Poor prognostic factors in patients with stage IB non-small cell lung cancer according to the seventh edition TNM classification.
This study investigated poor prognostic factors in patients with stage IB non-small cell lung cancer (NSCLC) according to the seventh edition of the TNM classification. Between July 1992 and December 2004, 1,204 consecutive patients with stage I NSCLC diagnosed based on the sixth edition TNM classification underwent complete resection with systematic node dissection. Of these patients, 434 were reclassified as stage IB according to the seventh edition TNM classification. Univariate analyses were performed using the log-rank test to select prognostic factors. The Cox proportional hazards regression model was used for multivariate analyses to identify independent factors indicating an unfavorable prognosis. On multivariate analyses, two variables were independent significant factors indicating an unfavorable prognosis: presence of intratumoral vascular invasion and presence of visceral pleural invasion. According to subgroup analyses combining these two risk factors, 5-year disease-specific survival probabilities were 93%, 83%, and 73% for patients with zero, one, or two risk factors, respectively. The 5-year disease-specific survival of patients without risk factors was not statistically different from that of patients with stage IA cancer. In addition, the 5-year disease-specific survival curve of patients with two risk factors lay beneath that of patients with T2b or T3N0M0, stage II cancer, and there were no statistically significant differences between them. We identified the presence of intratumoral vascular invasion and the presence of visceral pleural invasion as independent poor prognostic factors in patients with stage IB NSCLC. When these two factors are combined, higher- and lower-risk subgroups can be identified, which will help to personalize adjuvant chemotherapy.


Psychological morbidity among informal caregivers of older people: a 2-year follow-up study.
It has long been assumed that mental frailty in older care-recipients results in a deterioration in family caregivers' psychological well-being. This hypothesis has not been tested in longitudinal studies. Research about the impact on families of supporting older people in institutions is limited. The present study examined psychological morbidity in informal caregivers of frail older people at home and in institutions. Caregivers were followed up over 2 years. Predictors of psychological morbidity in caregivers and factors related to deterioration in their well-being over time were identified. Two-year panel survey of informal caregivers of older care-recipients, using semi-structured interview schedules and the 30-item GHQ. Care-recipients were those defined as physically or mentally frail after screening a stratified random sample of people aged > or = 65. Respondents were 276 caregivers of older people living at home at baseline and 47 visitors of those in long-term care at baseline. There were no differences in GHQ scores between caregivers at home and visitors, and no changes in GHQ score over time. The strongest predictors of psychological morbidity at follow-up, and of change in GHQ scores over time, were baseline GHQ score and indicators of subjective well-being. Characteristics of care-recipients, including frailty type (mental or physical), were not significantly associated with changes in caregivers' psychological morbidity. Mental frailty in care-recipients was not associated with deterioration over time in caregivers' psychological well-being. Caregiver characteristics were stronger than those of care-recipients in predicting psychological morbidity at follow-up and in predicting deteriorating well-being over time.


Strategies for iron supplementation: oral versus intravenous.
Iron supplementation has become an integral part of the management of patients receiving epoetin therapy, and clinicians have found it necessary to learn how and when to use it to the best advantage. Three routes of administration for iron are available: oral, intramuscular, and intravenous. Oral iron has the advantage of being simple and cheap, but it is limited by side-effects, poor compliance, poor absorption, and low efficacy. Intravenous iron is the best means of guaranteeing delivery of readily available iron to the bone marrow, but it requires greater clinical supervision. The i.v. iron preparations vary widely in their degradation kinetics, bioavailability, side-effect profiles, and maximum dose for single administration. Iron dextran is hampered by a small but significant risk of anaphylaxis, whereas all i.v. iron preparations can induce "free iron" reactions if the circulating plasma transferrin is overloaded. Intravenous iron may be given in advance of epoetin therapy, as concomitant treatment to prevent the development of iron deficiency, as treatment of absolute or functional iron deficiency, or as adjuvant therapy to enhance the response to epoetin in iron-replete patients. Markers of iron status that may indicate a need for i.v. iron include a serum ferritin of less than 100 microg/liter, a transferrin saturation of less than 20%, and a percentage of hypochromic red cells more than 10%. Various regimens are available for giving i.v. iron: low-dose administration of 20 to 60 mg every dialysis session in hemodialysis patients, medium-dose administration of 100 to 400 mg, and high-dose administration of 500 to 1000 mg. Iron sodium gluconate can only be given as a low-dose regimen because of toxicity, whereas the only preparation suitable for high-dose administration is iron dextran. Although concerns have been raised regarding iron overload and long-term toxicity with i.v. iron therapy in terms of increased risk of infections, cardiovascular disease, and malignancy, there is little evidence to substantiate this in patients receiving epoetin. Care should be taken, however, to prevent the serum ferritin rising above 800 to 1000 microg/liter and the transferrin saturation above 50%. Provided this is done, the benefits of i.v. iron almost certainly outweigh the risks in terms of optimizing the response to epoetin therapy.


Differential IL-17 production and mannan recognition contribute to fungal pathogenicity and commensalism.
In this study, we present evidence of differential Th17 responses in human monocyte-derived dendritic cells exposed to the pathogenic Candida albicans or the nonpathogenic Saccharomyces cerevisiae. We use different forms of the microorganisms, cells, hyphae, and spores, as a toolbox to dissect the role of surface mannan in the fungal immune response. In contrast to the S. cerevisiae yeast cell-induced Th1 response, dendritic cells stimulated with spores or C. albicans hyphae induce cellular responses shifted toward Th17 differentiation. The differential recognition of specific mannan structures is the master regulator of the discrimination between harmful and harmless fungi. The switch between spores and yeast is crucial for the commensalism of S. cerevisiae and depends on the use of a different receptor repertoire. Understanding the role of cell wall recognition during infection might lead to understanding the boundaries between safety and pathogenicity.


Histophatologic changes of lung in asthmatic male rats treated with hydro-alcoholic extract of Plantago major and theophylline.
Plantago major (P. major) is one of the medicinal crops in the world which has therapeutic properties for treatment of respiratory and gastrointestinal diseases. Theophylline is commonly used for the treatment of respiratory diseases. In this study, we investigated the protective effects of hydro-alcoholic extract of P. major on lung in asthmatic male rats. 32 male adult rats were randomly divided into 4 groups: The control group (C) received normal saline; Asthma (A) group received a normal diet; Asthma group treated with Theophylline (200 mg/kg b.w.) (T); Asthma group which received p.major (100 mg/kg b.w.) (P). Asthma was induced by citric acid, 0.1 mg in form of spraying. The injection of P.major extract and theophylline was administered intraperitoneally for four weeks. At the end of the treatment, all of the rats were sacrificed and lungs were taken out, fixed, and stained with H&E, toluidine blue, and PAS, then histological studies were followed with light microscope. RESULTS showed that, in asthmatic group, the mean number of mast cells was significantly increased (p<0.05). Thickness of alveolar epithelium and accumulation of glycoprotein in airways was increased. Moreover, in some of alveolar sac hemorrhaging was observed. Administration of p.major extract in asthmatic rats restored these changes towards normal group. The present study revealed that P. major compared with theophylline, has a protective effect on lung in asthmatic rats.


Earliest Bedside Assessment of Hemodynamic Parameters and Cardiac Biomarkers: Their Role as Predictors of Adverse Outcome in Patients with Septic Shock.
Early assessment and aggressive hemodynamic treatment have been shown to increase the survival of patients in septic shock. Current and past sepsis guidelines recommend a resuscitation protocol including central venous pressure (CVP), mean arterial blood pressure (MAP), urine output and central venous oxygen saturation (ScvO2) for resuscitation within the first six hours. Currently, the established severity score systems like APACHE II score, SOFA score or SAPS II score predict the outcome of critically ill patients on the bases of variables obtained only after the first 24 hours. The present study aims to evaluate the risk of short-term mortality for patients with septic shock by the earliest possible assessment of hemodynamic parameters and cardiac biomarkers as well as their role for the prediction of the adverse outcome. 52 consecutive patients treated for septic shock in the intensive care unit of one centre (Marien Hospital Herne, Ruhr University Bochum, Germany) were prospectively enrolled in this study. Hemodynamic parameters (MAP, CVP, ScvO2, left ventricular ejection fraction, Hematocrit) and cardiac biomarkers (Troponin I) at the ICU admission were evaluated in regard to their influence on mortality. The primary endpoint was all-cause mortality within 28 days after the admission. A total of 52 patients (31 male, 21 female) with a mean age of 71.4±8.5 years and a mean APACHE II score of 37.0±7.6 were enrolled in the study. 28 patients reached the primary endpoint (mortality 54%). Patients presenting with hypotension (MAP <65 mmHg) at ICU admission had significantly higher rates of 28-day mortality as compared with the group of patients without hypotension (28-day mortality rate 74 % vs. 32 %, p<0.01). Furthermore, the patients in the hypotension present group had significantly higher lactate concentration (p=0.002), higher serum creatinin (p=0.04), higher NTproBNP (p=0.03) and after the first 24 hours higher APACHE II scores (p=0.04). A MAP <65 mmHg was the only hemodynamic parameter significantly predicting the primary endpoint (OR: 4.1, CI: 1.1 - 14.8, p=0.008), whereas the remaining hemodynamic variables CVP, ScvO2, Hematocrit, Troponin I and left ventricular ejection fraction (LVEF) seemed to have no influence on survival. Besides, non-survivors had a significantly higher age (74.1±9.0 vs. 68.4±6.9, p=0.01). If hypotension coincided with an age ≥72 years, the 28-day mortality rate escalated to 88%. In our study, we identified a risk group with an exceedingly high mortality rate: the patients with an age ≥72 years and presenting with hypotension (MAP <65 mmHg). These data can be easily obtained at the time of the very first patient contact. As a result, an aggressive and a more effective treatment can be initiated within the first minutes of the primary care, possibly reducing organ failure and short-term mortality in this risk group.


