1%; range, 0.5% to -46.6%) for SEMS compared with IFM localization (P < .05). Dose tolerances were exceeded for stomach, duodenum, and small bowel for 3, 3, and 5 of 9 patients, respectively, when SEMS localization was used. SEMS-based compared with IFM-based localization results in significant variability of radiation therapy localization for pancreatic cancer. IFM-based localization should be considered the standard of care for tumor-directed pancreatic cancer IGRT.


Three-dimensional imaging of small intestine morphology using non-linear optical microscopy and endogenous signals.
Two-photon microscopy (2PM) has become a gold standard for deep-tissue observations in the living animal as well as on thick samples. Using 2PM, the endofluorescence properties of biomolecules have shown an interesting potential for the imaging of tissues without any staining. In this short communication, we report a method to observe the different layers of mouse small intestine explants with subcellular resolution and without any staining or clearing. This method allows rapid observations of samples with little to no preparation thanks to the endofluorescence properties of biomolecules such as NAD(P)H or flavins and second-harmonic generation. Finally, we show different three-dimensional reconstructions of the mouse small intestine anatomy obtained with this approach to show the potential of this method in morphological studies.


A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients.
Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients.


Auxins increase expression of the brassinosteroid receptor and brassinosteroid-responsive genes in Arabidopsis.
Auxins and brassinosteroids are essential phytohormones that synergistically regulate physiological and developmental processes in plants. Previously, we demonstrated that auxins stimulate brassinosteroid perception by regulating the level of brassinosteroid receptor in rice. Here we showed that auxin treatment increased expression of the Arabidopsis brassinosteroid receptor gene BRI1. The promoter of BRI1 has an auxin-response element that is targeted by auxin-response factor transcription factors. Auxin pretreatment increased the sensitivity to brassinosteroids of brassinosteroid-responsive genes. Although multilevel interactions between auxins and brassinosteroids have previously been reported, our findings suggest a possibility that auxins control the degree of brassinosteroid perception by regulating the expression of gene for brassinosteroid receptor, and this phenomenon is conserved between monocots (rice) and dicots (Arabidopsis).


Significance of main pulmonary artery dilation on imaging studies.
Proper and early identification of patients who harbor serious occult illness is the first step in developing a disease-management strategy. Identification of illnesses through the use of noninvasive techniques provides assurance of patient safety and is ideal. PA dilation is easily measured noninvasively and is due to a variety of conditions, including pulmonary hypertension (PH). The clinician should be able to thoroughly assess the significance of PA dilation in each individual patient. This involves knowledge of the ability of PA dilation to accurately predict PH, understand the wide differential diagnosis of causes of PA dilation, and reverse its life-threatening complications. We found that although PA dilation is suggestive of PH, data remain inconclusive regarding its ability to accurately predict PH. At this point, data are insufficient to place PA dilation into a PH risk-score equation. Here we review the causes and complications of PA dilation, define normal and abnormal PA measurements, and summarize the data linking its association to PH, while suggesting an algorithm designed to assist clinicians in patient work-up after recognizing PA dilation.


Evaluation of postoperative discomfort following third molar surgery using submucosal dexamethasone - a randomized observer blind prospective study.
Surgical removal of impacted lower third molar is still the most frequent procedure done by Oral and Maxillofacial surgeons and is often associated with pain, swelling and trismus. These postoperative sequelae can cause distress to the patient as a result of tissue trauma and affect the patient's quality of life after surgery. Use of antiseptic mouthwashes, drains, muscle relaxants, cryotherapy, antibiotics, corticosteroids and physiotherapy seems to decrease postoperative discomfort. Among them corticosteroids are well-known adjuncts to surgery for suppressing tissue mediators of inflammation, thereby reducing transudation of fluids and lessening edema. The rationale of this study is to determine the effectiveness of submucosal injection of dexamethasone in reducing postoperative discomfort after third molar surgery. 100 patients requiring surgical removal of third molar under local anesthesia were randomly divided into 2 groups, group I receiving 4 mg dexamethasone as submucosal injection and the control group II received no steroid administration. Facial swelling was quantified by anatomical facial landmarks. Furthermore, pain and patient satisfaction, as well as neurological score and the degree of mouth opening were observed from each patient. Patients receiving dexamethasone showed significant reduction in pain, swelling, trismus, a tendency to less neurological complaints and improved quality of life compared with the control group. Submucosal injection of dexamethasone is more efficient to manage postoperative discomfort after removal of third molars compared to no steroid administration.


Burnout of Physicians Working in Primary Health Care Centers under Ministry of Health Jeddah, Saudi Arabia.
Introduction The levels of physicians' job satisfaction and burnout directly affect their professionalism, punctuality, absenteeism, and ultimately, patients' care. Despite its crucial importance, little is known about professional burnout of the physicians in Saudi Arabia. The objectives of this research are two-fold: (1) To assess the prevalence of burnout in physicians working in primary health care centers under Ministry of Health; and (2) to find the modifiable factors which can decrease the burnout ratio. Methodology Through a cross-sectional study design, a representative sample of the physicians working in primary health care centers (PHCCs) Jeddah (n=246) was randomly selected. The overall burnout level was assessed using the validated abbreviated Maslach burnout inventory (aMBI) questionnaire. It measures the overall burnout prevalence based on three main domains i.e., emotional exhaustion, depersonalization, and personal accomplishment. Independent sample T-test, analysis of variance (ANOVA), and multivariate regression analysis were performed using Statistical Package for the Social Sciences (SPSS Version 22, IBM, Armonk, NY). Results Overall, moderate to high burnout was prevalent in 25.2% of the physicians. Emotional exhaustion was noted in 69.5%. Multivariate regression analysis showed that patient pressure/violence (p <0.001), unorganized patients flow to clinics (p=0.021), more paperwork (p<0.001), and less co-operative colleague doctors (p=0.045) were the significant predictors for high emotional exhaustion. A positive correlation was noted between the number of patients per day and burnout. The patient's pressure/violence was the only significant independent predictor of overall burnout. Conclusion Emotional exhaustion is the most prominent feature of overall burnout in the physicians of primary health care centers. The main reasons include patient's pressure/violence, unorganized patient flow, less cooperative colleague doctors, fewer support services at the PHCCs, more paperwork, and less cooperative colleagues. Addressing these issues could lead to a decrease in physician's burnout.


Changes in the expression of genes involved in cell cycle regulation and the relative telomere length in the process of canceration induced by omethoate.
Organophosphorous pesticides (OPs), with high efficiency, broad-spectrum and low residue, are widely used in China. Omethoate is a broad category of organophosphorous pesticides and is more domestically utilized which has chronic toxic effect on human health caused by long-term, low-dose exposure to Ops, recently its potential genotoxicity has attracted wide attention which can cause chromosomal DNA damage. Thus, the aim of this study is screen susceptible biomarkers and explore the mechanism of canceration induced by omethoate. 180 long-term organophosphorus pesticide-exposed workers and 115 healthy controls were recruited. Quantitative polymerase chain reaction method was applied to determine the relative telomere length in peripheral lymphocyte DNA as well as p53 and p21 gene expression levels. Genetic polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Multiple linear regression was conducted to explore the effects of exposure, expression levels, and polymorphisms in genes on the telomere length. The results showed the relative telomere lengths in the exposure group were significantly longer than that in the control group. The messenger RNA expression levels of p53 and p21 in exposure group were significantly lower than that in the control group; telomere lengths of the CA genotype individuals of p21 rs1801270 polymorphism locus were significantly longer than that of the CC genotype in the control group that were estimated using the Bonferroni method; and bivariate correlation analysis showed that the messenger RNA expression level of gene p53 was negatively correlated with telomere length, and the messenger RNA expression level of gene p21 was positively correlated with telomere length. Multivariate analysis found that p53 messenger RNA and p21 messenger RNA had an impact on telomere length. These results demonstrated that the messenger RNA expression levels of p53 and p21 may have a relationship with the changes in telomere length induced by omethoate and provided strong evidence for the mechanism of canceration induced by poison.


The bromopentadienyl acrylate approach to himbacine.
[reaction: see text] The syntheses of 4,4a-didehydrohimbacine and 4,4a-didehydrohimandravine are presented. Key steps include an intramolecular Diels-Alder reaction of a bromopentadienyl acrylate and Suzuki-Miyaura and Stille coupling reactions.


Children's Specialized Hospital and GetWellNetwork Collaborate to Improve Patient Education and Outcomes Using an Innovative Approach.
Patient education in a pediatric setting is unique. There are different patient ages, degrees of learning, and diagnoses to take into account when educating children and their families. A new and innovative trend in practice called Interactive Patient Care (IPC) integrates technology into care processes to advance pediatric nursing education and patient and family satisfaction. Children's Specialized Hospital is the first pediatric rehabilitation hospital to develop and implement this type of program using an IPC platform from the GetWellNetwork. With the implementation of the GetWellNetwork, Children's Specialized Hospital has achieved positive results in patient satisfaction, health care utilization, quality, and safety measures.


