Genetic variation and gastric cancer risk: a field synopsis and meta-analysis.
Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.


Slit-Slat and Multislit-Slat Collimator Design and Experimentally Acquired Phantom Images from a Rotating Prototype.
We have previously found and validated expressions for slit-slat (SS) geometric efficiency and resolution. These expressions have suggested that SS may be a good choice for imaging mid-size objects or objects that are long axially since (i) the geometric efficiency increases near the slit as h(-1) (instead of h(-2) for pinhole (PIN) and either decreases near the collimator for fan-beam (FB) or remains constant for parallel-beam (PB)), where h is the distance from a point to the slit plane; (ii) the transverse resolution is comparable to that of PIN, which is better than that of FB and PB for small objects; (iii) the axial resolution is worse than that of PIN since there is no axial magnification; (iv) there is a large axial FOV, unlike PIN, which is likely to be useful when imaging mid-size or long objects; and (v) there is no need for 3D orbits (e.g., helical) since each slice is complete (like PB and FB).We have developed a rotating prototype SS collimator that is capable of single-slit or multi-slit acquisition of data. The focal length (FL) is shorter than that of a typical PIN since increasing the FL requires taller slats to maintain resolution; taller slats reduce geometric efficiency. A lead rectangular box was used to provide support and shielding around the slit-slat collimator. Lead slats, spaced with Rohacell foam, were mounted in an assembly with 3 mm pitch.We have performed preliminary characterization with point sources and acquired micro hot- and cold-rod phantoms and a Deluxe Jaszczak phantom. The projections have been reconstructed using an MLEM algorithm and show good resolution.Comparisons indicate that SS is more sensitive than PB and FB for the same resolution for smaller-diameter objects. The advantage of SS over PB and FB increases as the desired resolution improves. SS can also be used in configurations that yield projections that have non-isotropic resolution; it is possible for SS to achieve transverse resolutions that are unreachable by PB, since PB does not magnify, and by FB, since its magnification factor for small objects is much smaller than that of SS. Experimental results show that the resolution of the reconstructed phantoms is consistent with theoretical expectations.


Eye-gaze independent EEG-based brain-computer interfaces for communication.
The present review systematically examines the literature reporting gaze independent interaction modalities in non-invasive brain-computer interfaces (BCIs) for communication. BCIs measure signals related to specific brain activity and translate them into device control signals. This technology can be used to provide users with severe motor disability (e.g. late stage amyotrophic lateral sclerosis (ALS); acquired brain injury) with an assistive device that does not rely on muscular contraction. Most of the studies on BCIs explored mental tasks and paradigms using visual modality. Considering that in ALS patients the oculomotor control can deteriorate and also other potential users could have impaired visual function, tactile and auditory modalities have been investigated over the past years to seek alternative BCI systems which are independent from vision. In addition, various attentional mechanisms, such as covert attention and feature-directed attention, have been investigated to develop gaze independent visual-based BCI paradigms. Three areas of research were considered in the present review: (i) auditory BCIs, (ii) tactile BCIs and (iii) independent visual BCIs. Out of a total of 130 search results, 34 articles were selected on the basis of pre-defined exclusion criteria. Thirteen articles dealt with independent visual BCIs, 15 reported on auditory BCIs and the last six on tactile BCIs, respectively. From the review of the available literature, it can be concluded that a crucial point is represented by the trade-off between BCI systems/paradigms with high accuracy and speed, but highly demanding in terms of attention and memory load, and systems requiring lower cognitive effort but with a limited amount of communicable information. These issues should be considered as priorities to be explored in future studies to meet users' requirements in a real-life scenario.


Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus.
Osteochondral lesions of the talus are common injuries in the athletic patient. They present a challenging clinical problem as cartilage has a poor potential for healing. Current surgical treatments consist of reparative (microfracture) or replacement (autologous osteochondral graft) strategies and demonstrate good clinical outcomes at the short and medium term follow-up. Radiological findings and second-look arthroscopy however, indicate possible poor cartilage repair with evidence of fibrous infill and fissuring of the regenerative tissue following microfracture. Longer-term follow-up echoes these findings as it demonstrates a decline in clinical outcome. The nature of the cartilage repair that occurs for an osteochondral graft to become integrated with the native surround tissue is also of concern. Studies have shown evidence of poor cartilage integration, with chondrocyte death at the periphery of the graft, possibly causing cyst formation due to synovial fluid ingress. Biological adjuncts, in the form of platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have been investigated with regard to their potential in improving cartilage repair in both in vitro and in vitro settings. The in vitro literature indicates that these biological adjuncts may increase chondrocyte proliferation as well as synthetic capability, while limiting the catabolic effects of an inflammatory joint environment. These findings have been extrapolated to in vitro animal models, with results showing that both PRP and BMAC improve cartilage repair. The basic science literature therefore establishes the proof of concept that biological adjuncts may improve cartilage repair when used in conjunction with reparative and replacement treatment strategies for osteochondral lesions of the talus.


College readiness for all: the challenge for urban high schools.
Melissa Roderick, Jenny Nagaoka, and Vanessa Coca focus on the importance of improving college access and readiness for low-income and minority students in urban high schools. They stress the aspirations-attainment gap: although the college aspirations of all U.S. high school students, regardless of race, ethnicity, and family income, have increased dramatically over the past several decades, significant disparities remain in college readiness and enrollment. The authors emphasize the need for researchers and policy makers to be explicit about precisely which sets of knowledge and skills shape college access and performance and about how best to measure those skills. They identify four essential sets of skills: content knowledge and basic skills; core academic skills; non-cognitive, or behavioral, skills; and "college knowledge," the ability to effectively search for and apply to college. High schools, they say, must stress all four. The authors also examine different ways of assessing college readiness. The three most commonly recognized indicators used by colleges, they say, are coursework required for college admission, achievement test scores, and grade point averages. Student performance on all of these indicators of readiness reveals significant racial and ethnic disparities. To turn college aspirations into college attainment, high schools and teachers need clear indicators of college readiness and clear performance standards for those indicators. These standards, say the authors, must be set at the performance level necessary for high school students to have a high probability of gaining access to four-year colleges. The standards must allow schools and districts to assess where their students currently stand and to measure their progress. The standards must also give clear guidance about what students need to do to improve. College readiness indicators can be developed based on existing data and testing systems. But districts and states will require new data systems that provide information on the college outcomes of their graduates and link their performance during high school with their college outcomes.


Surgical management of critical limb ischemia.
At the present time, infrainguinal bypass using autogenous vein is the most effective and durable treatment for chronic limb ischemia caused by long-segment, diffuse, atherosclerotic occlusive disease. Quality of the vein conduit is the most important factor that determines operative success. Preoperative vein mapping is useful to identify an optimal vein conduit as well as to suggest vein segments that should not be explored due to occlusion, significant calcification, poor caliber, or sclerosis. Reversed, nonreversed, and in situ vein bypass grafts all perform equally well, and the choice of technique depends on anatomic considerations and surgeon preference. Bypass grafts originating from inflow sources distal to the common femoral artery may be appropriate in selected cases without compromising graft patency. All vein graft patients should be followed by postoperative, duplex-based graft surveillance. Antiplatelet therapy is indicated in all infrainguinal bypass patients; oral anticoagulation may be worthwhile in selected, high-risk patients, but hemorrhagic risks are significantly increased.


Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer.
The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.