Coexistence of magnetism and superconductivity in thin films of the Fe-based superconductor Ba1-xLaxFe2As2.
Magnetization measurements have been performed to understand the role of the magnetic structure on the superconducting properties of epitaxial thin films of Ba1-x La x Fe2As2 (x = 0.08, 0.13, and 0.18) deposited on single crystal (001)-oriented MgO substrates by pulsed laser deposition. All samples exhibit a reentrant-spinglass like behavior at normal state. At lower temperatures, we observe the same magnetic state coexisting with superconductivity and it is also observed a prominent non-linear giant diamagnetism in an intermediate temperature range just above the superconducting phase transition temperature. Furthermore, no significant change in the magnetic domain structure was detected by the onset of superconductivity. Based on their magnetic states, we claim that each domain (as a disconnected superconducting island) has its own bulk superconducting properties. Finally, we discussed the dual character played by the La atoms in the superconducting properties. That duality character has been also confirmed by analyzing resistivity data.


Measurement of pulpal blood flow in humans using laser Doppler flowmetry: a technique allowing stability and repeatability of pulpal blood flow measurement during surgical manipulations.
This study was undertaken to validate the repeatability of pulpal blood flow in human teeth with the laser Doppler flowmetry technique using a repeatable method of attachment of the laser Doppler probe. The variation in laser Doppler flowmetry measurements was evaluated over time periods that ranged from hours to days. In a prospective study, the pulpal blood flow was recorded from a maxillary central incisor (randomly selected) at a site directly gingival to the orthodontic bracket of three subjects. Measurements were made eight times over a 2-week period and every 30 minutes over 4 hours for eight recordings. The results indicated that there was only a slight difference between the temporal variability of the laser Doppler measurements over the course of 4 hours (intraday variability) or 2 weeks (interday variability). Furthermore, it appeared that subjects varied in their mean value recordings and may have varied widely in their respective signal-to-noise ratios.


Scleral punch method with topical mitomycin C for safe revision of failed deep sclerectomy in nanophthalmic uveal effusion syndrome.
To describe a novel surgical technique for revision of deep sclerectomy surgery in nanophthalmic uveal effusion syndrome. A 46-year-old woman with recessively inherited nanophthalmos and chronic uveal effusions underwent a revision of previous failed deep sclerectomy surgery. In the presence of scar tissue, revision of sclerectomies was greatly facilitated by the use of a Kelly scleral punch (Katena Products, Inc., Denville, NJ, USA). To inhibit further scarring, mitomycin-C (MMC) was applied topically in each quadrant posterior to the equator. The scleral punch allowed outward scleral dissection from the suprachoroidal space, and brisk enlargement of sclerectomies in all quadrants without perforation of choroidal tissue. Post-operative conjunctival wound healing appeared unimpeded by the posteriorly placed MMC sponges. Near-total resolution of the effusions had occurred by 3 months. The scleral punch provides a safe and effective method for constructing and revising full-thickness sclerectomies in the nanophthalmic eye, minimizing the risk of choroidal trauma. The use of topical MMC may reduce the risk of late failure of trans-scleral outflow due to fibrosis.


Cost-effectiveness of white cell-reduction filters in treatment of adult acute myelogenous leukemia.
The objective of this study was to compare the cost and cost-effectiveness of three transfusion strategies in the treatment of acute myelogenous leukemia: 1) the use of unfiltered pooled platelets until alloimmunization developed and of crossmatch-compatible single-donor platelets thereafter; 2) the use of filtered blood components until alloimmunization occurred and of crossmatch-compatible single-donor platelets thereafter; and 3) the use of single-donor platelets from the beginning. The data sources were English language articles on transfusion medicine in acute leukemia and the management of acute leukemia and review of the transfusion experience at the H. Lee Moffitt Cancer Center. The method was decision analysis with a software program for cost-effectiveness, sensitivity analysis, threshold evaluation, and Monte Carlo sensitivity analysis. In the basic models, the total costs of the first, second, and third strategies are, respectively, $12,557.14, $11,406.17, and $13,016.16 without bone marrow transplant and $14,002.72, $12,281.89, and $13,727.48 with bone marrow transplant. The threshold between the first and second strategies in regard to risk of refractoriness to filtered blood components and pooled platelets was 0.30 and 0.27, respectively, without bone marrow transplant and 0.28 and 0.40 with bone marrow transplant. According to a Monte Carlo sensitivity analysis of 500 samples, the second strategy is more cost-effective than the first in 76 percent of cases. It is concluded that the use of filtered blood components is unlikely to increase the cost of treatment.


Docosahexaenoic Acid Suppresses Silica-Induced Inflammasome Activation and IL-1 Cytokine Release by Interfering With Priming Signal.
Occupational exposure to respirable crystalline silica (cSiO2) has been etiologically linked to human autoimmunity. Intranasal instillation with cSiO2 triggers profuse inflammation in the lung and onset of autoimmunity in lupus-prone mice; however, dietary supplementation with the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) abrogates these responses. Inflammasome activation, IL-1 cytokine release, and death in alveolar macrophages following cSiO2 exposure are early and critical events that likely contribute to triggering premature autoimmune pathogenesis by this particle. Here we tested the hypothesis that DHA suppresses cSiO2-induced NLRP3 inflammasome activation, IL-1 cytokine release, and cell death in the macrophage. The model used was the murine macrophage RAW 264.7 cell line stably transfected with the inflammasome adapter protein ASC (RAW-ASC). Following priming with LPS, both the canonical activator nigericin and cSiO2 elicited robust inflammasome activation in RAW-ASC cells, as reflected by IL-1β release and caspase-1 activation. These responses were greatly diminished or absent in wild-type RAW cells. In contrast to IL-1β, cSiO2 induced IL-1α release in both RAW-ASC and to a lesser extent in RAW-WT cells after LPS priming. cSiO2-driven effects in RAW-ASC cells were confirmed in bone-marrow derived macrophages. Pre-incubating RAW-ASC cells with 10 and 25 μM DHA for 24 h enriched this fatty acid in the phospholipids by 15- and 25-fold, respectively, at the expense of oleic acid. DHA pre-incubation suppressed inflammasome activation and release of IL-1β and IL-1α by nigericin, cSiO2, and two other crystals - monosodium urate and alum. DHA's suppressive effects were linked to inhibition of LPS-induced Nlrp3, Il1b, and Il1a transcription, potentially through the activation of PPARγ. Finally, nigericin-induced death was inflammasome-dependent, indicative of pyroptosis, and could be inhibited by DHA pretreatment. In contrast, cSiO2-induced death was inflammasome-independent and not inhibited by DHA. Taken together, these findings indicate that DHA suppresses cSiO2-induced inflammasome activation and IL-1 cytokine release in macrophages by acting at the level of priming, but was not protective against cSiO2-induced cell death.


Improving resolution by the second-order correlation of light fields.
As important analysis tools, microscopes with high spatial resolution are indispensable for scientific research and clinical diagnosis. We report a proof-of-principle experimental demonstration of a two-arm microscope scheme and show that, by measuring the second-order correlation of light fields, more details of an object can be obtained through recording more information about the initial illumination field. The effects arising from the transverse coherence length and the axial correlation depth of the illumination field are also discussed.


In vitro mammalian cytotoxicological study of PAMAM dendrimers - towards quantitative structure activity relationships.
Dendritic polymer nanoparticles such as polyamidoamine dendrimers (PAMAM) show exciting potential for biomedical applications. While the potential commercial applications of such dendrimers have received considerable attention, little is known about their possible adverse effects on both humans and the environment. In this study, the in vitro cytotoxicocity of full generation PAMAM dendrimers to two mammalian cell lines was investigated. Generations G4, G5 and G6 were chosen. Metabolic, lysosomal and mitochondrial activities were evaluated after 24h exposure. Long term toxicity was evaluated using the clonogenic assay. Particle size and zeta potential were measured in all media. In culture medium, the particle size was largely unchanged from that observed in phosphate buffer. The zeta potential changed significantly, however, from positive in deionized water to negative in culture medium. A linear correlation was found between the change in zeta potential of the dendrimers in media and their surface area measured in phosphate buffer. The interaction of the dendrimer nanoparticles with 5% FBS supplemented media was also studied using UV/visible spectroscopy. The data suggest significant interaction of nanoparticles with FBS and other media components which increased with dendrimer generation. The toxicity also correlated linearly with the zeta potential and notably the change in zeta potential in the media, further pointing towards indirect toxic mechanisms. A trend of generation dependent toxic response and interaction of the dendrimers with the cell culture media was observed which may lay the basis of structure activity relationships.


HIV testing and care in Canadian Aboriginal youth: a community based mixed methods study.
HIV infection is a serious concern in the Canadian Aboriginal population, particularly among youth; however, there is limited attention to this issue in research literature. The purpose of this national study was to explore HIV testing and care decisions of Canadian Aboriginal youth. A community-based mixed-method design incorporating the Aboriginal research principles of Ownership, Control, Access and Possession (OCAP) was used. Data were collected through surveys (n = 413) and qualitative interviews (n = 28). Eleven community-based organizations including urban Aboriginal AIDS service organizations and health and friendship centres in seven provinces and one territory assisted with the recruitment of youth (15 to 30 years). Average age of survey participants was 21.5 years (median = 21.0 years) and qualitative interview participants was 24.4 years (median = 24.0). Fifty-one percent of the survey respondents (210 of 413 youth) and 25 of 28 interview participants had been tested for HIV. The most common reason to seek testing was having sex without a condom (43.6%) or pregnancy (35.4%) while common reasons for not testing were the perception of being low HIV risk (45.3%) or not having had sex with an infected person (34.5%). Among interviewees, a contributing reason for not testing was feeling invulnerable. Most surveyed youth tested in the community in which they lived (86.5%) and 34.1% visited a physician for the test. The majority of surveyed youth (60.0%) had tested once or twice in the previous 2 years, however, about one-quarter had tested more than twice. Among the 26 surveyed youth who reported that they were HIV-positive, 6 (23.1%) had AIDS at the time of diagnosis. Delays in care-seeking after diagnosis varied from a few months to seven years from time of test. It is encouraging that many youth who had tested for HIV did so based on a realistic self-assessment of HIV risk behaviours; however, for others, a feeling of invulnerability was a barrier to testing. For those who tested positive, there was often a delay in accessing health services.