Pulmonary artery stenosis resulting in ventilation-perfusion mismatch in a young female.
Pulmonary embolism is a disorder associated with significant morbidity and mortality in which early, accurate diagnosis is imperative. Controversy exists as to whether this disorder is being overdiagnosed or underdiagnosed. Processes other than pulmonary embolism may produce scintigraphic ventilation-perfusion mismatch and alter the diagnostic specificity of this technique in a small but significant subset of patients. We report a case in which pulmonary ventilation-perfusion mismatch was produced by pulmonary vessel stenosis without evidence of embolic disease. Paradoxically, although the specificity in diagnosing pulmonary embolism with scintigraphic techniques has increased markedly, still greater caution must be exercised in order to preserve this specificity.


[Treatment with Soave's technic and long-term results in 270 cases of Hirschsprung disease].
The authors present the surgical technique for the correction of Hirschsprung disease following SOAVE's original description. A series of 270 cases observed in 20 years at the Pediatric Surgery Department of the "Instituto Giannina Gaslini" in Genova, Italy, are examined. These cases, all treated by surgery, were followed up in long term for more than one year both clinically and radiologically. Additionally 73 cases treated from 1977 on were also followed up with the aid of ano-rectal electro-manometry. The most recent diagnostic aspects are discussed, such as ano-manometry, and some conclusions are drawn about long term results.


Delayed post-myocardial infarction invasive measures, helpful or harmful? A subgroup analysis.
In patients who have experienced acute myocardial infarction (MI), primary percutaneous coronary intervention (PCI) has been shown to be of benefit in terms of clinical outcomes. However, the value of performing routine PCI in patients with early MI (ie, an MI occurring > 12 h to < or = 7 days before patient presentation) or recent MI (ie, an MI occurring > or = 8 days to < 30 days before patient presentation) has not been established. The purposes of this prospective observational study were to evaluate the impact of PCI on outcomes, and to delineate the predictors of lack of response to reperfusion and the prognostic determinants in patients with this clinical condition. A total of 377 consecutive unselected patients who had experienced early or recent MI underwent PCI. Successful reperfusion (ie, Thrombolysis in Myocardial Infarction flow grade 3 of the infarct-related artery [IRA]) was achieved in 90.2% of patients. By multiple stepwise logistic regression analysis, high-burden thrombus formation (odds ratio [OR], 15.53; 95% confidence interval [CI], 6.09 to 39.60; p < 0.0001) in the IRA, early PCI (ie, < or = 3 days) [OR, 4.10; 95% CI, 1.79 to 7.36; p = 0.0008], advanced congestive heart failure (CHF) [OR, 4.10; 95% CI, 1.70 to 9.91; p = 0.002], and diabetes (OR, 3.03; 95% CI, 1.03 to 7.06; p = 0.010) were independent predictors for lack of response to reperfusion. The 30-day mortality rate was 6.8%. The only variables that were independently related to the 30-day mortality rate were advanced CHF (OR, 29.85; 95% CI, 7.84 to 113.7; p < 0.0001), lack of response to reperfusion (OR, 7.57; 95% CI, 2.29 to 25.07; p = 0.0009), early PCI (OR, 4.81; 95% CI, 1.60 to 14.41; p = 0.005), and multivessel disease (OR, 9.22; 95% CI, 1.63 to 52.04; p = 0.0119). The surviving 351 patients were discharged from the hospital and followed-up for a mean (+/- SD) 38.9 +/- 14.2 months. Coronary angiographic follow-up was performed in 285 patients (81.2%). Restenosis of the IRA was found in 101 patients (35.4%). Reinterventions of the IRA were required in 69 patients (24.2%). Follow-up measurements of left ventricular ejection fraction (LVEF) showed significantly more improvement than the initial LVEF (59.3 +/- 13.8% vs 50.4 +/- 13%; p < 0.0001). The total cumulative mortality rate after hospital discharge was 6.5% for the entire group. Only advanced CHF (OR, 3.46; 95% CI, 1.26 to 9.52; p = 0.016) and old age (ie, > or = 70 years of age) [OR, 4.41; 95% CI, 1.59 to 12.24; p = 0.004] were independent predictors of long-term mortality. The performance of PCI on > or = day 4 in patients after they had experienced an MI was safe and had a high rate of success. The clinical benefits of a relative low mortality rate associated with successful PCI for patients with early and recent MI was maintained during the long-term follow-up. However, patients with advanced CHF along with old age continued to have a poor prognosis.


We Need Studies of the Mortality Effect of Vitamin A Supplementation, Not Surveys of Vitamin A Deficiency.
It is usually acknowledged that high-dose vitamin A supplementation (VAS) provides no sustained improvement in vitamin A status, and that the effect of VAS on mortality is more likely linked to its immunomodulating effects. Nonetheless, it is widely assumed that we can deduce something about the need for continuing or stopping VAS programs based on studies of the biochemical prevalence of vitamin A deficiency (VAD). This is no longer a tenable assumption. The justification for using VAS is to reduce child mortality, but there is now doubt that VAS has any effect on overall child mortality. What we need now are not surveys of VAD, but proper randomized trials to evaluate whether VAS has beneficial effects on overall child survival.


Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics.
Orexin A and B, orexigenic peptides produced primarily by the lateral hypothalamus that signal through two G protein-coupled receptors, orexin receptors 1/2, have been implicated in the regulation of several physiological processes in mammals. In avian (nonmammalian vertebrates) species; however, the physiological roles of orexin are not well defined. Here, we provide novel evidence that not only is orexin and its related receptors 1/2 (ORXR1/2) expressed in chicken muscle tissue and quail muscle (QM7) cell line, orexin appears to be a secretory protein in QM7 cells. In vitro administration of recombinant orexin A and B (rORX-A and B) differentially regulated prepro-orexin expression in a dose-dependent manner with up-regulation for rORX-A (P < 0.05) and downregulation for rORX-B (P < 0.05) in QM7 cells. While both peptides upregulated ORXR1 expression, only a high dose of rORX-B decreased the expression of ORXR2 (P < 0.05). The presence of orexin and its related receptors and the regulation of its own system in avian muscle cells indicate that orexin may have autocrine, paracrine, and/or endocrine roles. rORXs differentially regulated mitochondrial dynamics network. While rORX-A significantly induced the expression of mitochondrial fission-related genes (DNM1, MTFP1, MTFR1), rORX-B increased the expression of mitofusin 2, OPA1, and OMA1 genes that are involved in mitochondrial fusion. Concomitant with these changes, rORXs differentially regulated the expression of several mitochondrial metabolic genes (av-UCP, av-ANT, Ski, and NRF-1) and their related transcriptional regulators (PPARγ, PPARα, PGC-1α, PGC-1β, and FoxO-1) without affecting ATP synthesis. Taken together, our data represent the first evidence of the presence and secretion of orexin system in the muscle of nonmammalian species and its role in mitochondrial fusion and fission, probably through mitochondrial-related genes and their related transcription factors.


Echocardiographic detection of free-floating thrombus in left ventricle during coronary artery bypass grafting.
We report an incident of detection of a free-floating thrombus in the left ventricle (LV) using intraoperative two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE) during proximal coronary artery bypass graft anastomosis. A 58-year-old man presented to us with a 6-month history of chest pain without any history suggestive of myocardial infarction or transient ischemic attacks. His preoperative echocardiography revealed the systolic dysfunction of LV, mild hypokinesia of basal and mid-anterior wall, and the absence of an aneurysm. He was scheduled for on-pump coronary artery bypass surgery. On intraoperative TEE before establishing cardiopulmonary bypass (CPB), a small immobile mass was found attached to LV apical area. After completion of distal coronary artery grafting, when the aortic cross-clamp was removed, the heart was filled partially and beating spontaneously. TEE examination using 2D mode revealed a free-floating mass in the LV, which was suspected to be a thrombus. Additional navigation using biplane and 3D modes confirmed the presence of the thrombus and distinguished it from papillary muscles and artifact. The surgeon opened the left atrium after re-establishing electromechanical quiescence and removed a thrombus measuring 1.5 cm Χ 1 cm from the LV. The LV mass in the apical region was no longer seen after discontinuation of CPB. Accurate TEE-detection and timely removal of the thrombus averted disastrous embolic complications. Intraoperative 2D and recent biplane and 3D echocardiography modes are useful monitoring tools during the conduct of CPB.


The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy.
Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens.