A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy.
Post-asphyxia neonatal encephalopathy (NE) is one of the main causes of disabilities in term-born infants. This review attempted to investigate the developmental outcomes of term-born infants with post-asphyxia NE. An electronic search on various databases identified 13 empirical studies against the selection criteria modified from the consensus statement from the International Cerebral Palsy Task Force. The overall quality of methodology of these studies was average. The random effect meta-estimate of the proportion of infants having adverse developmental outcomes such as death, cognitive impairment, sensory-motor impairments was 47% (95% CI 36-57%). Significant heterogeneity (I(2)=87.7%, p<0.00001) between studies indicated variations in number of subjects in studies and their characteristics. For those studies using the Sarnat grading of NE, the proportion of infants with adverse outcomes was nil in stage 1 (mild) NE, 32% in stage 2 (moderate) and almost 100% in stage 3 (severe) NE. At present, researchers are using very loose diagnostic criteria of perinatal asphyxia and post-asphyxia NE, making the study samples heterogeneous. Clinicians and researchers are urged to make use of the recent consensus statement regarding diagnostic criteria for intrapartum asphyxia and to identify these high-risk infants for early intervention.


Photon counting detectors for Fabry-Perot interferometers.
Sealed channel plate photomultipliers with multiple discrete anodes for use as photon counting detectors in the image plane of Fabry-Perot interferometers are described. The influence of design and construction on performance of completed devices is discussed. Effects on spatial resolution, lifetime, and counting efficiency are described. It is shown that devices can be optimized for particular applications. The results should be generally applicable to resistive anode and wedge and strip anode types of sealed detectors.


Objective evaluation for analgesia of the distal interphalangeal joint, the navicular bursa and perineural analgesia in horses with naturally occurring forelimb lameness localised to the foot.
The outcome and interpretation of intra-synovial diagnostic analgesia of the distal interphalangeal joint (DIPJ) and the navicular bursa (NB) remain in dispute, and no objective studies have been carried out to establish the percentage of improvement over time from these two analgesia techniques. To investigate the qualitative and time-dependent outcome of DIPJ-A and NB-A in naturally occurring forelimb lameness. Case series. Twenty-three clinical cases with forelimb lameness were evaluated objectively using a body mounted inertial sensor system (BMIS). Lameness was localised to the foot with a palmar digital nerve block and/or an abaxial sesamoidean nerve block on day 1, and analgesia of the DIPJ (DIPJ-A) and NB (NB-A) were performed on days 2 and 3. Improvement following perineural analgesia was measured after 10 min and intra-synovial blocks after 2-, 5- and 10-min. Horses with at least 70% improvement measured objectively after diagnostic analgesia were included in the study. There was no significant association between improvement following perineural analgesia and the DIPJ-A and NB-A. The mean improvement in the lameness differed between DIPJ-A and NB-A at 2 min (p < 0.001) and at 5 min (p = 0.04), and it was no longer observed after 10 min (p = 0.06). A positive NB-A produced a high degree of improvement that remained stable, whereas the DIPJ-A improved over time. Perineural and intra-synovial analgesia were performed without contrast medium to assess the diffusion of mepivacaine. Our results suggest that perineural analgesia is not reliable enough to differentiate pain originating from DIPJ and NB. Early evaluation of the DIPJ-A and NB-A can determine the origin of the pain. An improvement following NB-A was constant over time, but an improvement following DIPJ-A varied by up to 10 min.


Motor Control Training for the Shoulder with Smart Garments.
Wearable technologies for posture monitoring and posture correction are emerging as a way to support and enhance physical therapy treatment, e.g., for motor control training in neurological disorders or for treating musculoskeletal disorders, such as shoulder, neck, or lower back pain. Among the various technological options for posture monitoring, wearable systems offer potential advantages regarding mobility, use in different contexts and sustained tracking in daily life. We describe the design of a smart garment named Zishi to monitor compensatory movements and evaluate its applicability for shoulder motor control training in a clinical setting. Five physiotherapists and eight patients with musculoskeletal shoulder pain participated in the study. The attitudes of patients and therapists towards the system were measured using standardized survey instruments. The results indicate that patients and their therapists consider Zishi a credible aid for rehabilitation and patients expect it will help towards their recovery. The system was perceived as highly usable and patients were motivated to train with the system. Future research efforts on the improvement of the customization of feedback location and modality, and on the evaluation of Zishi as support for motor learning in shoulder patients, should be made.


Pharmacokinetic Investigation of Commercially Available Edible Marijuana Products in Humans: Potential Influence of Body Composition and Influence on Glucose Control.
The purpose of the study was to describe and compare the pharmacokinetics of five commercial edible marijuana products, determine the influence of body composition on pharmacokinetics, and, in light of epidemiology suggesting marijuana may offer diabetes protection, explore the influence of edible marijuana on glucose tolerance. Seven regular users of marijuana self-administered five edible products in a randomized crossover design; each product contained 10 mg of delta-9-tetrahydrocannabinol (THC). Thirty minutes following marijuana ingestion, participants imbibed a 75 g glucose beverage. Time-to-peak plasma THC concentration ranged between 35 and 90 min; maximal plasma THC concentration (Cmax) ranged between 3.2 and 5.5 ng/mL. Differences between products in plasma THC concentration during the first 20-30 min were detected (p = 0.019). Relations were identified between body composition and pharmacokinetic parameters for some products; however, none of these body composition characteristics were consistently related to pharmacokinetics across all five of the products. Edible marijuana had no effect on oral glucose tolerance compared with a marijuana-free control (Matsuda Index; p > 0.395). Commercially available edible marijuana products evoke different plasma THC concentrations shortly after ingestion, but do not appear to influence acute glucose regulation. These data may allow recreational marijuana users to make informed decisions pertaining to rates of edible marijuana ingestion and avoid overdose.


Effect of diarachidonin on prostaglandin E2 synthesis in rabbit kidney medulla slices.
The effect of diarachidonin on the synthesis of prostaglandin E2 in rabbit kidney medulla slices was examined. The addition of diarachidonin stimulated prostaglandin E2 production in a dose-dependent manner. At three concentrations (10, 50 and 100 microM), increases in prostaglandin E2 formation induced by exogenous diarachidonin were 2-fold greater than those induced by exogenous arachidonic acid. Diacylglycerol or phosphatidic acid from egg lecithin had little or no effect on prostaglandin E2 production. Moreover, EGTA failed to inhibit diarachidonin-stimulated prostaglandin E2 formation, indicating that the stimulatory effect of diarachidonin is not mediated through the activation of endogenous phospholipase A2 (including phosphatidic acid-specific phospholipase A2). These results are discussed in the light of our former hypothesis that arachidonic acid release from kidney medulla phospholipids might occur through the sequential action of a phospholipase C coupled to diacylglycerol and monoacylglycerol lipases [Fujimoto, Akamatsu, Hattori & Fujita (1984) Biochem. J. 218, 69-74].


Arterial Stiffening in Perspective: Advances in Physical and Physiological Science Over Centuries.
Arterial stiffening is not a new issue in medicine or research but was the prime concern of Richard Bright in the early 19th century and of the prominent London physicians and pathologists who tried to unscramble the relationship between kidney, heart, and cerebrovascular disease and hardness of the pulse in the late 19th century. It was of major concern to medical educators including Osler and Mackenzie who were still active in practice 100 years ago. It is all too easy (when dependent on the Internet) to consider arterial stiffness to be a new issue. The terms arterial stiffness, aortic stiffness, or wave reflection do not appear as categories for articles such as this in respectable journals, nor in categories for meetings of specialized physicians. Yet as described in this article, the subject was of interest to clinicians, to investigators such as Harvey in the 17th century, and to physicists who developed laws and principles of elasticity from the study of biological materials including ligaments and arteries. This paper provides a perspective on arterial stiffness from the time of William Harvey and Isaac Newton to the present, with a glance into the future.