Anti-MDA5 Associated Clinically Amyopathic Dermatomyositis With Rapidly Progressive Interstitial Lung Disease.
Anti-melanoma differentiation-associated protein 5 (anti-MDA5) associated clinically amyopathic dermatomyositis (CADM) is a rare entity that is frequently associated with rapidly progressive interstitial lung disease. The disease is characterized by its association with a distinct myositis specific antibody, the lack of muscle involvement seen with other inflammatory myopathies, and a strong correlation with the development of rapidly progressive interstitial lung disease. Diagnosis is based on clinical findings and the presence of autoantibodies. Management generally involves combination immunosuppression therapy. However, the disease course is often aggressive and lends a poor prognosis. We report a case of a healthy 55-year-old male who presented with dyspnea, dry cough, and joint pain for 1 month. The patient was diagnosed with anti-MDA5 associated CADM with interstitial lung disease after a complete rheumatological workup found elevated titers of MDA5 antibodies and computed tomography of the chest without contrast revealed radiographic evidence of interstitial lung involvement. Disease course was complicated by the development of Pneumocystis pneumonia as a result of profound immunosuppression from combination immunosuppressant therapy. Our patient eventually succumbed to his illness approximately 10 weeks following initial symptom onset. This case highlights the aggressive nature of the disease and the challenges in management. Further research is warranted to establish more effective therapeutic options.


High-resolution micro-Doppler imaging during neurosurgical resection of an arteriovenous malformation: illustrative case.
Given the high-risk nature of arteriovenous malformation (AVM) resections, accurate pre- and intraoperative imaging of the vascular morphology is a crucial component that may contribute to successful surgical results. Surprisingly, current gold standard imaging techniques for surgical guidance of AVM resections are mostly preoperative, lacking the necessary flexibility to cater to intraoperative changes. Micro-Doppler imaging is a unique high-resolution technique relying on high frame rate ultrasound and subsequent Doppler processing of microvascular hemodynamics. In this paper the authors report the first application of intraoperative, coregistered magnetic resonance/computed tomograpy, micro-Doppler imaging during the neurosurgical resection of an AVM in the parietal lobe. The authors applied intraoperative two-dimensional and three-dimensional (3D) micro-Doppler imaging during resection and were able to identify key anatomical features including draining veins, supplying arteries and microvasculature in the nidus itself. Compared to the corresponding preoperative 3D-digital subtraction angiography (DSA) image, the micro-Doppler images could delineate vascular structures and visualize hemodynamics with higher, submillimeter scale detail, even at significant depths (>5 cm). Additionally, micro-Doppler imaging revealed unique microvascular morphology of surrounding healthy vasculature. The authors conclude that micro-Doppler imaging in its current form has clear potential as an intraoperative counterpart to preoperative contrast-dependent DSA, and the microvascular details it provides could build new ground to further study cerebrovascular pathophysiology.


A glutamate-activated chloride current in cone-driven ON bipolar cells of the white perch retina.
Cone-driven ON-type bipolar cells were patch clamped in white perch retinal slices. Application of glutamate activated a current (IGlu) that was mediated by a conductance increase. The reversal potential for IGlu followed ECl closely when the intracellular chloride concentration was varied. IGlu was not blocked by 100 microM picrotoxin or 1 microM strychnine, indicating that it was not caused by inhibitory input. IGlu is not mediated by a typical ionotropic glutamate receptor since it was not activated by kainate, AMPA, or NMDA, or blocked by kynurenic acid, CNQX, DNQX, or AP-V. Further, IGlu is not mediated by a known metabotropic glutamate receptor since it was not activated by quisqualic acid, AP-4, ACPD, or ibotenate. IGlu required the presence of extracellular sodium and could be partially inhibited by the glutamate uptake inhibitors THA and tPDC. This is suggestive of sodium-dependent glutamate transport. However, when intracellular sodium was greatly increased, neither the magnitude nor reversal potential of IGlu was substantively affected. Thus, IGlu appears to involve a chloride channel activated by a glutamate receptor with transporter-like pharmacology. IGlu is localized to the dendrites of the bipolar cell, where bipolar cells receive an endogenous glutamatergic input from photoreceptors. Further, the reversal potential of the light response in these cells is the same as that of IGlu. Thus, it seems likely that IGlu is the current responsible for the cone component of the ON bipolar cell light response in the teleost retina.


ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.
This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.


Mechanism of bariatric and metabolic surgery: beyond surgeons, gastroenterologists and endocrinologists.
Bariatric-metabolic surgery is the safest, most effective and long-lasting treatment for obesity and its associated co-morbidities, whether they be metabolic (type 2 diabetes, hyperlipidemia non-alcoholic fatty liver disease) or cardiovascular (myocardial infarction, stroke). Due to the obesity pandemic, bariatric-metabolic surgery is the second most frequent intra-abdominal procedure and the gastroenterologist and the surgeon must be aware of the physiologic changes caused by the anatomic reconfiguration following surgery. Among the mechanisms of action, independent of the loss of weight and fat tissue, surgery leads to the release of gut hormones related to carbohydrate metabolism (the rapid and continuous release of insulin), appetite and degree of satiety (glucagon-like peptide 1, peptide Y-Y, grhelin). As a result, indications for surgery have been extended to earlier disease stages. Apart from the neurohormonal effects, changes in the metabolism of biliary acids and the microbiota have also been reported. The aim of this review is to describe the physiologic changes caused by bariatric-metabolic surgery.


The Effects of Unsupervised Home-based Exercise Upon Functional Capacity After 6 Months of Discharge From Cardiac Rehabilitation: A Retrospective Observational Study.
It remains unclear whether self-regulated exercise is sufficient to maintain the benefits acquired during formal cardiac rehabilitation (CR). This retrospective observational study investigated the effects of a home-based exercise intervention after discharge from CR upon anthropometric and aerobic capacity markers in clinically stable patients. Fifty patients with cardiovascular disease were discharged after 6 months of CR and encouraged to maintain aerobic exercise without supervision. Subsequent to 6 months of follow-up, patients were assigned to compliant (n = 34) or noncompliant (n = 16) groups according to their compliance to the home-based program. Maximal aerobic capacity (VO2peak) and anthropometric data were assessed before CR, at discharge, and after 6 months of follow-up. No statistical differences between compliant and noncompliant groups were observed at baseline and at discharge from CR. At the end of the follow-up, statistical differences across groups were not found for body mass or body mass index, but increases in VO2peak (+3.6 vs. -0.6 ml/kg·min, P = 0.004) and oxygen pulse (+1.5 vs. +0.2 ml/bpm, P = .03) were greater in compliant than noncompliant group. Self-regulated exercising following CR discharge seems to be effective to maintain gains in exercise capacity acquired during supervised center-based programs.


String method solution of the gating pathways for a pentameric ligand-gated ion channel.
Pentameric ligand-gated ion channels control synaptic neurotransmission by converting chemical signals into electrical signals. Agonist binding leads to rapid signal transduction via an allosteric mechanism, where global protein conformational changes open a pore across the nerve cell membrane. We use all-atom molecular dynamics with a swarm-based string method to solve for the minimum free-energy gating pathways of the proton-activated bacterial GLIC channel. We describe stable wetted/open and dewetted/closed states, and uncover conformational changes in the agonist-binding extracellular domain, ion-conducting transmembrane domain, and gating interface that control communication between these domains. Transition analysis is used to compute free-energy surfaces that suggest allosteric pathways; stabilization with pH; and intermediates, including states that facilitate channel closing in the presence of an agonist. We describe a switching mechanism that senses proton binding by marked reorganization of subunit interface, altering the packing of β-sheets to induce changes that lead to asynchronous pore-lining M2 helix movements. These results provide molecular details of GLIC gating and insight into the allosteric mechanisms for the superfamily of pentameric ligand-gated channels.


Sexually transmitted parasitic diseases.
An increasing number of diseases are recognized as being sexually transmitted. The majority of these are bacterial or viral in nature; however, several protozoan and nematode infections can also be transmitted by sexual activity. For most of these diseases, the primary mode of transmission is nonsexual in nature, but sexual activity that results in fecal-oral contact can lead to transmission of these agents. Two parasitic diseases commonly transmitted by sexual contact are amebiasis and giardiasis. The management of these conditions is discussed.


Multi-trait mimicry of ants by a parasitoid wasp.
Many animals avoid attack from predators through toxicity or the emission of repellent chemicals. Defensive mimicry has evolved in many species to deceive shared predators, for instance through colouration and other morphological adaptations, but mimicry hardly ever seems to involve multi-trait similarities. Here we report on a wingless parasitoid wasp that exhibits a full spectrum of traits mimicing ants and affording protection against ground-dwelling predators (wolf spiders). In body size, morphology and movement Gelis agilis (Ichneumonidae) is highly similar to the black garden ant (Lasius niger) that shares the same habitat. When threatened, G. agilis also emits a volatile chemical that is similar to an ant-produced chemical that repels spiders. In bioassays with L. niger, G. agilis, G. areator, Cotesia glomerata and Drosophila melanogaster, ants and G. agilis were virtually immune to spider attack, in contrast the other species were not. Volatile characterisation with gas chromatography-mass spectrometry identified G. agilis emissions as 6-methyl-5-hepten-2-one, a known insect defence semiochemical that acts as an alarm pheromone in ants. We argue that multi-trait mimicry, as observed in G. agilis, might be much more common among animals than currently realized.