Influence of community satisfaction with individual happiness: comparative study in semi-urban and rural areas of Tikapur, Nepal.
Happiness is a subjective indicator of overall living conditions and quality of life. Recently, community- and national-level investigations connecting happiness and community satisfaction were conducted. This study investigated the effects of community satisfaction on happiness in Nepal. A factor analysis was employed to examine 24 items that are used to measure community satisfaction, and a multiple regression analysis was conducted to investigate the effects of these factors on happiness. In semi-urban areas, sanitation showed a positive relationship with happiness. In rural areas, edu-medical services were negatively related to happiness, while agriculture was positively related. Gender and perceived health were closely associated with happiness in rural areas. Both happiness and satisfaction are subjective concepts, and are perceived differently depending on the socio-physical environment and personal needs. Sanitation, agriculture (food) and edu-medical services were critical factors that affected happiness; however, the results of this study cannot be generalized to high-income countries.


[Post-traumatic glaucoma].
This paper presents theoretical aspects concerning the physiopathological mechanisms involved in producing the glaucoma following trauma, especially the lens related glaucoma, correct identification of the ethiopathogeny of the intraocular pressure elevation in this situation is essential for the appropriate management. These aspects are illustrated by two cases of recent glaucoma following trauma lens related (lens subluxation) treated by medication and surgery. The surgical procedure consisted of intracapsular extraction of the lens, anterior vitrectomy, iridectomy and implantation of sulcus sutured posterior chamber lens. We present the technique, the difficulties met intra- and postoperative, evolution and prognosis.


Critical analysis of the international classification of headache disorders diagnostic criteria (ICHD I-1988) and (ICHD II-2004), for migraine in children and adolescents.
The present study analyzed the (ICHD I-1988) and (ICHD II-2004) diagnostic criteria in children and adolescents. Our population consisted of 496 patients of the Headache Outpatient Ward for Children and Adolescents retrospectively studied from 1992 to 2002. Individuals were classified according to three diagnostic groups: Intuitive Clinical Diagnosis (Gold Standard), ICHD I-1988 and ICHD II-2004. They were statistically compared using the variables: Sensitivity (S), Specificity (Sp), Positive Predictive Value (PPV), Negative Predictive Value (NPV). When ICHD I-1988 was used, the sensitivity of migraine without and with aura was 21% and 27%, respectively, whereas in ICHD II-2004 it changed to 53% and 71% without affecting specificity. As a conclusion, the current classification criteria (ICHD II-2004) showed greater sensitivity and high specificity for migraine than ICHD I-1988, although it improved migraine diagnosis in children and adolescents, the sensitivity remains poor.


Characterization of gels composed of blends of collagen I, collagen III, and chondroitin sulfate.
Type I collagen is explored heavily for use in biomaterials, but the role of other extracellular matrix components in regulating collagen organization is gaining attention. We show that as the ratio of type III to type I collagen increases, fibril diameter decreases. A mixture of the two collagen types results in a more open structural network, corresponding to a more compliant material, as compared to a material composed of only one collagen type. Glycosaminoglycans also affect collagen organization and tissue properties. We show that chondroitin sulfate decreases the collagen fibril diameter. Additionally, chondroitin sulfate (CS) increases the void space of a collagen I or collagen III gel, resulting in a more compliant material, but the interactions between types I and III collagen negate the effects of CS. The simple combination of these components results in materials with unique structural, mechanical, and biological cues that can be useful in tailoring biomaterials for tissue engineering.


Rapid and simple detection of Japanese encephalitis virus by reverse transcription loop-mediated isothermal amplification combined with a lateral flow dipstick.
Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in geographical areas, such as Asia and Western Pacific, where it is a threat to human and animal health. To control this disease, it is necessary to develop a rapid, simple, accurate method for diagnosis. In this study, a method based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) coupled with a lateral flow dipstick (LFD) has been developed to detect JEV (JEV RT-LAMP-LFD). The entire assay can be completed within 70 min, and in this study, no false positive results were observed when other pathogens were tested, indicating that the assay is a highly specific method for the detection of JEV. Additionally, the sensitivity of the RT-LAMP-LFD assay for SA14-14-2 strain was 50 pg of RNA, which was similar to that of RT-PCR and RT-LAMP combined with gel electrophoresis, and was 10-fold more sensitive than RT-LAMP combined with calcein. The limit of detection for this assay was 5 pg of RNA. In addition, no false positive results were obtained with 14 serum samples. Our results indicate that this RT-LAMP-LFD assay will be of great value for JEV infection testing due to its rapid and highly specific and sensitive properties.


The origin and early evolution of cytokinin signaling.
Angiosperms, especially Arabidopsis and rice, have long been at the center of plant research. However, technological advances in sequencing have led to a dramatic increase in genome and transcriptome data availability across land plants and, more recently, among green algae. These data allowed for an in-depth study of the evolution of different protein families - including those involved in the metabolism and signaling of phytohormones. While most early studies on phytohormone evolution were phylogenetic, those studies have started to be complemented by genetic and biochemical studies in recent years. Examples of such functional analyses focused on ethylene, jasmonic acid, abscisic acid, and auxin. These data have been summarized recently. In this review, we will focus on the progress in our understanding of cytokinin biology. We will use these data to synthesize key points about the evolution of cytokinin metabolism and signaling, which might apply to the evolution of other phytohormones as well.


Quantification of induction of rat oesophageal, gastric and pancreatic glutathione and glutathione S-transferases by dietary anticarcinogens.
Four dietary, naturally occurring anticarcinogens (flavone, coumarin, alpha-angelicalactone and ellagic acid) were studied with respect to their effects on oesophageal, gastric and pancreatic (i) glutathione S-transferase (GST) enzyme activity, (ii) GST isozyme levels and (iii) glutathione (GSH) content in male Wistar rats. GST enzyme activity was significantly increased in the oesophagus by flavone, coumarin and alpha-angelicalactone (125, 240 and 155% respectively) and in the stomach by coumarin and alpha-angelicalactone (140 and 230%). No change in pancreatic GST activity was observed. In addition, class- and tissue-specific changes in GST isozyme levels occurred. Class alpha GSTs were induced in the oesophagus by flavone, coumarin and alpha-angelicalactone (570, 1580 and 570%), but did not change in the stomach. GST-alpha was undetectable in the pancreas. GST-mu was expressed at high levels in all three tissues investigated, but only pancreatic GST-mu levels of ellagic acid-fed rats were increased (160%). GST-pi was induced in the stomach by coumarin and alpha-angelicalactone (470 and 1120%) and in the pancreas by flavone (200%). GST-pi was detectable at low levels in rat oesophageal epithelium of coumarin-fed animals only. GSH concentrations were uninfluenced by the dietary anticarcinogens in all tissues. These results suggest that dietary ellagic acid and, more especially, flavone, coumarin and alpha-angelicalactone may exert strong chemoprotective effects by selective enhancement of members of the GST detoxification system in the oesophagus or stomach and, to a lesser extent, in the pancreas.


Liver biopsy in sheep.
Liver biopsies were performed in the same group of 16 sheep on 8 consecutive wk using an apparatus with a fibre optic continuous light source and a telescope. The sheep were placed in a sternal position on a special table constructed of metal pipes (3.8 cm diameter) and 4.5 cm spacing. Approximately 300 mg of fresh liver sample was removed from each sheep to be analyzed for copper or vitamin E.