Patient affect experiencing following therapist interventions in short-term dynamic psychotherapy.
The aim of this research was to examine the relationship between therapist interventions and patient affect responses in Short-Term Dynamic Psychotherapy (STDP). The Affect Experiencing subscale from the Achievement of Therapeutic Objectives Scale (ATOS) was adapted to measure individual immediate affect experiencing (I-AES) responses in relation to therapist interventions coded within the preceding speaking turn, using the Psychotherapy Interaction Coding (PIC) system. A hierarchical linear modelling procedure was used to assess the change in affect experiencing and the relationship between affect experiencing and therapist interventions within and across segments of therapy. Process data was taken from six STDP cases; in total 24 hours of video-taped sessions were examined. Therapist interventions were found to account for a statistically significant amount of variance in immediate affect experiencing. Higher levels of immediate affect experiencing followed the therapist's use of Confrontation, Clarification and Support compared to Questions, Self-disclosure and Information interventions. Therapist Confrontation interventions that attempted to direct pressure towards either the visceral experience of affect or a patient's defences against feelings led to the highest levels of immediate affect experiencing. The type of therapist intervention accounts for a small but significant amount of the variation observed in a patient's immediate emotional arousal. Empirical findings support clinical theory in STDP that suggests strategic verbal responses promote the achievement of this specific therapeutic objective.


Michelson interferometer with a holographic memory for measuring fidelity of aberrated phase conjugated beams.
A new interferometer has been developed which combines aspects of a Michelson interferometer with the storage capabilities of holography. The instrument makes it possible to compare interferometrically beams that are not coherent with one another. The instrument was used to measure fidelity of phase conjugation by common mode rejection of aberrators.


An investigation into the presence of secondary electrons in megavoltage photon beams.
The presence of secondary electrons in photon beams of 60Co and 4, 8, 10, 15 and 25 MV x-rays has been studied by measuring surface charge using thin window ionisation chambers. Measurements have been made for square fields from 4 X 4 cm2 to 35 X 35 cm2 for locations from the collimator head to a distance of 4 m from the target. In addition, measurements have been made for rectangular fields at 10 MV and 25 MV for fields of equivalent area from 5 X 5 cm2 to 25 X 25 cm2. By eliminating the inverse square effect, the presence of contaminants from the head and the effect of build-up in air are clearly seen and well separated. Comparison between the curves at different energies indicates an increasing effect of contamination from the head with energy and a decreasing effect of electron production in air with increasing energy.


Photo-induced graft-versus-host disease.
Overlap chronic graft-versus-host disease (GVHD) associates both features of acute and chronic GVHD. Trigger factors for chronic GVHD are unclear. We describe two patients who received allogenic haematopoietic stem-cell transplantation, and who later developed overlap chronic GVHD after sun exposure. Available data from in vivo investigations suggest ultraviolet B radiation (UVB) has a beneficial effect on acute and chronic GVHD. The role of sun irradiation as a trigger for isomorphic cutaneous GVHD has been rarely reported in the literature. Herein, we demonstrate for the first time, using repetitive broadband phototesting, that UVB triggers chronic GVHD.


Intravenous drug users and broken needles--a hidden risk?
To determine the frequency with which intravenous drug users (IDUs) experience broken needles during their injecting careers. Cross-sectional survey. Seventy intravenous drug users held in police custody in Bristol between May and September 2002. Self-reported history of experience of broken needles. Fourteen (20%, 95% CI 11-29%) had experienced a needle breaking while injecting. The total number of broken needles was 23, of which 14 (61%) were recovered, four by surgical intervention, and the remainder as a result of direct action by the individual. Of the 23 broken needles, nine (39%) were reported to be fresh needles, whereas the remainder were being re-used. IDUs may well experience, directly or indirectly, incidents involving broken needles during the course of their injecting careers. Given the potential for embolization and the risk of subsequent complications when this occurs, we recommend that harm minimization guidance should include advice about this potential hazard and the need for early action to retrieve broken needles.


The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat.
Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of zacopride (i.v. infusion) were observed in the settings of pre-treatment (zacopride given 3 min prior to coronary occlusion), post-treatment (zacopride given 3 min after coronary occlusion) and therapeutic treatment (zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, zacopride (15 μg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 μmol/L zacopride were reversed by 1 μmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, zacopride (1 μmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.


Energy-Selective Decomposition of Organometallic Compounds by Slow Electrons: The Case of Chloro(dimethyl sulfide)gold(I).
Gold-containing compounds offer many applications in nanoscale materials science, and electron-beam methods are versatile for shaping nanostructures. In this study, we report the energy-selective fragmentation of chloro(dimethyl sulfide)gold(I) (ClAuS(CH3)2) induced by slow electrons. We observe the resonant formation of four fragment anions, namely [Cl]-, [S]-, [CH2S]-, and [ClAuH···SH]-, which are generated in the energy range of 0-9 eV. The predominant fragment anion is formed below 1 eV from the cleavage of a single Au-Cl bond to produce the [Cl]- anion. The resonant states and the energetics of the fragmentation are investigated by DFT methods. These findings may contribute to future strategies in the elaboration of specific nanomaterials or for selective chemistry using electron-beam techniques.


[Autologous serum tears: Long-term treatment in dry eye syndrome].
Dry eye disease is a multifactorial pathology of the ocular surface. The high incidence of this pathology, as well as its significant impact on quality of life and vision and its financial cost, makes it a real public health problem. While the treatment of mild cases is generally simple and effective, treatment of severe forms is often disappointing. The use of autologous serum tears (AST) represents a therapeutic alternative for the most severe cases. The purpose of our study is to evaluate the efficacy of long-term AST treatment in patients with severe dry eye disease refractory to conventional treatment or secondary to systemic diseases such as Sjögren's syndrome or Graft versus Host disease (GVH), or ocular pathologies such as neurotrophic keratitis, chemical burns and ocular cicatricial pemphigoid. This is a monocentric retrospective observational study conducted on 47 patients, with 83 eyes treated with autologous serum eye drops for isolated or secondary dry eye disease at the Marseille Public Hospitals between April 2014 and April 2017. The patients' subjective symptoms (ocular surface disease index [OSDI] score), their degree of satisfaction and the side effects were collected using questionnaires. Tear Break Up Time (BUT) and Schirmer scores were noted. A clinical evaluation based on fluorescein staining (Oxford score) was carried out prior to treatment with AST at P0 followed by 5 periods: P1 (between 1 and 3 months), P2 (3 to 9 months), P3 (9 to 15 months), P4 (15 months to 24 months), and P5 (>24 months). Out of the 83 eyes treated, the mean age was 54.39±21.56. There were 20 males (42.55 %) and 27 females (57.44 %); treatment indications consisted mainly of 25.53 % GVH, 21.27 % severe dry eye disease and 19.14 % Sjögren syndrome. The mean duration of follow-up was 9.82 months±15.50. The OSDI score decreased by 19.32 points±29.37 (P<0.05) between P0 and P1 and by 23.06 points±18.41 (P<0.05) between P0 and P4. The Oxford clinical score showed a significant decrease by the third month of treatment, between P0 and P2, by 1.32 points±1.76 (P<0.05). The Schirmer test and the BUT also showed an improvement in dry eye symptoms over time with AST, significantly at P1 (P<0.05). Complementary biological analyzes on the composition of AST are under way in order to identify predictive factors of effectiveness; patients not responding to AST treatment might respond to allogeneic serum from healthy donor cord blood. On this first series of 83 eyes treated with ASD, clinical efficacy was noted in most of the patients. No infectious complications were reported, and the satisfaction rate was very high.