Expression profile and subcellular localization of Torque teno sus virus proteins.
In the present study, the expression, generation and subcellular localization of Torque teno sus virus (TTSuV) proteins were characterized into two genetically distinct TTSuV species (TTSuV1 and TTSuV2). Following transfection of three TTSuV1 and TTSuV2 full-length ORF (ORF1, ORF2 and ORF3) expression constructs into porcine kidney cells, alternative splice variants encoding new TTSuV protein isoforms were identified for the first time. Proteins encoded from ORF1 and ORF3 were localized in the nucleoli of porcine kidney cells and that of ORF2 in the cytoplasm and nucleus excluding the nucleoli. The subcellular localization of the different protein isoforms was not only similar between distinct TTSuV species but also to the ones described in human Torque teno virus (TTV). Results of the present in vitro study were not based on full-length viral clones but suggested that alternative splicing strategy to generate TTSuV protein isoforms probably occurs in vivo. Obtained data provide new information on molecular biology of TTSuV and anelloviruses, which until now has been solely based on results obtained from human TTV.


The colorimetric detection and quantitation of total protein.
Protein quantification is an important step for handling protein samples for isolation and characterization; it is a prerequisite step before submitting proteins for chromatographic, electrophoretic, or immunochemical analysis and separation. Colorimetric methods are fast, simple, and not laborious. This unit describes a number of assays able to detect protein concentrations in the low microgram to milligram per milliliter ranges in a variety of formats.


A simple method to assess the oxidative susceptibility of low density lipoproteins.
BACKGROUND: Oxidative modification of low density lipoproteins (LDL) is recognized as one of the major processes involved in atherogenesis. The in vitro standardized measurement of LDL oxidative susceptibility could thus be of clinical significance. The aim of the present study was to establish a method which would allow the evaluation of oxidative susceptibility of LDL in the general clinical laboratory. RESULTS: LDL was isolated from human plasma by selective precipitation with amphipathic polymers. The ability of LDL to form peroxides was assessed by measuring thiobarbituric acid reactive substances (TBARS) after incubation with Cu2+ and H2O2. Reaction kinetics showed a three-phase pattern (latency, propagation and decomposition phases) which allowed us to select 150 min as the time point to stop the incubation by cooling and EDTA addition. The mixture Cu2+/H2O2 yielded more lipoperoxides than each one on its own at the same time end-point. Induced peroxidation was measured in normal subjects and in type 2 diabetic patients. In the control group, results were 21.7 +/- 1.5 nmol MDA/mg LDL protein, while in the diabetic group results were significantly increased (39.0 +/- 3.0 nmol MDA/mg LDL protein; p < 0.001). CONCLUSION: a simple and useful method is presented for the routine determination of LDL susceptibility to peroxidation in a clinical laboratory.


CRISPR interference can prevent natural transformation and virulence acquisition during in vivo bacterial infection.
Pathogenic bacterial strains emerge largely due to transfer of virulence and antimicrobial resistance genes between bacteria, a process known as horizontal gene transfer (HGT). Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci of bacteria and archaea encode a sequence-specific defense mechanism against bacteriophages and constitute a programmable barrier to HGT. However, the impact of CRISPRs on the emergence of virulence is unknown. We programmed the human pathogen Streptococcus pneumoniae with CRISPR sequences that target capsule genes, an essential pneumococcal virulence factor, and show that CRISPR interference can prevent transformation of nonencapsulated, avirulent pneumococci into capsulated, virulent strains during infection in mice. Further, at low frequencies bacteria can lose CRISPR function, acquire capsule genes, and mount a successful infection. These results demonstrate that CRISPR interference can prevent the emergence of virulence in vivo and that strong selective pressure for virulence or antibiotic resistance can lead to CRISPR loss in bacterial pathogens.


The MAPK kinase BcMkk1 suppresses oxalic acid biosynthesis via impeding phosphorylation of BcRim15 by BcSch9 in Botrytis cinerea.
The mitogen-activated protein kinase (MAPK) cassette of the cell wall integrity (CWI) pathway is primarily responsible for orchestrating changes of cell wall. However, functions of this cassette in other cellular processes are not well understood. Here, we found that the Botrytis cinerea mutant of MAPK kinase (BcMkk1) displays more serious defects in mycelial growth, conidiation, responses to cell wall and oxidative stresses, but possesses less reduced virulence than the mutants of its upstream (BcBck1) and downstream (BcBmp3) kinases. Interestingly, BcMkk1, but not BcBck1 and BcBmp3, negatively regulates production of oxalic acid (OA) and activity of extracellular hydrolases (EHs) that are proposed to be virulence factors of B. cinerea. Moreover, we obtained evidence that BcMkk1 negatively controls OA production via impeding phosphorylation of the Per-Arnt-Sim (PAS) kinase BcRim15 by the Ser/Thr kinase BcSch9. In addition, the fungal Pro40 homolog BcPro40 was found to interact simultaneously with three MAPKs, implying that BcPro40 is a scaffold protein of the CWI pathway in B. cinerea. Taken together, results of this study reveal that BcMkk1 negatively modulates virulence via suppressing OA biosynthesis in B. cinerea, which provides novel insight into conserved and species-specific functions of the MAPK kinase in fungi.


Striatal dopamine release codes uncertainty in pathological gambling.
Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors.


Contrasting Granite Metallogeny through the Zircon Record: A Case Study from Myanmar.
Granitoid-hosted mineral deposits are major global sources of a number of economically important metals. The fundamental controls on magma metal fertility are tectonic setting, the nature of source rocks, and magma differentiation. A clearer understanding of these petrogenetic processes has been forged through the accessory mineral zircon, which has considerable potential in metallogenic studies. We present an integrated zircon isotope (U-Pb, Lu-Hf, O) and trace element dataset from the paired Cu-Au (copper) and Sn-W (tin) magmatic belts in Myanmar. Copper arc zircons have juvenile εHf (+7.6 to +11.5) and mantle-like δ18O (5.2-5.5‰), whereas tin belt zircons have low εHf (-7 to -13) and heavier δ18O (6.2-7.7‰). Variations in zircon Hf and U/Yb reaffirm that tin belt magmas contain greater crustal contributions than copper arc rocks. Links between whole-rock Rb/Sr and zircon Eu/Eu* highlight that the latter can monitor magma fractionation in these systems. Zircon Ce/Ce* and Eu/Eu* are sensitive to redox and fractionation respectively, and here are used to evaluate zircon sensitivity to the metallogenic affinity of their host rock. Critical contents of Sn in granitic magmas, which may be required for the development of economic tin deposits, are marked by zircon Eu/Eu* values of ca. ≤0.08.


High human papillomavirus (HPV) prevalence in South African adolescents and young women encourages expanded HPV vaccination campaigns.
The objectives of the study were to investigate prevalence of cervical human papillomavirus (HPV) genotypes to inform HPV vaccination strategy in South Africa and to study factors associated with HPV prevalence. Sexually active, HIV-negative women, aged 16-22 years recruited from Soweto (n = 143) and Cape Town (n = 148) were tested for cervical HPV and other genital infections. Overall HPV prevalence was 66.7% (194/291) in young women. Cape Town women were more likely to have multiple HPV infections than the Soweto women (48.0%, 71/148 versus 35.0%, 50/143 respectively, p = 0.033) and probable HR-HPV types (34.5%, 51/148 versus 21.7%, 31/143 respectively, p = 0.022). The most frequently detected HPV types were HPV-16 (11.7%), HPV-58 (10.3%), HPV-51 (8.9%), HPV-66 (8.6%), HPV-18 and HPV-81 (7.6% each). HPV types targeted by the bivalent HPV vaccine (HPV-16/18) were detected in 18.6% (54/291) of women, while those in the quadrivalent vaccine (HPV-6/11/16/18) were detected in 24.7% (72/291) of women; and those in the nonavalent vaccine (HPV-6/11/16/18/31/33/45/52/58) were detected in 38.5% (112/291) of women. In a multivariable analysis, bacterial vaginosis remained significantly associated with HPV infection (OR: 4.0, 95% CI: 1.4-12.6). Women were more likely to be HPV positive if they had received treatment for STI during the past 6-months (OR: 3.4, 95% CI: 1.1-12.4) or if they had ever been pregnant (OR: 2.3, 95% CI: 1.1-5.5). Compared to women who reported only one sexual partner, those with increased number of lifetime sex partners were more likely to have HPV (4-10 partners: OR: 2.9, 95% CI: 1.1-8.0). The high prevalence of HPV types targeted by the nonavalent HPV vaccine encourages the introduction of this vaccine and catch-up HPV vaccination campaigns in South Africa. The high burden of BV and concurrent STIs also highlights the need to improve the prevention and appropriate management of sexually-acquired and other genital tract infections in South African youth.


HPTN 071 (PopART): rationale and design of a cluster-randomised trial of the population impact of an HIV combination prevention intervention including universal testing and treatment - a study protocol for a cluster randomised trial.
Effective interventions to reduce HIV incidence in sub-Saharan Africa are urgently needed. Mathematical modelling and the HIV Prevention Trials Network (HPTN) 052 trial results suggest that universal HIV testing combined with immediate antiretroviral treatment (ART) should substantially reduce incidence and may eliminate HIV as a public health problem. We describe the rationale and design of a trial to evaluate this hypothesis. A rigorously-designed trial of universal testing and treatment (UTT) interventions is needed because: i) it is unknown whether these interventions can be delivered to scale with adequate uptake; ii) there are many uncertainties in the models such that the population-level impact of these interventions is unknown; and ii) there are potential adverse effects including sexual risk disinhibition, HIV-related stigma, over-burdening of health systems, poor adherence, toxicity, and drug resistance.In the HPTN 071 (PopART) trial, 21 communities in Zambia and South Africa (total population 1.2 m) will be randomly allocated to three arms. Arm A will receive the full PopART combination HIV prevention package including annual home-based HIV testing, promotion of medical male circumcision for HIV-negative men, and offer of immediate ART for those testing HIV-positive; Arm B will receive the full package except that ART initiation will follow current national guidelines; Arm C will receive standard of care. A Population Cohort of 2,500 adults will be randomly selected in each community and followed for 3 years to measure the primary outcome of HIV incidence. Based on model projections, the trial will be well-powered to detect predicted effects on HIV incidence and secondary outcomes. Trial results, combined with modelling and cost data, will provide short-term and long-term estimates of cost-effectiveness of UTT interventions. Importantly, the three-arm design will enable assessment of how much could be achieved by optimal delivery of current policies and the costs and benefits of extending this to UTT. ClinicalTrials.gov NCT01900977.