Importance of serotype-related antigen in the induction of experimental hypersensitivity pneumonitis by Trichosporon cutaneum in rabbits. Correlation between granulomatous alveolitis and cellular and humoral immune responses to polysaccharide-rich antigen.
We evaluated the immunopathogenic properties of Trichosporon cutaneum, a major etiologic agent of Japanese summer-type hypersensitivity pneumonitis (HP). When the culture filtrate antigen of T. cutaneum was chromatographed on DEAE-cellulose, two peaks of polysaccharide, fractions A and B, were obtained. Fraction B was highly reactive to the specific IgG and IgA antibodies in the serum and bronchoalveolar lavage fluid samples obtained from sensitized rabbits, whereas fraction A was mainly reactive to the IgG antibodies. When the rabbits sensitized by intratracheal injection with the particulate antigen of T. cutaneum were challenged intratracheally by these antigenic fractions, fraction B induced granulomatous alveolitis, but fraction A induced alveolitis rather than granuloma. Lymphocytes of the mediastinal lymph nodes responded prominently to fraction B, but less to fraction A, as assessed by proliferative response. Each of the fractions B obtained from two strains of different serotypes (TIMM 1573, serotype I and TIMM 1318, serotype II) was reactive in enzyme-linked immunosorbent assay to the serum samples from the rabbits sensitized with homologous antigen, but far less to that from the rabbits sensitized with heterologous antigen, that is, the antigenic specificity of fraction B was related to the serotype of T. cutaneum. Fractionation by gel filtration on Sepharose CL-4B revealed that the molecular weight of the antigenic components in fraction B was larger than 1,000,000 and that the components consisted mainly of polysaccharide.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathology underrates colon cancer extranodal and nodal metastases; ex vivo radioimmunodetection helps staging.
Colorectal carcinoma is frequently accompanied by small lymph nodes metastases that often escape pathologic examination. We evaluated whether ex vivo radioimmunodetection with the Affinity Enhancement System (AES) could improve detection of mesocolonic metastases. A bivalent 111In-labeled hapten was injected (16 patients) 4 days after a bispecific antibody (anticarcinoembryonic antigen, antihapten). Surgery was done 1 to 3 days later, and radioactive uptake in the mesocolon was recorded. Extensive pathologic examination of the mesocolon (reference method) was done after fat dissolution. This method visualizes all lymph nodes but is not in routine use. The reference method disclosed 705 nodes. There was no significant difference between the number of node metastases detected by AES or by the reference method (16 versus 17). Better detection would have been obtained by AES than by routine pathology (P<0.01). In addition 12 extranodal metastases were found in this study of which eight were detected by AES. The prognostic importance of such extranodal metastases has been underlined in the literature. Routine pathology combined with AES would have disclosed all node metastases and 86% of total metastases versus 35% by routine pathology alone. Ex vivo radioimmunodetection could improve nodal and extranodal metastases detection in patients with colorectal cancer. Its value for improving pathologic analysis, together with the effect of these small metastases on prognosis, should be further evaluated. The benefit of adjuvant chemotherapy for patients upstaged with radioimmunodection should also be assessed because adjuvant chemotherapy improves the 5-year survival of stage III patients.


Bi-Directional Pseudo-Three-Dimensional Network for Video Frame Interpolation.
Recent video frame interpolation methods have employed the curvilinear motion model to accommodate nonlinear motion among frames. The effectiveness of such model often hinges on motion estimation and occlusion detection, and therefore is greatly challenged when these methods are used to handle dynamic scenes that contain complex motions and occlusions. We address the challenges by proposing a bi-directional pseudo-three-dimensional network to exploit the correlation between motion estimation and depth-related occlusion estimation that considers the third dimension: depth. Specifically, the network exploits the correlation by learning shared multi-scale spatiotemporal representations, and by coupling the estimations, in both the past and future directions, to synthesize intermediate frames through a bi-directional pseudo-three-dimensional warping layer, where adaptive convolution kernels are estimated progressively from the coalescence of motion and depth-related occlusion estimations across multiple scales to acquire nonlocal and adaptive neighborhoods. The proposed network utilizes a novel multi-task collaborative learning strategy, which facilitates the supervised learning of video frame interpolation using complementary self-supervisory signals from motion and depth-related occlusion estimations. Across various benchmark datasets, the proposed method outperforms state-of-the-art methods in terms of accuracy, model size and runtime performance.


Clinical and radiological improvement in Gorham-Stout disease after sirolimus treatment.
Gorham-Stout disease (GSD) is a rare syndrome characterized by lymphatic malformations, mainly in bone structures, causing progressive osteolysis. Lymphatic endothelial cell proliferation depends on several growth factors that use the phosphoinositide-3 kinase (PI3K)/Akt pathway and converge on the mammalian target molecule of the rapamycin (mTOR) pathway. These findings have allowed treating GSD with mTOR pathway inhibitors such as sirolimus or everolimus. We present the case of a one-year-old female patient referred to our institution after a right femur fracture and progressive limb volume increase, disproportionately to the trauma. After several episodes of soft tissue infections, imaging studies showed pseudarthrosis, lytic lesions, and progressive loss of the right femur that ended in total absence. A femur biopsy showed lymphatic structures positive with D2-40 staining, diagnosing GSD. After six months of non-response to traditional treatments, the limb was disarticulated at the hip level, and oral sirolimus treatment was initiated, showing clinical and radiological improvement with minor lytic lesions and evidence of ossification after 20 months of treatment. Oral sirolimus treatment for GSD inhibits angiogenesis and osteoclastic activity, stimulating bone anabolism and leading to arrested osteolysis progression and improved ossification, quality of life, and patient prognosis. Therefore, sirolimus should be considered a therapeutic option for this rare disease.


A Multi-Hop LoRa Linear Sensor Network for the Monitoring of Underground Environments: The Case of the Medieval Aqueducts in Siena, Italy.
In this paper, a pervasive monitoring system to be deployed in underground environments is presented. The system has been specifically designed for the so-called "Bottini", i.e., the medieval aqueducts dug beneath the Centre of Siena, Italy. The results of a measurement campaign carried out in the deployment scenario show that the transmission range of LoRa (Long Range) technology is limited to a maximum of 200 m, thus, making the adoption of a classical star topology impossible. Hence, a Linear Sensor Network topology is proposed based on multi-hop LoRa chain-type communications. In this scenario, an ad-hoc transmission scheme is presented that optimally evaluates the wake-up time of all nodes with the aim of minimizing the average energy dissipation deriving from clock offsets. Numerical results show that the proposed wake-up time optimization leads in the best case to a 50% reduction in power dissipation with respect to a scheme that evaluates the wake-up time in a non-optimal way.


Menopausal Impact on the Association Between Thyroid Dysfunction and Lipid Profiles: A Cross-Sectional Study.
Both dyslipidemia and thyroid dysfunction have a high prevalence rate and are important risk factors for cardiovascular diseases. However, the relationship between blood lipids and thyroid dysfunction is still controversial. This study aims to analyze the blood lipids in people with different thyroid functions. A total of 80937 adults were included in this population-based cross-sectional TIDE survey, which collected demographic and clinical data on thyroid function, blood lipid levels and other metabolic indicators. After screening, the final analysis included 10,747 participants, who were divided into hypothyroidism (n=311), subclinical hypothyroidism (n=5015), hyperthyroidism (n=203), subclinical hyperthyroidism (n=118) and control (n=5100) groups. The risk of dyslipidemia was analyzed by a logistic regression model and divided into groups of female menopausal. After full adjustment, significant associations were found between hypothyroidism and hypertriglyceridemia. Subclinical hypothyroidism was associated with a significantly higher risk of hypertriglyceridemia and hyper-low density lipoprotein cholesterolemia. Hyperthyroidism was significantly correlated with a reduced risk of hypercholesterolemia and hyper-low density lipoprotein cholesterolemia but positively correlated with the risk of low-high density lipoprotein cholesterolemia. There was no significant association between subclinical hyperthyroidism and blood lipids. Hypothyroidism increased the risk of hypertriglyceridemia in both premenopausal and postmenopausal females. Subclinical hypothyroidism was significantly associated with increased hypertriglyceridemia and low-high density lipoprotein cholesterolemia in premenopausal females. Hyperthyroidism was significantly associated with a reduced risk of hypercholesterolemia and hyper-low density lipoprotein cholesterolemia in premenopausal females and an increased risk of low-high density lipoprotein cholesterolemia in postmenopausal female. Abnormal thyroid function has an important effect on blood lipids and is closely related to female menopause.


Simvastatin-induced dermatomyositis in a 50-year-old man.
Dermatomyositis (DM) is a rare inflammatory autoimmune disease for which an iatrogenic origin has been described in a few cases. The authors report a case of DM occurring after simvastatin intake. A 50-year-old male sought medical attention for a photodistributed rash and considerable muscular weakness present for 3 months. One year earlier, simvastatin had been introduced. Serum creatine kinase levels were elevated. Histological examination of a muscle biopsy was consistent with a diagnosis of DM. Investigation for neoplasia and associated autoimmune disease proved negative. All clinical and laboratory abnormalities diminished corticosteroid therapy (1 mg/kg/day). Case reports have suggested that lipid-lowering drugs, especially statins, could induce or reveal chronic muscle diseases. In statins myopathy, reduction of coenzyme Q has been discussed as a key mechanism. Our case of DM in a patient receiving simvastatin adds to the previous reported cases in the literature and highlights the potential role of statins as triggers of immune systemic diseases.


Evaluation of acellular pertussis vaccine: comparisons among different strains of mice.
The current study was designed to comparatively analyse the reactions of different mouse strains in response to acellular pertussis (aP) vaccine, with attempt to further provide a reference for aP vaccine evaluation. NIH mice, ICR mice, and BALB/c mice adopted from different pharmacopoeias and studies were utilized to measure the immune protection and immunogenicity of the same batch of aP vaccine according to the Modified intracerebral challenge assay (MICA) from some Asian pharmacopoeias and the pertussis serological potency test (PTST) method from European Pharmacopoeia. Based on our results, the aP vaccine detected by NIH mice had the best potency. So the NIH mice were more suitable for detecting the immune protection of aP vaccine by the MICA method. Given that the levels of PT-IgG and FHA-IgG antibodies in ICR mice were the highest, and the levels of Th1 and Th2 cells were significantly increased (P < .01), it was more suitable for the detection of immunogenicity of aP vaccine by PSPT method. Spleen lymphocytes were stimulated by PT and FHA. And the levels of IL-4 in ICR mice and NIH mice were significantly increased, so were the levels of IL-17, IL-23, IL-27, and TNF-α in BALB/c mice. NIH mice have stronger adaptive immunity and the weakest inflammatory response, and ICR mice have enhanced adaptive immunity and inflammatory responses, both of which can be thereby used for evaluation by different pharmacopoeia methods. NIH was more suitable for the MICA method of Chinese Pharmacopoeia, and ICR for the PSPT method of European Pharmacopoeia.