Know your dose: RADDOSE.
The program RADDOSE is widely used to compute the dose absorbed by a macromolecular crystal during an X-ray diffraction experiment. A number of factors affect the absorbed dose, including the incident X-ray flux density, the photon energy and the composition of the macromolecule and of the buffer in the crystal. An experimental dose limit for macromolecular crystallography (MX) of 30 MGy at 100 K has been reported, beyond which the biological information obtained may be compromised. Thus, for the planning of an optimized diffraction experiment the estimation of dose has become an additional tool. A number of approximations were made in the original version of RADDOSE. Recently, the code has been modified in order to take into account fluorescent X-ray escape from the crystal (version 2) and the inclusion of incoherent (Compton) scattering into the dose calculation is now reported (version 3). The Compton cross-section, although negligible at the energies currently commonly used in MX, should be considered in dose calculations for incident energies above 20 keV. Calculations using version 3 of RADDOSE reinforce previous studies that predict a reduction in the absorbed dose when data are collected at higher energies compared with data collected at 12.4 keV. Hence, a longer irradiation lifetime for the sample can be achieved at these higher energies but this is at the cost of lower diffraction intensities. The parameter 'diffraction-dose efficiency', which is the diffracted intensity per absorbed dose, is revisited in an attempt to investigate the benefits and pitfalls of data collection using higher and lower energy radiation, particularly for thin crystals.


Mother-infant hearing status and intuitive parenting behaviors during the first 18 months.
Infants enter the world prepared to learn about their environments and to become effective social partners, while most parents are equally prepared to support these early emergent skills. Through subtle, non-conscious behaviors, parents guide their infants in the regulation of emotions, language acquisition, and participation in social exchanges. For example, Deaf mothers modify their signed communication when it is directed to an infant, in much the same way that hearing adults vary their pitch and melodic contours when speaking to an infant. Both hearing and Deaf parents may also accommodate to an infant's hearing status during play interactions in ways that facilitate the child's attention to both the object and the social world. In the present study, such intuitive parenting behaviors were compared at infant ages 6, 9, 12, and 18 months, based on observations of Deaf and hearing mother-infant dyads.


Compensation for Asbestos-Related Diseases in Japan: Utilization of Standard Classifications of Industry and Occupations
Background: Asbestos-related diseases (ARD) are occupational hazards with high mortality rates. To identify asbestos exposure by previous occupation is the main issue for ARD compensation for workers. This study aimed to identify risk groups by applying standard classifications of industries and occupations to a national database of compensated ARD victims in Japan. Methods: We identified occupations that carry a risk of asbestos exposure according to the International Standard Industrial Classification of All Economic Activities (ISIC). ARD compensation data from Japan between 2006 and 2013 were retrieved. Each compensated worker was classified by job section and group according to the ISIC code. Risk ratios for compensation were calculated according to the percentage of workers compensated because of ARD in each ISIC category. Results: In total, there were 6,916 workers with ARD who received compensation in Japan between 2008 and 2013. ISIC classification section F (construction) had the highest compensated risk ratio of 6.3. Section C (manufacturing) and section F (construction) had the largest number of compensated workers (2,868 and 3,463, respectively). In the manufacturing section C, 9 out of 13 divisions had a risk ratio of more than 1. For ISIC divisions in the construction section, construction of buildings (division 41) had the highest number of workers registering claims (2,504). Conclusion: ISIC classification of occupations that are at risk of developing ARD can be used to identify the actual risk of workers' compensation at the national level.


Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma.
Recombinant adenoviral mediated delivery of suicide and cytokine genes has been investigated as a treatment for hepatic metastases of colon carcinoma in mice. Liver tumors were established by intrahepatic implantation of a poorly immunogenic colon carcinoma cell line (MCA-26), which is syngeneic in BALB/c mice. Intratumoral transfer of the herpes simplex virus type 1 thymidine kinase (HSV-tk) and the murine interleukin (mIL)-2 genes resulted in substantial hepatic tumor regression, induced an effective systemic antitumoral immunity in the host and prolonged the median survival time of the treated animals from 22 to 35 days. The antitumoral immunity declined gradually, which led to tumor recurrence over time. A recombinant adenovirus expressing the mIL-12 gene was constructed and tested in the MCA-26 tumor model. Intratumoral administration of this cytokine vector alone increased significantly survival time of the animals with 25% of the treated animals still living over 70 days. These data indicate that local expression of IL-12 may also be an attractive treatment strategy for metastatic colon carcinoma.


Electron transfer and catalytic activity of nitric oxide synthases. Chimeric constructs of the neuronal, inducible, and endothelial isoforms.
The nitric oxide synthases (NOS) are single polypeptides that encode a heme domain, a calmodulin binding motif, and a flavoprotein domain with sequence similarity to P450 reductase. Despite this basic structural similarity, the three major NOS isoforms differ significantly in their rates of .NO synthesis, cytochrome c reduction, and NADPH utilization and in the Ca2+ dependence of these rates. To assign the origin of these differences to specific protein domains, we constructed chimeras in which the reductase domains of endothelial and inducible NOS, respectively, were replaced by the reductase domain of neuronal NOS. The results with the chimeric proteins confirm the modular organization of the NOS polypeptide chain and demonstrate that (a) similar residues establish the necessary contacts between the reductase and heme domains in the three NOS isoforms, (b) the maximal rate of .NO synthesis is determined by the maximum intrinsic ability of the reductase domain to deliver electrons to the heme domain, (c) the Ca2+ independence of inducible NOS requires interactions of calmodulin with both the calmodulin binding motif and the flavoprotein domain, and (d) the effects of tetrahydrobiopterin and L-arginine on electron transfer rates are mediated exclusively by heme domain interactions.


Converting Double-Stranded DNA-Encoded Libraries (DELs) to Single-Stranded Libraries for More Versatile Selections.
DNA-encoded library (DEL) is an efficient high-throughput screening technology platform in drug discovery and is also gaining momentum in academic research. Today, the majority of DELs are assembled and encoded with double-stranded DNA tags (dsDELs) and has been selected against numerous biological targets; however, dsDELs are not amendable to some of the recently developed selection methods, such as the cross-linking-based selection against immobilized targets and live-cell-based selections, which require DELs encoded with single-stranded DNAs (ssDELs). Herein, we present a simple method to convert dsDELs to ssDELs using exonuclease digestion without library redesign and resynthesis. We show that dsDELs could be efficiently converted to ssDELs and used for affinity-based selections either with purified proteins or on live cells.


Antigen Presenting Properties of a Myeloid Dendritic-Like Cell in Murine Spleen.
This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named "L-DC" since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11bhiCD11cloMHCII-CD43+Ly6C-Ly6G-Siglec-F- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4+ T cells, they are capable of antigen cross-presentation for activation of CD8+ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8- cDC and CD8+ cDC are quite distinct from L-DC. CD8+ cDC are distinguishable from the other two subsets by expression of CD24a, Clec9a, Xcr1 and Tlr11, while CD8- cDC are distinguished by expression of Ccnd1 and H-2Eb2. L-DC are distinct from the two cDC subsets through upregulated expression of Clec4a3, Emr4, Itgam, Csf1r and CD300ld. The L-DC gene profile is quite distinct from that of cDC, confirming a myeloid cell type with distinct antigen presenting properties.