Field evaluation of a dual rapid diagnostic test for HIV infection and syphilis in Lima, Peru.
Screening for HIV and syphilis in key populations is recommended by the WHO to reduce the morbidity, mortality and transmission associated with undiagnosed and untreated infections. Rapid point-of-care tests that can detect multiple infections with a single fingerprick whole blood specimen using a single device are gaining popularity. We evaluated the field performance of a rapid dual HIV and syphilis test in people at high risk of HIV and syphilis infections. Participants included men who have sex with men and transgender women recruited in Lima, Peru. Reference standard testing for detection of HIV and syphilis infections, conducted using blood samples from venipuncture, included Treponema pallidum particle agglutination and fourth-generation HIV enzyme immunoassay for which positive results had a confirmation HIV Western blot test. For the evaluation test, SD BIOLINE HIV/Syphilis Duo test (Standard Diagnostics, Korea), a fingerprick blood specimen was used. Sensitivity and specificity were calculated and the exact binomial method was used to determine 95% CIs. A total of 415 participants were recruited for the study. The dual test sensitivity for detection of T. pallidum infection was 89.2% (95% CI 83.5% to 93.5%) and specificity 98.8% (95% CI 96.5% to 99.8%). For detection of HIV infection, the sensitivity of the dual test was 99.1% (95% CI 94.8% to 100%) and specificity 99.4% (95% CI 97.7% to 99.9%). This high performing dual test should be considered for the use in clinical settings to increase uptake of simultaneous testing of HIV and syphilis and accelerate time to treatment for those who need it.


[Torsion of a preperitoneal pedunculated lipoma of anterior abdominal wall mimicking acute appendicitis].
Lipoma is the most common benign tumor of adipose tissue. Lipomas can occur almost anywhere in the body, but are rarely found in parietal peritoneum of abdominal wall. Occasionally lipomas are detected incidentally during abdominal surgery for other organ pathologies. Presently described is rare case of torsion of pedunculated lipoma originating in parietal peritoneum of anterior abdominal wall causing abdominal pain that mimicked acute appendicitis in 35-year-old woman.


A stimulus to define informatics and health information technology.
Despite the growing interest by leaders, policy makers, and others, the terminology of health information technology as well as biomedical and health informatics is poorly understood and not even agreed upon by academics and professionals in the field. The paper, presented as a Debate to encourage further discussion and disagreement, provides definitions of the major terminology used in biomedical and health informatics and health information technology. For informatics, it focuses on the words that modify the term as well as individuals who practice the discipline. Other categories of related terms are covered as well, from the associated disciplines of computer science, information technology and health information management to the major application categories of applications used. The discussion closes with a classification of individuals who work in the largest segment of the field, namely clinical informatics. The goal of presenting in Debate format is to provide a starting point for discussion to reach a documented consensus on the definition and use of these terms.


Ventricular Assist Device in Children with Cardiac Graft Failure.
We sought to determine whether ventricular assist device (VAD) support is an effective therapy in children with cardiac graft dysfunction. We conducted a retrospective review of VAD usage in this scenario at our institution. Although short-term VAD support was highly successful (89% [eight out of nine] were bridged to recovery), only 29% (2 out of 7) with long-term VAD survived to retransplant. Of note, three out of five mortalities with long-term VAD were related to sepsis (two fungal and one Gram-negative bacterial). Infectious risk imposed by ongoing immunosuppressive therapy limits the role of long-term VAD in this population.


Management of recurrent symptoms after per-oral endoscopic myotomy in achalasia.
Per-oral endoscopic myotomy (POEM) has been rapidly gaining ground as a treatment for achalasia. Although POEM is a safe and effective treatment, a subset of patients has persistent or recurrent symptoms after POEM. This study aimed to examine the efficacy of different retreatments after failed POEM. POEM was performed on 441 patients with achalasia at 3 tertiary-care hospitals between 2010 and 2015. A review of prospectively collected data was conducted. All patients with achalasia with significant persistent or recurrent symptoms within 3 years after POEM, defined as an Eckardt symptom score >3, were included. Forty-three of 441 patients (9.8%) had persistent or recurrent symptoms after POEM, of which 34 (8%) received 1 or more retreatments. Retreatment with laparoscopic Heller myotomy and retreatment with POEM showed a modest efficacy of 45% and 63%, respectively, whereas pneumatic dilatation showed a poor efficacy of only 0% to 20%, depending on the size of the balloon. Male patients were more likely to have retreatment failure than female patients (P = .038). In patients with achalasia with persistent or recurrent symptoms after failed POEM, retreatment with laparoscopic Heller myotomy or retreatment with POEM has a higher efficacy than retreatment with pneumatic dilatations. Failure of retreatment occurred more often in male patients.


Understanding medication oversupply and its predictors in the outpatient departments in Thailand.
Medication oversupply is an important problem in the healthcare systems. It causes unnecessary avoidable healthcare costs. Although some studies have determined the magnitude and financial loss due to medication oversupply in western countries, they may not be applicable to Asia-pacific countries. This study aims to determine the prevalence, financial loss, and patterns of medication oversupply and the factors associated with such oversupply in Thailand. A retrospective database analysis was used from 3 public hospitals. Patients visiting the outpatient department of the hospitals in 2010 and receiving at least 2 prescriptions within 6 months were included. The modified medication possession ratio (MPRm) was used to determine the medication supply. Patients having MPRm > 1.20 were defined as receiving a medication oversupply. The measures were prevalence of medication oversupply, the number of oversupplied medications, and financial loss (2012 dollars) due to medication oversupply. Hierarchical logistic regression was used to determine the factors associated with the prevalence of medication oversupply. A total of 99,743 patients were included. Patients were on average 49.7 ± 21.2 years of age, and 42.8% were male. Most of them were adult (53.7%). Among those patients, 60.2% of the patients were under universal coverage schemes. Around 13.4% of all the patients received a medication oversupply, and the patients in regional hospitals had a higher prevalence of medication oversupply than patients in district hospitals (13.8% VS 8.2%). The patients under civil servant medical benefit schemes (CSMBS) (13.6%) had the most prevalence of medication oversupply. The total financial loss was $189,024 per year. The average financial loss was $1.9 ± 19.0 per patient/year. Patients under CSMBS experienced the highest average financial loss (2.6 ± 23.2 $/patient/year). Age, gender, health insurance schemes, and the number of medications that the patients received were the factors associated with medication oversupply. Medication oversupply is an important problem for the health system. Patients receiving care from regional hospitals had a higher likelihood of medication oversupply. Policymakers may consider developing policies for preventing medication oversupply. The policy should be implemented in regional hospitals and especially in children or patients with poly-pharmacy.


Significance of endorsement of psychotic symptoms by US Latinos.
In US regional studies, Latinos frequently endorse psychotic symptoms associated with impairment and mental health service use, yet do not meet criteria for psychotic disorder. Using a nationally representative Latino sample (N = 2554), we examined the prevalence of psychotic symptoms, their relationship to psychotic disorder, their correlates, and their relationship to mental health outcomes. In this sample, 9.5% (SE = 0.7) endorsed 1 or more lifetime psychotic symptoms, yet 93% of endorsers did not meet Structured Clinical Interview for DSM-IV criteria for psychotic disorders. Endorsement was associated with physical and emotional distress, particularly lifetime anxiety and current substance use disorder. Acculturation to US society and reliance on spiritual/religious help were also associated with psychotic symptom endorsement. These symptoms have substantial clinical significance, being independently associated with suicidal ideation, mental health-related disability, and outpatient mental health service utilization. Endorsed psychotic symptoms in Latinos may constitute a clinically significant marker of general psychiatric vulnerability rather than a sign of psychotic disorder.


Hearts of some Antarctic fishes lack mitochondrial creatine kinase.
Creatine kinase (CK; EC 18.104.22.168) functions as a spatial and temporal energy buffer, dampening fluctuations in ATP levels as ATP supply and demand change. There are four CK isoforms in mammals, two cytosolic isoforms (muscle [M-CK] and brain [B-CK]), and two mitochondrial isoforms (ubiquitous [uMtCK] and sarcomeric [sMtCK]). Mammalian oxidative muscle couples expression of sMtCK with M-CK, creating an energy shuttle between mitochondria and myofibrils. We hypothesized that the expression pattern and activity of CK would differ between hearts of red- and white-blooded Antarctic notothenioid fishes due to their striking differences in cardiac ultrastructure. Hearts of white-blooded icefishes (family Channichthyidae) have significantly higher mitochondrial densities compared to red-blooded species, decreasing the diffusion distance for ATP between mitochondria and myofibrils and potentially minimizing the need for CK. The distribution of CK isoforms was evaluated using western blotting and maximal activity of CK was measured in mitochondrial and cytosolic fractions and tissue homogenates of heart ventricles of red- and white-blooded notothenioids. Transcript abundance of sMtCK and M-CK was also quantified. Overall, CK activity is similar between hearts of red- and white-blooded notothenioids but hearts of icefishes lack MtCK and have higher activities of M-CK in the cytosol compared to red-blooded fishes. The absence of MtCK may compromise cardiac function under stressful conditions when ATP supply becomes limiting.