Current-induced effective Dzyaloshinskii-Moriya interaction and its Kondo enhancement in double quantum dot.
We studied the nonequilibrium transport of serially coupled double quantum dots connected to ferromagnetic electrodes. We demonstrated that the nonadiabatic part of the spin gauge field resulted in a current-induced Dzyaloshinskii-Moriya (DM) interaction effect in a double quantum dot and numerically confirmed this observation through the hierarchical equations of motion approach. We report that the spin current and the effective DM interaction are enhanced in the Kondo regime. We demonstrate that this enhancement occurs because the Kondo resonance, which is supposed to be suppressed by the local ferromagnetic exchange, is enhanced by the inter-dot coupling. This additional Kondo resonance channel increases the spin current. In addition, the impact of the spin-spin interaction and the Kondo effect on tunnel magnetoresistance is discussed. Our results offer a new approach for controlling the non-collinear spin interaction in double quantum dot devices.


Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease.
Microvascular pericytes and the more recently discovered adventitial pericyte-like progenitor cells are a subpopulation of vascular stem cells closely associated with small and large blood vessels respectively. These populations of perivascular cells are remarkably abundant in the heart. Pericytes control important physiological processes such as angiogenesis, blood flow and vascular permeability. In the heart, this pleiotropic activity makes pericytes extremely interesting for applications in regenerative medicine. On the other hand, dysfunction of pericytes could participate in the pathogenesis of cardiovascular disease, such as arterial hypertension, fibro-calcific cardiovascular remodeling, myocardial edema and post-ischemic coronary no-reflow. On a therapeutic standpoint, preclinical studies in small animal models of myocardial infarction have demonstrated the healing potential of pericytes transplantation, which has been ascribed to direct vascular incorporation and paracrine pro-angiogenic and anti-apoptotic activities. These promising findings open the door to the clinical use of pericytes for the treatment of cardiovascular diseases.


Basic Verification of β-D Glucan in Leukocyte-Rich Plasma for the Diagnosis of Deep Mycosis.
Currently, supplementary serological testing for β-D glucan (BDG) is often selected to diagnose deep mycosis in care covered by the health insurance in Japan. The Wako method used by our center has low sensitivity, and different studies have used different cut-off values due to factors that cause false positives and false negatives. One possible cause of false negatives is the use of platelet-rich plasma (PRP) as the sample material. Because phagocytic white blood cells (WBC) are precipitated by centrifugation and only plasma is measured, it seems unlikely that the actual amount of BDG is being measured when using PRP. Further, a frequent cause of false positives is contamination from blood products and gauze containing BDG. To resolve these issues, the blood cell separator, hydroxyethyl starch, is used to precipitate only the red blood cells to obtain leukocyte-rich plasma (LRP). We hypothesized that it might be possible to improve the diagnostic rate of deep mycosis by measuring the BDG content of plasma containing WBC and fungal components and by comparing the BDG content of PRP and LRP measured simultaneously. Healthy human blood, albumin-added blood, wrung-out gauze fluid-added blood, and fungal solution-added blood were prepared, and PRP and LRP were prepared using hydroxyethyl starch. The BDG content of each sample was measured using the Wako method and compared. In addition, PRP and LRP of fungal-added blood were Gram-stained and examined under a microscope, and the number of WBCs and phagocytosed fungi was counted visually and compared. Measuring the BDG content of LRP confirmed that there were no false positives with LRP, and in vitro experiments comparing albumin-added false-positive blood to fungal-added blood showed significant differences between PRP and LRP only in the fungal-added blood. Calculating the BDG-ratio (LRP/PRP) by measuring both LRP and PRP may eliminate false positives and false negatives of true deep mycosis and improve the diagnostic rate.


Estrogen-induced dendritic spine elimination on female rat ventromedial hypothalamic neurons that project to the periaqueductal gray.
Neurons of the ventromedial hypothalamic nucleus (VMH) that project to the periaqueductal gray (PAG) form a crucial segment of the motor pathway that produces the lordosis posture, the hallmark of female rat sexual behavior. One suggested mechanism through which estrogen facilitates lordosis is by remodeling synaptic connectivity within the VMH. For instance, estrogen alters VMH dendritic spine density. Little is known, however, about the local VMH microcircuitry governing lordosis nor how estrogen alters synaptic connectivity within this local circuit to facilitate sexual behavior. The goal of this study was to define better the neuron types within the VMH microcircuitry and to examine whether estrogen alters synaptic connectivity, as measured by dendritic spine density, on VMH projection neurons. A retrograde tracer was injected into the PAG of ovariectomized rats treated with vehicle or estradiol. Retrogradely labeled VMH neurons were filled with Lucifer yellow, then immunostained for estrogen receptor-alpha (ER alpha). VMH neurons that project to the PAG had more dendrites than functionally unidentified neurons. Additionally, VMH projection neurons could be subdivided into those located within the cluster of ER alpha-containing neurons and those medial to the cluster. Estrogen decreased spine density by 57% on the long primary dendrites of VMH projection neurons located within the ER alpha cluster but not on projection neurons medial to the cluster. Only 4% of the VMH projection neurons expressed ER alpha. These results suggest that estrogen may facilitate sexual behavior by decreasing spines selectively, via an indirect mechanism, on a subset of VMH neurons that project to the PAG.


Testosterone treatment of ovariectomized rats: effects on lipolysis regulation in adipocytes.
The effects of testosterone treatment (2 mg every 14 days, for three months) on adipocyte lipolysis of intact (250-300 g body weight) and ovariectomized female rats were studied. Testosterone treatment of intact rats had no effect. Ovariectomy was followed by an increase in fat cell size and a decrease of lipolysis stimulated by isoproterenol, norepinephrine, epinephrine, forskolin, cAMP and isobutylmethylxantine. The number of beta-adrenergic receptors was reduced. There was, however, no change in the antilipolytic effects of UK 14,304 (alpha 2-adrenergic agonist), nicotinic acid, N6-phenylisopropyladenosine or insulin. Testosterone treatment of ovariectomized rats restored the number of beta-adrenoceptors and lipolysis stimulated by cAMP and isobutylmethylxantine, but not lipolysis stimulated by catecholamines and forskolin, suggesting a remaining defect in the catalytic unit of adenylate cyclase. These results indicate that ovariectomy is followed by a profound derangement of the lipolytic pathway at several levels, from beta-adrenoceptors number to the triglyceride lipase activity. This is partially restored by treatment with testosterone, which, however, has no effect on intact female rats. This study emphasizes the importance of ovarian integrity for the lipolytic regulation and the inability of testosterone to replace ovarian function in this regard or to affect lipolysis in intact female rats.


Dissociating location-specific inhibition and attention shifts: evidence against the disengagement account of contingent capture.
The study of attentional capture has provided a rich context for assessing the relative influence of top-down and bottom-up factors in visual perception. Some have argued that attentional capture by a salient, irrelevant stimulus is contingent on top-down attentional set (e.g., Folk, Remington, & Johnston, Journal of Experimental Psychology: Human Perception and Performance 18:1030-1044, 1992). Others, however, have argued that capture is driven entirely by bottom-up salience and that top-down factors influence the postallocation speed of disengagement from the irrelevant stimulus (e.g., Theeuwes, Acta Psychologica 135:77-99, 2010a). In support of this speed-of-disengagement hypothesis, recent findings from the modified spatial-cuing paradigm show that cues carrying a no-go target property produce reverse, or negative, cuing effects, consistent with inhibition of the cue location from which attention has been very quickly disengaged (Belopolsky, Schreij, & Theeuwes, Perception, & Psychophysics, 72, 326-341, 2010). Across six experiments, we show that this inhibitory process can be dissociated from shifts of spatial attention and is, thus, not a reliable marker of capture. We conclude that the data are inconsistent with the predictions of the disengagement hypothesis.