Housing Conditions, Neighborhood Physical Environment, and Secondhand Smoke Exposure at Home: Evidence from Chinese Rural-to-Urban Migrant Workers.
Over the past two decades, health-related issues among rural-to-urban migrant workers in China have been widely discussed and documented by public health scholars. However, little, if any, scholarly attention has been paid to migrant workers' secondhand smoke (SHS) exposure at home. This study aims to explore the contours of SHS exposure at home and investigate the effects of inadequate housing conditions and poor neighborhood physical environments on such in-home exposure among Chinese migrant workers. A respondent-driven sampling method was employed to interview 1854 rural-to-urban migrant workers from the period June 2017 to June 2018 in Chengdu, China. The results indicate that Chinese migrant workers are at high risk of SHS exposure at home. Migrant workers who live in homes with inadequate conditions, such as substandard housing and crowdedness, are especially at high risk of SHS exposure at home. Moreover, poor neighborhood physical environments are significantly and positively associated with SHS exposure at home. These findings suggest that strategies that can help improve housing conditions and neighborhood physical environments should be developed and promoted to protect rural-to-urban migrant workers from SHS exposure at home.


Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study.
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent low-grade glioma to measure sustained response and/or stable disease lasting ≥6 months and progression-free survival. Thirty-five evaluable patients received 2 doses (10 mg/kg each) of single-agent BVZ intravenously 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included neuroimaging and expression of tumor angiogenic markers (vascular endothelial growth factor [VEGF], VEGF receptor 2, hypoxia-inducible factor 2α, and carbonic anhydrase 9). Thirty-five evaluable patients (median age 8.4 y [range, 0.6-17.6]) received a median of 12 courses of BVZ + CPT-11 (range, 2-26). Twenty-nine of 35 patients (83%) received treatment for at least 6 months. Eight patients progressed on treatment at a median time of 5.4 months (range, 1-17.8). Six patients (17.7%) still in follow-up have had stable disease without receiving additional treatment for a median of 40.1 months (range, 30.6-49.3) from initiating therapy. The 6-month and 2-year progression-free survivals were 85.4% (SE ± 5.96%) and 47.8% (SE ± 9.27%), respectively. The commonest toxicities related to BVZ included grades 1-2 hypertension in 24, grades 1-2 fatigue in 23, grades 1-2 epistaxis in 18, and grades 1-4 proteinuria in 15. The median volume of enhancement decreased significantly between baseline and day 15 (P < .0001) and over the duration of treatment (P < .037). The combination of BVZ + CPT-11 appears to produce sustained disease control in some children with recurrent low-grade gliomas.


Community Acquired Urosepsis: A surgical intensive care Experience.
Urosepsis contributes significantly to the epidemiology of sepsis. Urosepsis can be classified as community acquired or hospital acquired, depending upon the origin of infection acquisition: either from the community or from a healthcare facility. A great deal of literature is available about nosocomial urosepsis, but the literature regarding community-acquired urosepsis (CAUs) is limited, and studies are underpowered. The aim of our study was to determine the epidemiology, bacteriology, severity, and outcome of CAUs. Methods and Patients: All patients admitted from the emergency department to the surgical intensive care unit (SICU) with urosepsis over a period of 10 years were identified and included retrospectively from the SICU registry. The study was retrospective. Data were entered into the SPSS program version 23, and groups were compared by using chi-square and t-tests. Results were considered statistically significant at p ≤ 0.05. Results: During the study period, 302 patients with CAUs were admitted to the SICU. The common etiology was obstructive uropathy (60%). The Local Arab population outnumbered the non-Arab population (164/54.3%), and there were equal numbers of patients of both genders. Diabetes mellitus and hypertension together were the common comorbidities. Seventy-five percent of patients had acute kidney injury (AKI). Thirty-eight percent of patients had percutaneous nephrostomy, and 24.8% of patients underwent endoscopic stent insertion to relieve the obstruction. Ninety-three percent of patients were admitted with septic shock, and 71.5% had bacteremia. The common bacteria (36.1%) was extended-spectrum beta-lactamase-(ESBL)-producing bacteria, with a predominance of Escherichia coli (31.5%). Fifty-four percent of patients required a change of antibiotics to carbapenem. Eighty-two percent of patients had acute respiratory distress syndrome (ARDS). Patients with bacteremia had a statistically significant AKI, ARDS, and septic shock (p < 0.001). Male patients had a significantly higher incidence of oliguria, intubation, and ARDS (p < 0.05). Eight patients died of urosepsis during the study period, giving a mortality rate of 2.6%. Conclusion: In our patients, obstruction of urine flow was the most common cause of CAUs. Our urosepsis patients had a higher bacteremia rate, which led to higher incidences of organ dysfunction and septic shock. ESBL bacteria were a frequent cause of urosepsis, requiring a change of the initial antibiotic to carbapenem. Male patients had a significantly higher rate of organ dysfunction. Mortality in our urosepsis patients was lower than mentioned in the literature.


Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies.
The recent outbreak of the coronavirus (SARS-CoV2) is an unprecedented threat to human health and society across the globe. In this context, development of suitable interventions is the need of the hour. The viral spike protein (S Protein) and the cognate host cell receptor ACE2 can be considered as effective and appropriate targets for interventions. It is evident from the present computational study, that catechin and curcumin, not only exhibit strong binding affinity to viral S Protein and host receptor ACE2 but also to their complex (receptor-binding domain (RBD) of the spike protein of SARS-CoV2 and ACE2; RBD/ACE2-complex). The binding affinity values of catechin and curcumin for the S protein, ACE2 and RBD/ACE2-complex are - 10.5 and - 7.9 kcal/mol; - 8.9 and - 7.8 kcal/mol; and - 9.1 and - 7.6 kcal/mol, respectively. Curcumin directly binds to the receptor binding domain (RBD) of viral S Protein. Molecular simulation study over a period of 100 ns further substantiates that such interaction within RBD site of S Protein occurs during 40-100 ns out of 100 ns simulation trajectory. Contrary to this, catechin binds with amino acid residues present near the RBD site of S Protein and causes fluctuation in the amino acid residues of the RBD and its near proximity. Both catechin and curcumin bind the interface of 'RBD/ACE2-complex' and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein-protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.


Antiretroviral efficacy of a 98% solution of glycerol or ethylene oxide for inactivation of feline leukemia virus in bone.
To determine whether infectious retrovirus was inactivated in bones from FeLV-infected cats after ethylene oxide (ETO) sterilization or preservation in a 98% solution of glycerol in an in vitro cell culture system. Metatarsal bones obtained from 5 FeLV-infected cats and cultured with feline fibroblast cells. Metatarsal bones were treated with 100% ETO, a 98% solution of glycerol, or left untreated. Twenty-five flasks of feline fibroblast cells were assigned to 5 groups: negative control, positive control, ETO-treated bone, glycerol-treated bone, and untreated bone with 5 replicates/group for 4 passages. Media and cell samples were harvested from every flask at each passage to measure FeLV p27 antigen and the number of copies of provirus per 100 ng of DNA, respectively. All negative control and ETO-treated group replicates were negative for FeLV p27 antigen and provirus throughout the study. All positive control group replicates were positive for FeLV p27 antigen and provirus at passages 1 to 4. Untreated bone group replicates were positive for FeLV p27 antigen at passages 3 and 4 and provirus beginning at passage 2. Glycerol-treated group replicates had delayed cell replication and were negative for FeLV p27 antigen and provirus at passages 1 to 4 and 2 to 4, respectively. Ethylene oxide sterilization of bone from FeLV-infected cats appeared to abrogate transmission of infectious retrovirus and effectively sterilized bone allografts. Impact for Human Medicine-Additional studies to confirm effectiveness of ETO treatment of allograft tissues for prevention of pathogen transmission via transplantation are warranted.


Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination.
The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms other than inhibition of cholinesterase. In the current study, we examined the ability of CPF to evoke lipid peroxidation in the developing brain of fetal and neonatal rats. CPF given to pregnant rats on gestational days 17-20 or to neonatal rats on postnatal days 1-4, failed to elicit increases in thiobarbituric acid-reactive species (TBARS) in brain regions even when the dose was raised above the threshold for systemic toxicity and hepatic damage. In contrast, CPF administration during the second postnatal week, the peak period of neuronal cell differentiation and synaptogenesis, did evoke significant increases in TBARS even at a dose devoid of systemic toxicity. Terbutaline, which is chemically unrelated to CPF and which stimulates neuronal cell metabolism through direct actions on beta-adrenoceptors, also elicited oxidative damage in the developing brain with greater sensitivity in the second postnatal week. These results indicate that diverse compounds can exert convergent effects on brain development through their shared potential to elicit oxidative stress, and that the net outcome is dependent upon specific developmental stages in which metabolic demand is especially high. Furthermore, given the common use of terbutaline in the therapy of preterm labor, and the nearly ubiquitous exposure of the human population to organophosphorus pesticides, the combined oxidative burden of exposure to both agents may contribute to the worsened neurodevelopmental outcomes noted in animal models of such dual exposures.


Quality control in the endoplasmic reticulum: folding and misfolding of vesicular stomatitis virus G protein in cells and in vitro.
Parallel experiments in living cells and in vitro were undertaken to characterize the mechanism by which misfolded and unassembled glycoproteins are retained in the ER. A thermoreversible folding mutant of vesicular stomatitis virus (VSV) G protein called ts045 was analyzed. At 39 degrees C, newly synthesized G failed to fold correctly according to several criteria: intrachain disulfide bonds were incomplete; the B2 epitope was absent; and the protein was associated with immunoglobulin heavy chain binding protein (BiP), a heat shock-related, ER protein. When the temperature was lowered to 32 degrees C, these properties were reversed, and the protein was transported to the cell surface. Upon the shift up from 32 degrees C back to 39 degrees C, G protein in the ER returned to the misfolded form and was retained, while the protein that had reached a pre-Golgi compartment or beyond was thermostable and remained transport competent. The misfolding reaction could be reconstituted in a cell free system using ts045 virus particles and protein extracts from microsomes. Taken together, the results showed that ER is unique among the organelles of the secretory pathway in containing specific factors capable of misfolding G protein at the nonpermissive temperature and thus participating in its retention.


Selective neuronal death following exposure to methylenedioxypyrovalerone is accompanied by an inhibition of NMDA receptor NR2B subunit expression.
In a previous study, methylenedioxypyrovalerone (MDPV), a designer drug of the cathinone family, caused selective enhancement of Caspase3 immunoreactive (Casp3+) apoptotic cells in the nucleus accumbens (NAc) of 7‑day‑old mice. To further elaborate on the mechanism underlying MDPV‑elicited apoptosis, here, we investigated the appearance of Casp3+ cells in developing neural tube explants of E12.5 mice, following MDPV treatment in vitro. Apoptotic cells appeared in large number in the pallium as radial progenitor cells and multipolar neurons, and in the subpallium including the future NAc, both in control and MDPV treated specimens. MDPV did not cause gross morphological changes in the neural tube or in the abundance of Casp3+ cells, based on a visual impression, though quantification was not attempted. We also studied the changes in NMDA receptor (NMDAR) protein subunits NR1 and NR2B in the NAc of 7‑day‑old MDPV treated and control mice, using western blotting of tissue obtained by selective dissection. In MDPV treated animals, expression of NR2B was lower than in the control animals, whereas expression of NR1 did not differ significantly from controls. The findings indicate that, during early postembryonic development, downregulation of the NR2B receptor subunit (at this time predominant in the NMDAR) is accompanied by a decreased viability of neurons. Decreased viability is expressed, in this case, as enhanced susceptibility to stimulation by MDPV - essentially a robust dopaminergic agent, potently affecting the neurons of the NAc. The findings are likely relevant to dopaminergic/NMDAR interactions and a potential pro‑survival role of the NR2B subunit in critical phases of neural development.


Hepatic resection in patients with cirrhosis and hepatocellular carcinoma.
Hepatic resection can be performed safely in carefully selected patients with cirrhosis. To minimize morbidity and mortality, it is essential to reliably estimate functional hepatic reserve and the extent of tumor before resection is performed. Child's classification is a reliable predictor of long term survival, but a more sensitive measure of hepatic function is needed to predict early morbidity and mortality. Child's classification can also be used to stratify patients and exclude those at high risk from hepatic resection. Promising predictors of operative mortality focus on the mitochondrial function of hepatocytes and include cytochrome a (+a3) contents and the redox tolerance index. Patients with advanced cirrhosis are not candidates for extensive hepatic resection and require careful evaluation before consideration for any hepatic resection. In patients with well-compensated cirrhosis and unifocal tumors, the procedure of choice is an anatomic resection of the tumor. If tumor size and location allows, a segmentectomy offers the best outcome, minimizing postoperative liver dysfunction while offering a long term outcome not dissimilar to a major liver resection. In highly selected patients with incidental tumors, a central tumor and perhaps in patients with multifocal hepatocellular carcinoma, hepatic transplantation may be of benefit. By using the appropriate predictors of hepatic function, refined surgical techniques and optimal postoperative care, a mortality rate of less than 10 per cent is achievable in cirrhotic patients with hepatocellular carcinoma who require resection.


Implementation of the Dutch low back pain guideline for general practitioners: a cluster randomized controlled trial.
Cluster randomized controlled trial for a multifaceted implementation strategy. To assess the effectiveness of tailored interventions (multifaceted implementation strategy) to implement the Dutch low back pain guideline for general practitioners with regard to adherence to guideline recommendations. Guidelines for the management of low back pain in primary care have been developed in various countries, but little is known about the optimal implementation strategy. A multifaceted implementation strategy was developed to overcome identified barriers to the implementation of the Dutch low back pain guideline for general practitioners. General practitioners were randomized to an intervention or a control group. The general practitioners in the intervention group (n = 21) received tailored interventions consisting of the Dutch low back pain guideline for general practitioners, a 2-hour educational and clinical practice workshop; two scientific articles on low back pain management; the guideline for occupational physicians; a tool for patient education; and a tool for reaching agreement on low back care with physical, exercise, and manual therapists. The control group (n = 20) received no intervention. The participating general practitioners were asked to recruit consecutive patients with a new episode of low back pain as the main reason for consultation. General practitioners completed registration forms of each individual consultation with regard to the main outcome measures: advice and information, referral to other health-care providers, and prescription of medication. Forty-one of the 67 randomized general practitioners reported on a total of 616 consultations for 531 patients with nonspecific low back pain. The advice and explanation provided by the general practitioners, the prescription of paracetamol or nonsteroidal anti-inflammatory drugs, and prescription of pain medication on atime contingent or a pain contingent basis showed no statistically significant differences between the intervention and control groups. There were also no differences in overall referral rate. However, in follow-up consultations fewer patients were referred to a physical or exercise therapist by the general practitioners in the intervention group than in the control group. The multifaceted intervention strategy modestly improved implementation (for parts of the recommendations in) the Dutch low back pain guideline by general practitioners and produced small concomitant changes in patient management. The implementation strategy produced fewer referrals to therapists during follow-up consultations.