Effect of erythromycin on gastric emptying in healthy individuals assessed by radio-opaque markers and plasma acetaminophen levels.
We simultaneously recorded gastric emptying of radio-opaque markers (ROMs) and monitored serial changes in plasma acetaminophen (AAP) levels to demonstrate the relationship between the ROM and the AAP methods, and we investigated the effect of a single intravenous dose of erythromycin (EM) on gastric emptying in healthy human subjects. After an overnight fast, subjects were randomized to receive either placebo or EM lactobionate (Abbott, North Chicago, IL, USA) 250 mg intravenously in a single dose, given immediately before a standard meal. Subjects ingested 1.5 g of AAP and ROMs with the test meal. A supine plain abdominal radiograph was taken 1, 2, 3, and 6 h after ingestion of the test meal. Peripheral blood samples were obtained 0, 0.5, 1, 1.5, 2, 3, and 6 h after ingestion of the test meal. EM significantly accelerated gastric emptying of ROMs. By 6 h, no markers remained in the stomach in any of the subjects in the placebo or EM groups. By 120 min, half of the ROMs had passed into the duodenum in 12.5% of subjects after placebo, whereas EM injection resulted in gastric emptying of half of the ROMs in all subjects. There was no difference in plasma AAP concentration between the placebo and EM groups. There were significant correlations between maximum plasma AAP concentration and gastric emptying of ROMs 120 min after ingestion (r = 0.546; P = 0.019), and between time of maximum plasma AAP concentration and gastric emptying of ROMs 120 min after ingestion (r = -0.568; P = 0.014). The time taken to reach the peak concentrations ranged from 30 to 90 min after ingestion, whereas most ROMs were emptied 120 min after ingestion. We conclude that the gastric emptying assessed by ROMs and by serial changes in plasma AAP level are good, non-invasive, clinically applicable tests, with a significant correlation between the two tests. A single intravenous dose of EM had a prokinetic effect on gastric emptying, assessed by ROMs, in healthy human subjects.


Skyline: an open source document editor for creating and analyzing targeted proteomics experiments.
Skyline is a Windows client application for targeted proteomics method creation and quantitative data analysis. It is open source and freely available for academic and commercial use. The Skyline user interface simplifies the development of mass spectrometer methods and the analysis of data from targeted proteomics experiments performed using selected reaction monitoring (SRM). Skyline supports using and creating MS/MS spectral libraries from a wide variety of sources to choose SRM filters and verify results based on previously observed ion trap data. Skyline exports transition lists to and imports the native output files from Agilent, Applied Biosystems, Thermo Fisher Scientific and Waters triple quadrupole instruments, seamlessly connecting mass spectrometer output back to the experimental design document. The fast and compact Skyline file format is easily shared, even for experiments requiring many sample injections. A rich array of graphs displays results and provides powerful tools for inspecting data integrity as data are acquired, helping instrument operators to identify problems early. The Skyline dynamic report designer exports tabular data from the Skyline document model for in-depth analysis with common statistical tools. Single-click, self-updating web installation is available at http://proteome.gs.washington.edu/software/skyline. This web site also provides access to instructional videos, a support board, an issues list and a link to the source code project.


Anti-inflammatory coumarins from Paramignya trimera.
Paramignya trimera (Oliv.) Burkill (Rutaceae) has been used to treat liver diseases and cancer. However, the anti-inflammatory effects of this medicinal plant and its components have not been elucidated. This study investigated chemical constituents of the P. trimera stems and evaluated anti-inflammatory effects of isolated compounds. Cytotoxicity of isolated compounds (5-40 μM) toward BV2 cells was tested using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) for 24 h. Inhibitory effects of isolated compounds (5-40 μM) on nitrite and PGE2 concentrations were determined using Griess reaction and PGE2 ELISA kit, respectively (pretreated with the compounds for 3 h and then stimulated for 18 h with LPS). Inhibitory effects of compounds (5-40 μM) on iNOS and COX-2 protein expression were evaluated by Western blot analysis (pretreated with the compounds for 3 h and then stimulated for 24 h with LPS). Seven coumarins were isolated and identified as: ostruthin (1), ninhvanin (2), 8-geranyl-7-hydroxycoumarin (3), 6-(6',7'-dihydroxy-3',7'-dimethylocta-2'-enyl)-7-hydroxycoumarin (4), 6-(7-hydroperoxy-3,7-dimethylocta-2,5-dienyl)-7-hydroxycoumarin (5), 6-(2-hydroxyethyl)-2,2-dimethyl-2H-1-benzopyran (6), and luvangetin (7). Compounds 1-4 and 7 inhibited NO and PGE2 production in LPS-stimulated BV2 cells, with IC50 values ranging from 9.8 to 46.8 and from 9.4 to 52.8 μM, respectively. Ostruthin (1) and ninhvanin (2) were shown to suppress LPS-induced iNOS and COX-2 protein expression. The present study provides a scientific rationale for the use of P. trimera in the prevention and treatment of neuroinflammatory diseases. Ostruthin and ninhvanin might have potential therapeutic effects and should be considered for further development as new anti-neuroinflammatory agents.


Production of elastase, exotoxin A, and alkaline protease in sputa during pulmonary exacerbation of cystic fibrosis in patients chronically infected by Pseudomonas aeruginosa.
Secretion of Pseudomonas aeruginosa elastase, exotoxin A, and alkaline protease in sputum during bronchopulmonary exacerbations was examined in 18 cystic fibrosis patients chronically infected with this microorganism. The patients were studied during one or several exacerbation periods necessitating hospitalizations of 12 to 20 days. In all cases, P. aeruginosa was present in bronchial secretions at admission and was not eradicated after treatment. The P. aeruginosa density decreased significantly after antibiotic therapy but remained greater than 10(6) CFU/g of sputum in most cases. Significant amounts of P. aeruginosa exoproteins were measured in total homogenized bronchial secretions by immunoenzymatic assays. The detection of higher levels of exoproteins at admission, the significant decrease after treatment, and the absence of exoproteins during intercrisis phases constituted arguments for a renewal of virulence of P. aeruginosa during exacerbations. Nevertheless, the concomitant changes in bacteria load and the triggering of the inflammatory process and immune complex formation could also contribute to pulmonary exacerbations.


Disentangling Representations of Object Shape and Object Category in Human Visual Cortex: The Animate-Inanimate Distinction.
Objects belonging to different categories evoke reliably different fMRI activity patterns in human occipitotemporal cortex, with the most prominent distinction being that between animate and inanimate objects. An unresolved question is whether these categorical distinctions reflect category-associated visual properties of objects or whether they genuinely reflect object category. Here, we addressed this question by measuring fMRI responses to animate and inanimate objects that were closely matched for shape and low-level visual features. Univariate contrasts revealed animate- and inanimate-preferring regions in ventral and lateral temporal cortex even for individually matched object pairs (e.g., snake-rope). Using representational similarity analysis, we mapped out brain regions in which the pairwise dissimilarity of multivoxel activity patterns (neural dissimilarity) was predicted by the objects' pairwise visual dissimilarity and/or their categorical dissimilarity. Visual dissimilarity was measured as the time it took participants to find a unique target among identical distractors in three visual search experiments, where we separately quantified overall dissimilarity, outline dissimilarity, and texture dissimilarity. All three visual dissimilarity structures predicted neural dissimilarity in regions of visual cortex. Interestingly, these analyses revealed several clusters in which categorical dissimilarity predicted neural dissimilarity after regressing out visual dissimilarity. Together, these results suggest that the animate-inanimate organization of human visual cortex is not fully explained by differences in the characteristic shape or texture properties of animals and inanimate objects. Instead, representations of visual object properties and object category may coexist in more anterior parts of the visual system.


Diverse cellular actions of tert-butylhydroquinone, a food additive, on rat thymocytes.
Tertiary butylhydroquinone (TBHQ) is a food additive that possesses antioxidant activity. Its alternative applications have been explored in recent studies. However, there is controversy regarding safety. In this study using rat thymocytes, the cellular actions of TBHQ at sublethal concentrations were examined. TBHQ at concentrations of 3 μM or more elevated intracellular Zn2+ concentration ([Zn2+]i) in a dose-dependent manner, by increasing membrane Zn2+ permeability and releasing Zn2+ from cellular stores. TBHQ at 30 μM significantly increased side scatter (cell density) and the exposure of phosphatidylserine (PS) on cell membrane surfaces. It also decreased cellular glutathione (GSH) content without affecting cell lethality. Forward scatter was attenuated by 100 μM TBHQ. Thus, it is considered that TBHQ at sublethal concentrations (30 μM or less) exerts some adverse actions on cells. TBHQ at 10-30 μM attenuated the increase in cell lethality induced by hydrogen peroxide (H2O2), while potentiation of H2O2 cytotoxicity by 100 μM TBHQ was observed. The range of concentrations of TBHQ from benefit to toxicity under in vitro conditions may be 10-30 μM. Although TBHQ exhibits antioxidative actions at concentrations that are lower than those which elicit adverse cellular effects, sublethal levels of TBHQ cause some adverse actions that may be clinically concerned.


Thin multicomponent films for functional enzyme devices and bioreactor particles.
Complex functional films containing enzymes and other biomolecules are easily fabricated in nm-scale thicknesses by using layer-by-layer (LbL) methodologies first popularized by Lvov and Decher. In this review, we highlight the high level functional capabilities possible with LbL films of biomolecules based on our own research experiences. We first describe the basics of enzyme film fabrication by LbL alternate electrostatic adsorption, then discuss how to make functional enzyme-polyion films of remarkably high stability. Focusing on cytochrome P450s, we discuss films developed to electrochemically activate the natural catalytic cycle of these key metabolic enzymes. We then describe multifunctional, multicomponent DNA/enzyme/polyion films on arrays and particle surfaces for high throughput metabolic toxicity screening using electrochemiluminescence and LC-MS/MS. Using multicomponent LbL films, complex functionality for bioanalytical and biochemical purposes can be achieved that is difficult or impossible using conventional approaches.