Appetitive conditioning in neonatal rats: conditioned ingestive responding to stimuli paired with oral infusions of milk.
Components of rat pups' ingestive responses to orally infused milk came to be elicited by a novel odor conditioned stimulus (cedar) that had been repeatedly paired with milk infusions (Experiment I). Pups responded specifically to one odor, and they did not generalize their conditioned responding to either another odor or an unscented airstream (Experiment II). Ingestive responses could also be conditioned to a vibrotactile CS paired with milk, although levels of conditioned responding were lower than were obtained with an odor CS (Experiment III). Pups' internal state determined the effectiveness of training, in that pups that were removed from their dam for 24 hr showed reliable conditioned responding, while nondeprived pups and dehydrated pups did not (Experiment IV). Finally, pups showed retention of conditioned responding for at least several days after training (Experiment V).


Optimum pelvic incidence minus lumbar lordosis value after operation for patients with adult degenerative scoliosis.
Schwab classification for adult degenerative scoliosis (ADS) concluded that health-related quality of life was closely related to curve type and three sagittal modifiers. It was suggested that pelvic incidence minus lumbar lordosis value (PI-LL) should be corrected within -10°~+10°. However, recent studies also indicated that ideal clinical outcomes could also be achieved in patients without the ideal PI-LL mentioned above. This study evaluated the relation between the clinical outcomes and the PI-LL of Chinese patients with ADS who received long posterior internal fixation and fusion. This was a single-center retrospective comparative study of patients treated by long posterior internal fixation and fusion in our hospital between 2010 and 2014. Inclusion criteria were age >45 years at the time of surgery, Cobb angle of lumbar curves ≥10°, long posterior internal fixation and fusion ≥least 3 motion segments, follow-up ≥2 years, complete preoperative and postoperative radiographic data, and functional evaluation results. Exclusion criteria were history of previous lumbar spine surgery, other kinds of scoliosis, history of severe spinal trauma, spinal tumor, ankylosing spondylitis, and spinal tuberculosis. Seventy-four patients were enrolled in this study. Operative parameters included intraoperative blood loss, duration of surgery, length of hospital stay, number of fusion levels, and decompression. The radiological measurements included Cobb angle of the curves and PI-LL. Clinical outcomes were evaluated by the Japanese Orthopaedic Association score, Oswestry Disability Index (ODI), visual analog scale, and Lumbar Stiffness Disability Index (LSDI). In addition, the complications of surgery were also collected. One-way analysis of variance, Student t test, Kruskal-Wallis test, Pearson chi-square test, and curve estimation were calculated for variables. All the patients were divided into Group 1 (long instrumentation and fusion to L5) and Group 2 (long instrumentation and fusion to S1). Operative parameters, radiological measurements, clinical outcomes, and complications of surgery were compared between two groups to confirm whether distal fusion level could influence therapeutic effect. Then patients were divided into PI-LL<10° (Group A), 10°≤PI-LL≤20° (Group B), PI-LL>20° (Group C). Operative parameters, radiological measurements, clinical outcomes, and complications of surgery were compared between each of the two groups. Curve estimation was performed to evaluate the relationship between postoperative PI-LL and clinical outcomes. No difference was found between Group 1 and Group 2 in all postoperative parameters (p>.05). There were significant differences in final ODI (p<.001) and final LSDI (p<.001) among Group A, Group B, and Group C. Cubic curve model fitted the relationship between PI-LL and final ODI better than other models (R2=0.379, p<.001). Cubic curve model fitted the relationship between PI-LL and final LSDI better than other models (R2=0.691, p<.001). There was a significant difference in proximal junctional kyphosis (PJK) among groups (p=.038). No significant difference was found in other parameters. Optimal PI-LL value may be achieved between 10° and 20° in Chinese patients with ADS after long posterior instrumentation and fusion surgery with excellent clinical outcomes and a lower PJK occurrence.


Cardiac sympathetic nerve activity during kainic acid-induced limbic cortical seizures in rats.
We sought to define changes in cardiac sympathetic nerve activity that occur during seizures. We studied kainic acid-induced limbic cortical seizures in urethane-anesthetized rats using cardiac sympathetic nerve, blood pressure, and electrocardiography (ECG) recordings. We studied changes in ventilation rate before and during seizures. Cardiac sympathetic nerve activity was increased during limbic cortical seizures. The modest increases were similar to changes induced by nitroprusside infusion. The normal relation of cardiac sympathetic nerve activity to ventilation rate was lost during seizure activity. Changes in cardiac sympathetic nerve activity caused by changes in ventilation rate became unpredictable, and could be extreme. We conclude that the modest changes in cardiac sympathetic nerve activity contribute to the predominantly parasympathetic effects on the heart during limbic cortical seizures and periods of asphyxia. Further, ventilation rate changes might be associated with large sudden increases or decreases in cardiac sympathetic outflow during seizures.


Dynamic analysis of a modified algae and fish model with aggregation and Allee effect.
In the paper, under the stress of aggregation and reproduction mechanism of algae, we proposed a modified algae and fish model with aggregation and Allee effect, its main purpose was to further ascertain the dynamic relationship between algae and fish. Several critical conditions were investigated to guarantee the existence and stabilization of all possible equilibrium points, and ensure that the model could undergo transcritical bifurcation, saddle-node bifurcation, Hopf bifurcation and B-T bifurcation. Numerical simulation results of related bifurcation dynamics were provided to verify the feasibility of theoretical derivation, and visually demonstrate the changing trend of the dynamic relationship. Our results generalized and improved some known results, and showed that the aggregation and Allee effect played a vital role in the dynamic relationship between algae and fish.


Single-Cell Stimulation in Barrel Cortex Influences Psychophysical Detection Performance.
A single whisker stimulus elicits action potentials in a sparse subset of neurons in somatosensory cortex. The precise contribution of these neurons to the animal's perception of a whisker stimulus is unknown. Here we show that single-cell stimulation in rat barrel cortex of both sexes influences the psychophysical detection of a near-threshold whisker stimulus in a cell type-dependent manner, without affecting false alarm rate. Counterintuitively, stimulation of single fast-spiking putative inhibitory neurons increased detection performance. Single-cell stimulation of putative excitatory neurons failed to change detection performance, except for a small subset of deep-layer neurons that were highly sensitive to whisker stimulation and that had an unexpectedly strong impact on detection performance. These findings indicate that the perceptual impact of excitatory barrel cortical neurons relates to their firing response to whisker stimulation and that strong activity in a single highly sensitive neuron in barrel cortex can already enhance sensory detection. Our data suggest that sensory detection is based on a decoding mechanism that lends a disproportionally large weight to interneurons and to deep-layer neurons showing a strong response to sensory stimulation.SIGNIFICANCE STATEMENT Rat whisker somatosensory cortex contains a variety of neuronal cell types with distinct anatomical and physiological characteristics. How each of these different cell types contribute to the animal's perception of whisker stimuli is unknown. We explored this question by using a powerful electrophysiological stimulation technique that allowed us to target and stimulate single neurons with different sensory response types in whisker cortex. In awake, behaving animals, trained to detect whisker stimulation, only costimulation of single fast-spiking inhibitory neurons or single deep-layer excitatory neurons with strong responses to whisker stimulation enhanced detection performance. Our data demonstrate that single cortical neurons can have measurable impact on the detection of sensory stimuli and suggest a decoding mechanism based on select cell types.


Perisynaptic Schwann Cells at the Neuromuscular Synapse: Adaptable, Multitasking Glial Cells.
The neuromuscular junction (NMJ) is engineered to be a highly reliable synapse to carry the control of the motor commands of the nervous system over the muscles. Its development, organization, and synaptic properties are highly structured and regulated to support such reliability and efficacy. Yet, the NMJ is also highly plastic, able to react to injury and adapt to changes. This balance between structural stability and synaptic efficacy on one hand and structural plasticity and repair on another hand is made possible by the intricate regulation of perisynaptic Schwann cells, glial cells at this synapse. They regulate both the efficacy and structural plasticity of the NMJ in a dynamic, bidirectional manner owing to their ability to decode synaptic transmission and by their interactions via trophic-related factors.


Emerging role of monoamine oxidase as a therapeutic target for cardiovascular disease.
In the past decade, accumulating evidence highlighted the role of monoamine oxidases (MAOs) in cardiovascular disease (CVD). MAOs are flavoenzymes located in the outer mitochondrial membrane, responsible for the degradation of neurotransmitters and biogenic amines. During this process they generate hydrogen peroxide, aldehydes and ammonia, species that can target mitochondria and induce mitochondrial dysfunction and cardiomyocyte death. Indeed, MAO inhibition affords cardioprotection in several models of CVD, such as ischemia/reperfusion, heart failure and diabetes. Importantly, a few studies provided encouraging results suggesting that MAO inhibition might be beneficial also in patients with CVD. Thus, selective and reversible MAO inhibitors, currently used as therapy for depression and neurodegenerative disorders, might be considered as candidate drugs for the treatment of CVD.