Chemical feasibility of the general acid/base mechanism of glmS ribozyme self-cleavage.
In numerous Gram-positive bacteria, the glmS ribozyme or catalytic riboswitch regulates the expression of glucosamine-6-phosphate (GlcN6P) synthase via site-specific cleavage of its sugar-phosphate backbone in response to GlcN6P ligand binding. Biochemical data have suggested a crucial catalytic role for an active site guanine (G40 in Thermoanaerobacter tengcongensis, G33 in Bacillus anthracis). We used hybrid quantum chemical/molecular mechanical (QM/MM) calculations to probe the mechanism where G40 is deprotonated and acts as a general base. The calculations suggest that the deprotonated guanine G40(-) is sufficiently reactive to overcome the thermodynamic penalty arising from its rare protonation state, and thus is able to activate the A-1(2'-OH) group toward nucleophilic attack on the adjacent backbone. Furthermore, deprotonation of A-1(2'-OH) and nucleophilic attack are predicted to occur as separate steps, where activation of A-1(2'-OH) precedes nucleophilic attack. Conversely, the transition state associated with the rate-determining step corresponds to concurrent nucleophilic attack and protonation of the G1(O5') leaving group by the ammonium moiety of the GlcN6P cofactor. Overall, our calculations help to explain the crucial roles of G40 (as a general base) and GlcN6P (as a general acid) during glmS ribozyme self-cleavage. In addition, we show that the QM/MM description of the glmS ribozyme self-cleavage reaction is significantly more sensitive to the size of the QM region and the quality of the QM-MM coupling than that of other small ribozymes.


Barcelona clinic liver cancer-stage C hepatocellular carcinoma: A novel approach to subclassification and treatment.
Barcelona clinic liver cancer-stage C (BCLC-C) encompasses a broad spectrum of tumor burdens, liver function statuses, patient prognoses, and treatment strategies. Currently, sorafenib is the only recommended treatment for patients with BCLC-C and outcomes remain suboptimal. The aims of this study were to assess the heterogeneity of BCLC-C hepatocellular carcinoma (HCC) cases, propose a novel subclassification for these cases, and suggest optimal treatment strategies other than sorafenib.We retrospectively analyzed 196 consecutive BCLC-C HCC patients who were diagnosed and treated between January 2008 and December 2015.All 196 patients were classified according to the modified Union for International Cancer Control (Stage I, 0.0%; Stage II, 8.2%; Stage III, 64.3%; Stage IVA, 21.9%; and Stage IVB, 5.6%) and American Joint Committee on Cancer TNM staging systems (Stage I, 0.0%; Stage II, 16.3%; Stage IIIA, 27.6%; Stage IIIB, 49.5%; Stage IIIC, 1.5%; Stage IVA, 1.0%; and Stage IVB, 4.1%). First-line treatment modalities included surgical resection (8.7%), transarterial chemoembolization (49.5%), hepatic arterial infusion therapy (5.6%), sorafenib therapy (9.2%), radiotherapy (9.2%), and best supportive care (10.7%). In univariate analysis, Child-Pugh score, tumor size, distant metastasis, multinodular or infiltrative/diffuse type of HCC, main portal vein invasion, hepatic vein invasion, and bile duct invasion were significantly associated with survival (P < .001). Tumor size, distant metastasis, HCC type, and bile duct invasion remained significantly associated with 1-, 3-, and 5-year survival rates in multivariate Cox regression analyses. Using these 4 characteristics, a novel subclassification of BCLC-C was developed and applied to the patient cohort. The subclassification included 5 substages (stages C0-C4), as defined based on the number of characteristics that were present in each HCC case (0-4). The subclassification showed significant associations with survival, with median survival times of 3026 days, 605 days, 224 days, 126 days, and 82 days for patients with Stage C0, C1, C2, C3, and C4 disease, respectively (P < .001). Additionally, diverse survival rates were observed when different treatment modalities were selected for cases within each substage.The proposed BCLC-C subclassification of HCC patients is effective in providing better prognostic subclassifications and more appropriate treatment strategies.


Reactions of the melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK) with the ABTS cation radical: identification of new oxidation products.
The melatonin metabolite N1-acetyl-5-methoxykynuramine (AMK; 1), which was previously shown to be a potent radical scavenger, was oxidized using the ABTS cation radical [ABTS = 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid)]. Several new oxidation products were obtained, which were separated by repeated chromatography and characterized by spectroscopic methods such as mass spectrometry (ESI-MS and ESI-HRMS), 1H-NMR and 13C-NMR, HMBC, HSQC, H,H COSY correlations and IR spectroscopy. The main products were oligomers of 1 (3 dimers, 1 trimer and 2 tetramers). In all cases, the amino group N2 was involved in the reactions. Two of the dimers turned out to be cis (2a) and trans (2b) isomers containing an azo bond. In the other dimer (3a), the nitrogen atom N2 was attached to atom C5 of the second aromatic amine, with loss of the methoxy group. In the trimer (5), one N2 formed a bridge to C5 of unit B, as in the respective dimer, while this one of C had bridged to C6 of B. One of the tetramers (6) was composed of a trimer 5 attached to N2 of a fourth 1 molecule via an azo bond as in 2a/b. In the other tetramer (7), an additional C-C bond between rings B and C in 6 is assumed. Although oligomers of AMK may only attain low in vivo concentrations, the types of reactions observed shed light on the physiologically possible metabolism of AMK once reacted with a free radical. The displacement of a methoxy group, rarely seen in the oxidation of methoxylated biomolecules, underlines the reactivity of AMK (1). Preliminary data show that, in the presence of ABTS cation radicals, AMK (1) can interact with side chains of aromatic amino acids, a finding which may be crucial for understanding to date unidentified protein modification by a melatonin metabolite detected earlier in experiments with radioactively labeled melatonin.


Hearts transplanted after circulatory death in children: Analysis of the International Society for Heart and Lung Transplantation registry.
We aimed to describe worldwide DCD HT experience in children using the International Society for Heart and Lung Transplantation Registry. The Registry was queried for primary HT performed in children (2005-2014). Kaplan-Meier analysis was used to assess survival for recipients grouped by DCD or DBD hearts. Recipient characteristics were compared between DCD and DBD and between survivors and non-survivors of DCD HT. Among 3877 pediatric HT performed, 21 (0.5%) were DCD. DCD 1-year survival was 61% vs 91% DBD, P < .01. DCD recipients were more often supported by ECMO pre-HT (24% vs 6%, P < .001) and more often receiving inhaled nitric oxide (10% vs 0.6%, P < .001) compared to DBD. Older DCD recipients had significantly lower 1-year survival of 57% vs 93% for DBD, P < .01. Survival for infant DCD recipients was not statistically different to DBD recipients (survival 62% at 1 year and 62% at 5 years for DCD vs 85% at 1 year and 77% at 5 years for DBD, P = .15). Recipients of DCD HT who died were more often supported by ECMO pre-HT (56% non-survivors vs 0% survivors, P = .004) and receiving mechanical ventilation (44% vs 0%, P = .012). DCD HT is uncommon in children. DCD-independent factors in recipients may have contributed to worse survival as DCD recipients who died were more often supported by ECMO and mechanical ventilation. More research is needed to identify donor factors and recipient factors that contribute to mortality after DCD HT.