Higher ambulatory blood pressure is associated with aortic valve calcification in the elderly: a population-based study.
Aortic valve calcification (AVC) without outflow obstruction (stenosis) is common in the elderly and increases the risk of cardiovascular morbidity and mortality. Although high blood pressure (BP) measured at the doctor's office is known to be associated with AVC, little is known about the association between 24-hour ambulatory BP (ABP) and AVC. Our objective was to clarify the association between ABP variables and AVC. The study population consisted of 737 patients (mean age, 71±9 years) participating in the Cardiovascular Abnormalities and Brain Lesions study who underwent 24-hour ABP monitoring. Each aortic valve leaflet was graded on a scale of 0 (normal) to 3 (severe calcification). A total valve score (values 0-9) was calculated as the sum of all leaflet scores. Advanced AVC (score ≥4) was present in 77 subjects (10.4%). All of the systolic ABP variables (except systolic BP nocturnal decline) and mean asleep diastolic BP were positively associated with advanced calcification, whereas normal dipping status and diastolic BP nocturnal decline were negatively associated. Multiple regression analysis indicated that mean awake diastolic BP (odds ratio, 1.31 [95% CI, 1.01-1.71]) and asleep diastolic BP (odds ratio, 1.34 [95% CI, 1.04-1.72]) remained independently associated with advanced calcification after adjustment for age, sex, cigarette smoking, diabetes mellitus, hypercholesterolemia, hypertension, serum creatinine, and any degree of aortic insufficiency. Diastolic ABP is independently associated with advanced calcification. This finding may have important implications in gaining further insight into the mechanism of AVC.


An Alternative Endovascular Technique for Vein of Galen Aneurysmal Malformation Treatment: Etylene Vinyl Alcohol Co-Polymer Embolization via Double-Lumen Balloon Microcatheter.
To present an alternative endovascular treatment option for the vein of Galen aneurysmal malformation by ethylene-vinyl alcohol copolymer embolization via a double-lumen balloon microcatheter. A female patient was suspected with the vein of Galen aneurysmal malformation in the prenatal period and diagnosed choroidal type vein of Galen aneurysmal malformation. Once the patient was symptomatic with severe cardiac failure, an endovascular treatment decision was made. In the first step, a mixture of N-butyl cyanoacrylate-lipiodol was used for embolization. In the second session of the treatment, ethylene-vinyl alcohol copolymer was administered through a double-lumen balloon microcatheter. Complete cure of the aneurysmal malformation was obtained by no filling was observed in arterial feeders, collapsed appearance of the vein of Galen, and arterial-venous shunts at the end of the five-year follow-up period with magnetic resonance imaging and angiography. Ethylene-vinyl alcohol copolymer embolization via double-lumen balloon microcatheter provides an alternative and effective endovascular treatment option for the vein of Galen aneurysmal malformations using less contrast agent in less procedural time. Also, the possibility of spontaneous regression of residual aneurysmal malformations with small feeders should be considered.


Protocol of the baseline assessment for the Environments for Healthy Living (EHL) Wales cohort study.
Health is a result of influences operating at multiple levels. For example, inadequate housing, poor educational attainment, and reduced access to health care are clustered together, and are all associated with reduced health. Policies which try to change individual people's behaviour have limited effect when people have little control over their environment. However, structural environmental change and an understanding of the way that influences interact with each other, has the potential to facilitate healthy choices irrespective of personal resources. The aim of Environments for Healthy Living (EHL) is to investigate the impact of gestational and postnatal environments on health, and to examine where structural change can be brought about to optimise health outcomes. The baseline assessment will focus on birth outcomes and maternal and infant health. EHL is a longitudinal birth cohort study. We aim to recruit 1000 pregnant women in the period April 2010 to March 2013. We will examine the impact of the gestational environment (maternal health) and the postnatal environment (housing and neighbourhood conditions) on subsequent health outcomes for the infants born to these women. Data collection will commence during the participants' pregnancy, from approximately 20 weeks gestation. Participants will complete a questionnaire, undergo anthropometric measurements, wear an accelerometer, compile a food diary, and have environmental measures taken within their home. They will also be asked to consent to having a sample of umbilical cord blood taken following delivery of their baby. These data will be complemented by routinely collected electronic data such as health records from GP surgeries, hospital admissions, and child health and development records. Thereafter, participants will be visited annually for follow-up of subsequent exposures and child health outcomes. The baseline assessment of EHL will provide information concerning the impact of gestational and postnatal environments on birth outcomes and maternal and infant health. The findings can be used to inform the development of complex interventions targeted at structural, environmental factors, intended to reduce ill-health. Long-term follow-up of the cohort will focus on relationships between environmental exposures and the later development of adverse health outcomes, including obesity and diabetes.


Perceptions and views of regulatory pharmacists on the registration system for generic drugs for human use in Kenya.
Generic drugs play an important role in the delivery of healthcare services in Kenya because of their affordability and availability. The Pharmacy and Poisons Board (PPB) is the body mandated to regulate the manufacture and supply of all drugs in Kenya. Approximately 90% of all applications for registration of drugs in Kenya are for generic drugs; however, there are concerns about the quality of generic drugs supplied to patients in Kenya. The study aimed to investigate the perceptions and views of the regulatory pharmacists on the registration system for generic drugs in Kenya, and the role of the National Quality Control Laboratory (NQCL). A cross-sectional survey was designed to collect the views and perceptions of regulatory pharmacists on the system for the registration of generic drugs for human use in Kenya. The survey was conducted in the capital city of Kenya, Nairobi from January to February 2007. Nairobi was selected because it has a high concentration of pharmaceutical manufacturers and distributors involved in drug registration. The sample included regulatory pharmacists working in the registration departments of pharmaceutical companies dealing in generic drugs for human use. A sample of 40 participants was recruited for the survey and a response rate of 60% was targeted. Over half (55.6%) of the respondents reported satisfaction with the drug registration system while 33.3% were unsatisfied. The level of satisfaction did not seem to be associated with the length of time it takes to register a generic drug (p-value=0.74) or the gender of the respondent (p-value=0.94). The respondents had confidence in the analytical procedures carried out by NQCL but were less satisfied with its role in generic drug registration process. The respondents made a number of recommendations towards better drug registration mechanisms for generic drugs in Kenya. The study suggests that although the drug registration procedures appear to be working, there is need for improvement. One area in which the registration of generic drugs in Kenya can benefit is in the observation of the operation of what other countries have done to streamline their drug registration systems.


Near infrared spectroscopy in natural products analysis.
Several medicinal and herbal plants properties are related to individual compounds such as essential oils, terpenoids, flavonoids, which are present in natural products in low concentrations (e. g., ppm or ppb). For many years, the use of classical separation and chromatographic and spectrometric techniques such as high performance liquid chromatography (HPLC), gas chromatography (GC), liquid chromatography (LC) and mass spectrometry (MS) were initially used for the elucidation of isolated compounds from different plant matrices. Spectroscopic techniques in the infrared (IR) wavelength region of the electromagnetic spectrum have been used in the food industry to monitor and evaluate the composition of foods. Although Herschel discovered light in the near-infrared (NIR) region as early as 1800, most spectroscopists of the first half of the last century ignored it, in the belief that it lacked any analytical interest. However, during the last 40 years NIR spectroscopy has become one of the most attractive and used methods for analysis. This mini-review highlights recent applications of NIR spectroscopy to the qualitative and quantitative analysis of plant natural products.


Shiga toxins and the pathophysiology of hemolytic uremic syndrome in humans and animals.
Food-borne diseases are estimated at 76 million illnesses and 5000 deaths every year in the United States with the greatest burden on young children, the elderly and immunocompromised populations. The impact of efficient food distribution systems and a truly global food supply ensures that outbreaks, previously sporadic and contained locally, are far more widespread and emerging pathogens have far more frequent infection opportunities. Enterohemorrhagic E. coli is an emerging food- and water-borne pathogen family whose Shiga-like toxins induce painful hemorrhagic colitis with potentially lethal complications of hemolytic uremic syndrome (HUS). The clinical manifestations of Shiga toxin-induced HUS overlap with other related syndromes yet molecular mechanisms differ considerably. As discussed herein, understanding these differences and the novel properties of the toxins is imperative for clinical management decisions, design of appropriate animal models, and choices of adjunctive therapeutics. The emergence of new strains with rapidly aggressive virulence makes clinical and research initiatives in this field a high public health priority.


Female sex work within the rural immigrant Latino community in the southeast United States: an exploratory qualitative community-based participatory research study.
Little is known about the structure and context of, and the risks encountered in, sex work in the United States. This community-based participatory research (CBPR) study explored female sex work and the feasibility of conducting a larger study of sex work within the immigrant Latino community in North Carolina. Twelve abbreviated life story interviews were conducted with Latina women who sold sex, other women who sold sex to Latino men, and Latino men who hired sex workers. Content analysis was used to analyze narrative data. Themes emerged to describe the structure of sex work, motivations to sell and hire sex, and the sexual health-related needs of sex workers. Lessons learned included the ease of recruiting sex workers and clients, the need to develop relationships with controllers and bar owners/managers, and the high compensation costs to reimburse sex workers for participation. Study findings suggest that it is possible to identify and recruit sex workers and clients and collect formative data within this highly vulnerable and neglected community; the prevention of HIV and STDs is a priority among sex workers, and the need for a larger study to include non-Latino men who report using Latina sex workers, other community insiders (e.g., bartenders), and service providers for Latina sex workers.


Exploring the molecular structures that confer ligand selectivity for galanin type II and III receptors.
Galanin receptors (GALRs) belong to the superfamily of G-protein coupled receptors. The three GALR subtypes (GALR1, GALR2, and GALR3) are activated by their endogenous ligands: spexin (SPX) and galanin (GAL). The synthetic SPX-based GALR2-specific agonist, SG2A, plays a dual role in the regulation of appetite and depression-like behaviors. Little is known, however, about the molecular interaction between GALR2 and SG2A. Using site-directed mutagenesis and domain swapping between GALR2 and GALR3, we identified residues in GALR2 that promote interaction with SG2A and residues in GALR3 that inhibit interaction with SG2A. In particular, Phe103, Phe106, and His110 in the transmembrane helix 3 (TM3) domain; Val193, Phe194, and Ser195 in the TM5 domain; and Leu273 in the extracellular loop 3 (ECL3) domain of GALR2 provide favorable interactions with the Asn5, Ala7, Phe11, and Pro13 residues of SG2A. Our results explain how SG2A achieves selective interaction with GALR2 and inhibits interaction with GALR3. The results described here can be used broadly for in silico virtual screening of small molecules for the development of GALR subtype-specific agonists and/or antagonists.