Synthesis and investigation of physico-chemical properties of dicationic ionic liquids.
A series of dicationic ionic liquids (ILs) including [C4(MIM)2][PF6]2, [C5(MIM)2][PF6]2, [C6(MIM)2][PF6]2 and [C4(PYR)2][PF6]2 were synthesized. Their thermal stability and melting points were analysed. It was found that dicationic ILs presented important implications in the design of homogeneous and heterogeneous system with water. A homogeneous system of dicationic ILs with water could be formed at a relatively high temperature and then a heterogeneous system was formed when the solution was cooled to a low temperature. The ILs recovered by altering the temperature were obtained in high percentage yields of [C4(MIM)2][PF6]2 (97.6%), [C5(MIM)2][PF6]2 (97.3%), [C6(MIM)2][PF6]2 (98.0%) and [C4(PYR)2][PF6]2 (94.2%). On the other hand, [C4(MIM)2][PF6]2 and [C5(MIM)2][PF6]2 exhibited good solubility in acetonitrile and acetone. A homogeneous system could be achieved with imidazolium-based ILs with a relatively low amount of water and acetonitrile at room temperature. All of the properties of dicationic ILs have a strong correlation with the nature of dications, the linkage chain and the symmetry of dications. Dicationic ILs may provide a new opportunity for some specific applications in order to enable the effective separation and isolation of products.


Pseudoxanthoma elasticum-like fibers in the inflamed skin of patients without pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is an inherited disorder leading to characteristic calcified elastic fibers in skin, eyes and vasculature. PXE-like fibers have not been described in inflammatory skin disease in the absence of other signs of PXE. The histopathology of inflamed skin from 13 patients that contained PXE-like fibers but lacked clinical evidence of PXE were studied. Six of these and six comparison specimens from known patients with PXE were subjected to polymerase chain reaction amplification and sequencing of exons 24 and 28 of the PXE-associated gene ABCC6. This genetic analysis employed a novel assay utilizing paraffin-embedded tissue. Incidental PXE-like fibers were found in patients without clinical suspicion of PXE in lesional tissue showing lipodermatosclerosis, granuloma annulare, lichen sclerosus, morphea profunda, erythema nodosum, septal panniculitis, basal cell carcinoma and fibrosing dermatitis. Two patients with PXE-like fibers but without clinical findings of PXE were heterozygous for a PXE-associated ABCC6 sequence alteration. This pilot study shows elastic fibers similar to those of PXE in the lesional skin of patients with a variety of inflammatory skin diseases in the absence of clinical evidence of PXE; and some of these patients harbor changes in ABCC6.


Bond durability of different resin cements to caries-affected dentin under simulated intrapulpal pressure.
To evaluate the durability of the bond of different resin cement systems to normal dentin (ND) and caries-affected dentin (CAD) with and without simulated intrapulpal pressure (IPP). Molars with midcoronal caries were used. Occlusal enamel was cut to expose both dentin substrates (ND and CAD). Dentin substrates were differentiated using visual, tactile, caries-detecting dye, and dye-permeability methods. Prepared crown segments were equally divided according to the tested resin cement systems: etch-and-rinse resin cement, self-etch resin cement containing methacryloyloxydecyl dihydrogen phosphate (MDP), and self-adhesive resin cement. In addition to the dentin substrates and the resin cement types, the effect of application/storage conditions (with or without simulated IPP and with or without thermocycling) were tested. A microtensile bond strength test was done using a universal testing machine. Failure modes were determined using a scanning electron microscope. Etch-and-rinse resin cement strength values were significantly affected by the difference in the dentin substrates as well as the different application/storage conditions. Self-etch adhesive containing MDP bonded equally to ND and CAD and remained stable under all tested conditions. Self-adhesive resin cement revealed a similar bond to ND and CAD; however, its values were the lowest, especially when IPP and thermocycling were combined. Mixed failure was the predominant failure mode. Etch-and-rinse resin cement was sensitive to dentin substrate and application/storage conditions. Resin cement with self-etch adhesive containing MDP revealed more reliable bonding to ND/CAD even when IPP and thermocycling were combined. The bonding of the self-adhesive resin cement could not compete with other resin cements.


Case of sodium-glucose cotransporter-2 inhibitor-associated euglycaemic diabetic ketoacidosis.
Following non-elective orthopaedic surgery, a 61-year-old man with poorly controlled type 2 diabetes mellitus on empagliflozin developed high anion gap metabolic acidosis in the high-dependency unit. Metabolic acidosis persisted despite intravenous sodium bicarbonate, contributing to tachycardia and a run of non-sustained ventricular tachycardia. He was euglycaemic throughout hospital admission. Investigations revealed elevated urine and capillary ketones, and a diagnosis of sodium-glucose cotransporter-2 inhibitor-associated euglycaemic diabetic ketoacidosis was made. He was treated with an intravenous sliding scale insulin infusion and concurrent dextrose 5% with potassium chloride. Within 24 hours of treatment, his arterial pH, anion gap and serum bicarbonate levels normalised. After a further 12 hours, the intravenous insulin infusion was converted to a basal/bolus regimen of subcutaneous insulin, and he was transferred to the general ward. He was discharged well on subcutaneous insulin 6 days postoperatively.


Elderly Patients with Colorectal Cancer - A Predisposed Category for Postoperative Complications.
Introduction: Colorectal cancer (CRC) is among the leading causes of cancer-related deaths around the world. Elderly patients are often considered as a high-risk category of patients, predisposed for postoperative complications. Materials and methods: 138 patients aged over 75 years and diagnosed with colorectal cancer were retrospectively reviewed. Patients were divided in two groups, as follows: Study Group including patients who developed postoperative complications, and Control Group including patients without problems in the postoperative period. There were compared clinical, preoperative, surgical, postoperative and oncological data. The aim of study was to determine possible risk factors for short-term postoperative complications and analyze of the influence of postoperative complications on survival. Results: Risk factors as male gender, obesity, heart failure, diabetes type II, severe anemia, low total protein level, ASA III-IV classification, emergency surgery, prolonged surgical intervention, increased intraoperative blood loss, prolonged hospital stay, distal localization of tumors, TNM stages III-IV, surgery for digestive cancer and non-cancerous major abdominal surgery in the medical history were identified. Conclusion: The surgical treatment of colorectal cancer in the aging population still remains a challenge, these category of patients should benefit of special attention in order to ensure a chance to minimize or avoid these complications.


Mesenteric Masses on 2D Mode and Contrast-Enhanced Ultrasound: A Retrospective Study in 69 Patients.
Detection of mesenteric masses (MM) by 2 D ultrasound often causes a diagnostic dilemma, and histological confirmation is required for definite diagnosis. The value of contrast-enhanced ultrasound (CEUS) for the diagnosis of MMs has not been investigated before. Here, we retrospectively evaluate 2D-mode and CEUS patterns of 69 patients with histologically confirmed MMs. Between January 2006 and January 2016, n = 69 patients were included in the study. Histopathological data, clinical data, 2D-mode ultrasound and CEUS enhancement were retrospectively analyzed. More than half of the MMs (n = 47/69, 68 %) revealed a malignant histology. The size of the MM, inflammation markers and clinical symptoms did not correlate with the histological outcome. 2 D mode revealed n = 46 (67 %) lesions as hypoechoic, n = 14 (20 %) as hyperechoic, and n = 9 (13 %) with a complex echo pattern. Hypoechogenicity and complex echo patterns as well as regular borders of MMs were significantly associated with malignancy (p < 0.05). On CEUS, malignant MMs showed arterial hyperenhancement (n = 11/47, 23 %), isoenhancement (n = 25/47, 52 %) and hypoenhancement (n = 7/47, 15 %). The majority of malignant MMs (n = 42/47, 89 %) revealed parenchymal hypoenhancement. Benign masses revealed arterial hyperenhancement in n = 1/22 (5 %), isoenhancement in n = 8/22 (36 %), and hypoenhancement in n = 10/22 (45 %). The majority of lesions showed parenchymal hypoenhancement (n = 19/22, 86 %). Hypoechogenicity and complex echogenicity in 2 D mode, irregular borders, and parenchymal wash-out were more often associated with malignancy. However, CEUS did not help to subclassify malignant MMs according to their histological entity.


Interactive region and volume growing for segmenting volumes in MR and CT images.
In radiation treatment planning it is necessary to mark out selected parts of CT or MR images which are clinically relevant before designing the treatment plan. This process is usually done manually with a mouse, and for a typical data set of some 40 slices it can be a time-consuming and tedious process. We report on a system for interactive region and volume growing that assists the clinical user in outlining relevant volumes. The algorithm detects regions of interest grown from a seed selected interactively by a user. The regions consist of connected areas or volumes having similar pixel intensity values. Threshold parameters for controlling the algorithm can be set interactively, or may be determined automatically from a sample region. Region growth can be successively extended into adjacent slices so building up a three-dimensional (3D volume. Direct 3D volume growth from a seed voxel is also possible. The algorithm has been integrated into one of the pilot systems developed as part of COVIRA, project A2003 in the EC's AIM programme.


Early invasive versus selectively invasive management for acute coronary syndromes.
Current guidelines recommend an early invasive strategy for patients who have acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level. However, randomized trials have not shown an overall reduction in mortality, and the reduction in the rate of myocardial infarction in previous trials has varied depending on the definition of myocardial infarction. We randomly assigned 1200 patients with acute coronary syndrome without ST-segment elevation who had chest pain, an elevated cardiac troponin T level (> or =0.03 mug per liter), and either electrocardiographic evidence of ischemia at admission or a documented history of coronary disease to an early invasive strategy or to a more conservative (selectively invasive) strategy. Patients received aspirin daily, enoxaparin for 48 hours, and abciximab at the time of percutaneous coronary intervention. The use of clopidogrel and intensive lipid-lowering therapy was recommended. The primary end point was a composite of death, nonfatal myocardial infarction, or rehospitalization for anginal symptoms within one year after randomization. The estimated cumulative rate of the primary end point was 22.7 percent in the group assigned to early invasive management and 21.2 percent in the group assigned to selectively invasive management (relative risk, 1.07; 95 percent confidence interval, 0.87 to 1.33; P=0.33). The mortality rate was the same in the two groups (2.5 percent). Myocardial infarction was significantly more frequent in the group assigned to early invasive management (15.0 percent vs. 10.0 percent, P=0.005), but rehospitalization was less frequent in that group (7.4 percent vs. 10.9 percent, P=0.04). We could not demonstrate that, given optimized medical therapy, an early invasive strategy was superior to a selectively invasive strategy in patients with acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level.


The KRÜPPEL-like transcription factor DATILÓGRAFO is required in specific cholinergic neurons for sexual receptivity in Drosophila females.
Courtship is a widespread behavior in which one gender conveys to the other a series of cues about their species identity, gender, and suitability as mates. In many species, females decode these male displays and either accept or reject them. Despite the fact that courtship has been investigated for a long time, the genes and circuits that allow females to generate these mutually exclusive responses remain largely unknown. Here, we provide evidence that the Krüppel-like transcription factor datilógrafo (dati) is required for proper locomotion and courtship acceptance in adult Drosophila females. dati mutant females are completely unable to decode male courtship and almost invariably reject males. Molecular analyses reveal that dati is broadly expressed in the brain and its specific removal in excitatory cholinergic neurons recapitulates the female courtship behavioral phenotype but not the locomotor deficits, indicating that these are two separable functions. Clonal analyses in female brains identified three discrete foci where dati is required to generate acceptance. These include neurons around the antennal lobe, the lateral horn, and the posterior superior lateral protocerebrum. Together, these results show that dati is required to organize and maintain a relatively simple excitatory circuit in the brain that allows females to either accept or reject courting males.


A validated HPLC method for the monitoring of thiopurine metabolites in whole blood in paediatric patients with inflammatory bowel disease.
Therapeutic drug monitoring (TDM) of major metabolites of thiopurine drugs is a widely used tool for assessing treatment efficacy and toxicity in patients with inflammatory bowel disease (IBD). We report the laboratory and clinical validation of a simple and reliable high performance liquid chromatography (HPLC) method for the measurement of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) on paediatric patients with IBD. The aim of this paper is to develop and validate a method for the measurement of 6-TGN and 6-MMP applicable to routine practice and to evaluate the usefulness of the TDM of thiopurine drugs in children with IBD attending our Gastroenterology Unit. The HPLC method was validated following international guidelines starting from red blood cells (RBC) and whole blood (WB). A comparison between RBC and WB was assessed. The usefulness of TDM was then evaluated using the new method from WB in 47 paediatric patients with IBD treated with thiopurine drugs. WB and RBC resulted in interchangeable matrices. The majority of patients had the metabolite levels inside the therapeutic ranges. A moderate correlation was found between 6-MMP concentration and the dose of thiopurines. A higher percentage of non responders was found among patients with lower levels of 6-TGN. Toxicity was found in eight patients and was evaluated in respect to the metabolite concentration. The described HPLC method is applicable to routine practice and it is suitable for its use in multicentric studies. Our results of TDM on paediatric IBD patients can contribute to clarify its role in their therapeutic management.


Neurotransmission and neurotoxicity by nitric oxide, catecholamines, and glutamate: unifying themes of reactive oxygen species and electron transfer.
This review treats the mechanism of nitric oxide, catecholamines, and glutamate as important neurotransmitters and as neurotoxins, based on involvement of reactive oxygen species (ROS) and electron transfer (ET). ROS and ET can serve as a unifying framework for both transmission and toxicity, with ROS concentration being a crucial issue. Cell signaling, electrochemistry, antioxidants, and apoptosis are also discussed.


[Prediction and analysis of the secreteomic in Trichoderma reesei].
We studied the secretomics' properties of Trichoderma reesei, an important industrial microorganism used for cellulase production. We analyzed the amino acid sequences coded by 9997 ORFs in Trichoderma reesei genome with bioinformatics approaches, identified 294 possible secreted protein sequences, and classified them by functions. We also applied motif search methods to search key motifs in the function-unknown sequences and preliminary predicted their functions. Moreover, we analyzed the signal peptide sequences of the secreted proteins. There were 188 hydrolytic enzymes in Trichoderma reesei's secretomics, including 114 glycosidases, 42 proteases, and 11 lipoidases. The glycosidases included 22 reported cellulases, and 15 chitinases, as well as 30 other protein sequences probably related to cellulose degradation. The homology of signal peptides of secreted proteins was low whereas sequences near the digesting site of signalase were conservative. This method gave insights into the whole secreted proteome of Trichoderma reesei and provided basis for further studies on secretomic features at a genome level.


Prevention of vitamin A deficiency by fortification of sugar. A field study.
The small amount of vitamin A in the diet of people living in some regions of Chile can be increased by adding this vitamin to sugar. In order to evaluate the effectiveness of a sugar fortification program, vitamin A fortified sugar was distributed to four indian villages in the mountainous region of Africa, whose inhabitants showed a severe vitamin A deficiency. The results of this study demonstrate that sugar fortification program is able to correct vitamin A deficiency by elevating the vitamin intake and consequently improve the circulating retinol, without substantially increasing the cost or modigying the organoleptic characteristics of sugar.


Immunocytochemical localization of heterologously expressed adrenodoxin and its electron acceptor cytochrome P45011B1 in Escherichia coli.
Adrenal steroid hydroxylase P45011B1 and its electron donor adrenodoxin were localized in the cortex of bovine adrenals by immunogold-silver staining. In order to test recently developed heterologous expression systems for both enzymes to enable structure-function studies, immunocytochemical marker methods were applied. Adrenodoxin, the ferredoxin of the adrenal gland, was successfully expressed and for the first time localized in Escherichia coli. By use of ultrathin cryosections and the protein A-gold technique, adrenodoxin was detectable in large amounts in the cytoplasm of the bacterial cells, and, following the insertion of the outer membrane protein A leader sequence of E. coli, also in the periplasmic space. A fusion protein between mature adrenodoxin and human P45011B1 was constructed and clearly localized in E. coli by antibodies against both proteins.


Siderophores in Cloud Waters and Potential Impact on Atmospheric Chemistry: Photoreactivity of Iron Complexes under Sun-Simulated Conditions.
In the present work, the photoreactivity of a mixture of iron(III)–pyoverdin (Fe(III)–Pyo) complexes was investigated under simulated cloud conditions. Pyoverdins are expected to complex ferric ions naturally present in cloudwater, thus modifying their availability and photoreactivity. The spectroscopic properties and photoreactivity of Fe(III)-Pyo were investigated, with particular attention to their fate under solar irradiation, also studied through simulations. The photolysis of the Fe(III)–Pyo complex leads to the generation of Fe(II), with rates of formation (RFe(II)f) of 6.98 and 3.96 × 10–9 M s–1 at pH 4.0 and 6.0, respectively. Interestingly, acetate formation was observed during the iron-complex photolysis, suggesting that fragmentation can occur after the ligand-to-metal charge transfer (LMCT) via a complex reaction mechanism. Moreover, photogenerated Fe(II) represent an important source of hydroxyl radical via the Fenton reaction in cloudwater. This reactivity might be relevant for the estimation of the rates of formation and steady-state concentrations of the hydroxyl radical by cloud chemistry models and for organic matter speciation in the cloud aqueous phase. In fact, the conventional models, which describe the iron photoreactivity in terms of iron–aqua and oxalate complexes, are not in accordance with our results.