Specific binding of T lymphocytes to macrophages. II. Role of macrophage-associated antigen.
Peritoneal exudate lymphocytes from immune guinea pigs that bind in vitro to autologous antigen-pulsed macrophages were allowed to proliferate for 1 week to give a population markedly enriched in antigen-specific T cells. This enriched population was then studied with regard to its binding to fresh autologous antigen-pulsed macrophages. Specific binding was not inhibited by a large excess of antigen in the media (5000-fold greater than the amount of antigen associated with the macrophages) either soluble or bound to Sepharose beads, or by coating the antigen-pulsed macrophags with antibody to the exogenous antigen, by reacting a second layer of antibody to the heterologous antibody, or by haptenating the antigen and treating the hapten-antigen macrophage complex with excess anti-hapten antibody. Results of treating antigen-pulsed macrophages with the proteolytic enzymes trypsin and pronase indicate that exogenous antigen is on the macrophage surface, but the experiments failed to prove that the removable antigen is essential for binding. The simplest interpretation of these results is that the T cell receptor is not specific for native exogenous antigen.


Younger and Older Adults' Lie-Detection and Credibility Judgments of Children's Coached Reports.
Previous research has examined young and middle-aged adults' perceptions of child witnesses; however, no research to date has examined how potential older adult jurors may perceive a child witness. The present investigation examined younger (18-30 years, N = 100) and older adults' (66-89 years, N = 100) lie-detection and credibility judgments when viewing children's truthful and dishonest reports. Participants viewed eight child interview videos where children (9 to 11 years of age) either provided a truthful report or a coached fabricated report to conceal a transgression. Participants provided lie-detection judgments following all eight videos and credibility assessments following the first two videos. Participants completed a General Lifespan Credibility questionnaire to assess credibility evaluations across various witness ages. Lie-detection results indicated that older adults had significantly lower discrimination scores, a stronger truth bias, and greater confidence compared to younger adults. Older adults also rated children as more competent to testify in court, credible, honest, believable, and likeable than younger adults. Participants with greater differences in their credibility evaluations for truth and lie-tellers were significantly more accurate at detecting lies. Responses to the Lifespan Credibility questionnaire revealed significant differences in younger and older adults' credibility evaluations across the lifespan.


Electrophysiological evidence for both perceptual and postperceptual selection during the attentional blink.
When two masked targets are presented in rapid succession, correct identification of the first target (T1) leads to a dramatic impairment in identification of the second target (T2). Several studies of this so-called attentional blink (AB) phenomenon have provided behavioral and physiological evidence that T2 is processed to the semantic level, despite the profound impairment in T2 report. These findings have been interpreted as an example of perception without awareness and have been explained by models that assume that T2 is processed extensively even though it does not gain access into consciousness. The present study reports two experiments that test this assumption. In Experiment 1, the perceptual load of the T1 task was manipulated and T2 was a word that was either related or unrelated to a context word presented at the beginning of each trial. The event-related potential (ERP) technique was used to isolate the context-sensitive N400 component evoked by the T2 word. The ERP data revealed that there was a complete suppression of the N400 during the AB when the perceptual load was high, but not when perceptual load was low. Experiment 2 replicated the high-load condition of Experiment 1 while ruling out two alternative explanations for the reduction of the N400 during the AB. The results of both experiments demonstrate that word meanings are not always accessed during the AB and are consistent with studies that suggest that attention can act to select information at multiple stages of processing depending on concurrent task demands.


The somatostatin analogue peptide TT-232 induces apoptosis and chromosome breakage in cultured human lymphocytes.
Somatostatin receptors are supposed to be important in the regulation of apoptosis. In this study, we measured apoptosis occurring spontaneously, or induced by the synthetic somatostatin analogue, the peptide TT-232. We examined isolated human peripheral blood lymphocytes (PBL) from 32 nurses exposed bedside to cytostatic drugs, 12 chronic lymphoid leukaemia (CLL) patients prior to treatment, and 19 unexposed, healthy donors without anamnestic occupational exposure to genotoxic agents. Cells were stimulated by phytohaemagglutinin-P (PHA) and cultured for 69 h with or without 15 microg/ml TT-232, respectively. Cell kinetic parameters and apoptosis were determined by flow cytometry after staining with FITC-labeled anti-BrdU and propidium iodide (PI) and the results on spontaneous and peptide-induced apoptosis were compared with the obtained chromosome aberration frequencies (CA). The peptide TT-232 unexpectedly induced chromosome breakage in addition to apoptosis. The mean spontaneous apoptotic fractions were 6.65+/-0.89%, 6.46+/-0. 53%, and 3.07+/-0.57%, and the mean CA yields in the samples without TT-232 were 1.74+/-0.46%, 2.44+/-0.40%, and 4.50+/-1.05%, for healthy subjects, nurses, and CLL patients, respectively. A total of 15 microg/ml TT-232 treatment in healthy subjects increased the mean CA frequency (10.38+/-1.57%), as well as the apoptotic cell fraction (2.63+/-0.45 times higher than the corresponding untreated sample). In TT-232-treated PBLs of nurses, CA remained unchanged and the mean apoptotic cell fraction showed only a slight increase (1.24+/-0.11 times higher than the untreated). Among CLL patients, TT-232 treatment significantly increased both CA (up to 17.83+/-4.04%) and the ratio of apoptotic cells (21.78+/-11.00 times higher than the untreated). These results demonstrated significant differences in apoptosis sensitivity in controls, nurses and CLL donors, after 15 microg/ml TT-232 treatment. Data also indicate that the induced CA yields in CLL donors with high CA are in correlation with TT-232-induced apoptosis.


Functional outcomes of mandibular distraction for the relief of severe airway obstruction and feeding difficulties in neonates with Pierre Robin sequence.
The purpose of this study was to review the application of mandibular distraction to relieve severe airway obstruction or feeding problems of neonates. Thirteen neonates with Pierre Robin sequence who underwent bilateral mandibular distraction between 2010 and 2013 for relief of their severe airway obstruction or feeding problems were retrospectively reviewed. The mean preoperative and postoperative airway diameters were 3.89±1.64 and 9.03±1.98 mm. respectively and significant difference was observed with distraction (p < 0.001). The rate of severe airway infection also significantly decreased from 69.2% to 23.1% (p=0.016). 84.6% of the patients were able to be fed orally at discharge whereas 6 patients (46.2%) required support via orogastric tube before distraction (p=0.125). No growth disturbance, dental complications or malocclusion was observed in the long-term follow up. Mandibular distraction appears to be a promising and effective surgical option for relieving airway obstruction and feeding problems in severe Pierre Robin Sequence patients.


Antibiotic prescription patterns of South African general medical practitioners for treatment of acute bronchitis.
Antibiotic resistance is a significant public health problem. Prudent use of antibiotics is crucial in reducing this resistance. Acute bronchitis is a common reason for consultations with general medical practitioners, and antibiotics are often prescribed even though guidelines recommend not prescribing them for uncomplicated acute bronchitis. To analyse the antibiotic prescription patterns of South African (SA) general medical practitioners in the treatment of acute bronchitis. The 2013 claims for members of 11 health insurance schemes were analysed to assess antibiotic prescription patterns for patients diagnosed with acute bronchitis. The patterns were assessed by type of bronchitis, chronic health status of the patients, sex and age group. The types of antibiotic prescribed were also analysed. Of 166 821 events analysed, an antibiotic was prescribed in more than half (52.9%). There were significant differences by type of bronchitis and chronic health status. Patients with viral bronchitis were more likely to be prescribed an antibiotic than those with bacterial bronchitis (odds ratio (OR) 1.17, 95% confidence interval (CI) 1.08 - 1.26). Patients with a chronic illness were less likely to be prescribed an antibiotic than those without (OR 0.58, 95% CI 0.57 - 0.60). More than 70% of the antibiotics prescribed were cephalosporins, penicillins and other beta-lactams. Prescription rates of antibiotics for acute bronchitis by SA general medical practitioners are high. There is an urgent need to follow the guidelines for antibiotic use for acute bronchitis to reduce the likelihood of increasing resistance to available antibiotics.


Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models.
Patient-derived human-in-mouse xenograft models of breast cancer (PDX models) that exhibit spontaneous lung metastases offer a potentially powerful model of cancer metastasis. In this study, we evaluated the malignant character of lung micrometastases that emerge in such models after orthotopic implantation of human breast tumor cells into the mouse mammary fat pad. Interestingly, relative to the parental primary breast tumors, the lung metastasis (met)-derived mammary tumors exhibited a slower growth rate and a reduced metastatic potential with a more differentiated epithelial status. Epigenetic correlates were determined by gene array analyses. Lung met-derived tumors displayed differential expression of negative regulators of cell proliferation and metabolism and positive regulators of mammary epithelial differentiation. Clinically, this signature correlated with breast tumor subtypes. We identified hsa-miR-138 (miR-138) as a novel regulator of invasion and epithelial-mesenchymal transition in breast cancer cells, acting by directly targeting the polycomb epigenetic regulator EZH2. Mechanistic investigations showed that GATA3 transcriptionally controlled miR-138 levels in lung metastases. Notably, the miR-138 activity signature served as a novel independent prognostic marker for patient survival beyond traditional pathologic variables, intrinsic subtypes, or a proliferation gene signature. Our results highlight the loss of malignant character in some lung micrometastatic lesions and the epigenetic regulation of this phenotype.