H-Ras signals to cytoskeletal machinery in induction of integrin-mediated adhesion of T cells.
The adhesive function of integrins is regulated through cytoplasmic signaling. The present study was performed to investigate the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemokines. Adhesion of T cells induced by chemokines macrophage inflammatory protein (MIP)-1alpha and MIP-1beta was inhibited by pertussis toxin, wortmannin, and cytochalasin B, suggesting that both G protein-sensitive phosphatidylinositol (PI) 3-kinase activation and cytoskeletal assemblies are involved. The chemokine-induced T cell adhesion could be mimicked by expression of small G proteins, fully activated H-RasV12, or H-RasV12Y40C mutant, which selectively binds to PI 3-kinase, in T cells, inducing activated form of LFA-1alpha and LFA-1-dependent adhesion to ICAM-1. H-Ras expression also induced F-actin polymerization which colocalized with profilin in T cells. Adult T cell leukemia (ATL) cells spontaneously adhered to ICAM-1, which depended on endogenous MIP-1alpha and MIP-1beta through activation of G protein-sensitive PI 3-kinase. H-Ras signal pathway, leading to PI 3-kinase activation, also induced active configuration of LFA-1 and LFA-1-mediated adhesion of ATL cells, whereas expression of a dominant-negative H-Ras mutant failed to do. Profilin-dependent spontaneous polymerization of F-actin in ATL cells was reduced by PI 3-kinase inhibitors. In this paper we propose that H-Ras-mediated activation of PI 3-kinase can be involved in induction of LFA-1-dependent adhesion of T cells, which is relevant to chemokine-mediated signaling, and that profilin may form an important link between chemokine- and/or H-Ras-mediated signals and F-actin polymerization, which results in triggering of LFA-1 on T cells or leukemic T cells.


Formation of heteroaromatic nitrogen after prolonged humification of vascular plant remains as revealed by nuclear magnetic resonance spectroscopy.
In the search for the mechanisms involved in the immobilization of organic nitrogen in humified remains of vascular plants, the efforts of the present investigation were directed toward the examination of the transformation of nitrogenous compounds during the peat and coal stage by means of solid-state nuclear magnetic resonance (NMR) spectroscopy. While accumulation of heteroaromatic-N is not detected in most of the studied peat layers, a clear shoulder in the chemical shift region of pyrrole- or indole-N is observed in the solid-state 15N NMR spectrum of material from the deepest (and thus oldest) peat layer underlying the sapropel from Mangrove Lake, Bermuda (10000 years). This points to the assumption that transformation of nitrogen occurs between an advanced stage of peatification and an early stage of coalification. The observed sudden alteration in nitrogen functionality indicates that continuous accumulation of newly synthesized or selectively preserved biogenic structures is not responsible for the presence of heteroaromatic-N in these fossilized deposits. It seems rather likely that abiotic conditions, occurring during advanced sediment maturation, have an effect on the observed N transformation. With increasing coalification, pyrrole-type-N becomes the dominant form in the macromolecular coal network. Pyridine-type-N was only detected in a coal of anthracite rank.


Characteristics of patients receiving allergy vaccination: to which extent do socio-economic factors play a role?
Little is known about characteristics of patients receiving allergen-specific immunotherapy. Identifying obstacles to appropriate treatment according to guidelines may facilitate the development of strategies aiming at improved treatment of patients with allergic respiratory diseases. The objective of this study was to investigate differences in disease severity, demographic and socioeconomic status between allergic rhinitis patients receiving allergen-specific immunotherapy and allergic rhinitis patients not receiving allergen-specific immunotherapy. A total of 366 patients were studied of whom 210 were going to receive subcutaneously administrated immunotherapy (SIT) against grass pollen and/or house dust mite allergy. The severity of rhino-conjunctivitis (hay fever) and/or asthma was classified according to international guidelines. The questionnaires included an EQ-5D visual analogue scale instrument and some socio-economic questions. Severity of disease, young age, high level of education as well as greater perceived impairment of health-related quality of life due to allergic symptoms were significantly associated with use of SIT. Somewhat unexpectedly, household income was not associated with use of SIT. Use of SIT was associated with both disease severity measures and educational level, but not income level. These results suggest social inequality as reflected by lower use of SIT among patients with lower educational level may represent an obstacle to treatment with SIT.


Phenol Concentrations During Childhood and Subsequent Measures of Adiposity Among Young Girls.
Phenolic compounds represent a class of environmental chemicals with potentially endocrine-disrupting capabilities. We investigated longitudinal associations between childhood exposure to phenols, from both manmade and natural sources, and subsequent measures of adiposity among girls enrolled in the Breast Cancer and the Environment Research Program between 2004 and 2007. Baseline (ages 6-8 years) urinary concentrations were obtained for creatinine and phenol metabolites: enterolactone, genistein, daidzein, benzophenone-3, bisphenol A, the sum of parabens (methyl, ethyl, and propyl parabens), 2,5-dichlorophenol, and triclosan. Body mass index (weight (kg)/height (m)2), waist circumference, and percent body fat were measured at annual or semiannual examinations through 2015 (n = 1,017). Linear mixed-effects regression was used to estimate how baseline concentrations of phenols (tertile groups) were related to changes in girls' adiposity measurements from ages 7 through 15 years. Enterolactone was inversely associated with body mass index, waist circumference, and percent body fat, while 2,5-dichlorophenol was positively associated with these measurements. A nonmonotonic association was observed for triclosan and girls' adiposity; however, it was due to effect modification by baseline overweight status. Triclosan was positively associated with adiposity only among overweight girls. These results suggest that exposure to specific phenols during childhood may influence adiposity through adolescence.


To adopt, to adapt, or to contextualise? The big question in clinical practice guideline development.
Developing new clinical practice guidelines (CPGs) can be time-consuming and expensive. A more efficient approach could be to adopt, adapt or contextualise recommendations from existing good quality CPGs so that the resultant guidance is tailored to the local context. The first steps are to search for international CPGs that have a similar purpose, end-users and patients to your situation. The second step is to critically appraise the methodological quality of the CPGs to ensure that your guidance is based on credible evidence. Then the decisions begin. Can you simply 'adopt' this (parent) clinical practice guidelines, and implement the recommendations in their entirety, without any changes, in your setting? If so, then no further work is required. However this situation is rare. What is more likely, is that even if recommendations from the parent clinical practice guidelines can be adopted, how they are implemented needs to address local issues. Thus you may need to 'contextualise' the guidance, by addressing implementation issues such as local workforce, training, health systems, equipment and/or access to services. Generally this means that additional information is required (Practice/Context Points) to support effective implementation of the clinical practice guidelines recommendations. In some cases, you may need to 'adapt' the guidance, where you will make changes to the recommendations so that care is relevant to your local environments. This may involve additional work to search for local research, or obtain local consensus, regarding how best to adapt recommendations. For example, adaptation might reflect substituting one drug for another (drugs have similar effects, but the alternative drug to the recommended one may be cheaper, more easily obtained or more culturally acceptable). There is lack of standardisation of clinical practice guidelines terminology, leading clinical practice guideline activities often being poorly conceptualised or reported. We provide an approach that would help improve efficiency and standardisation of clinical practice guidelines activities.


Dynamical feature extraction at the sensory periphery guides chemotaxis.
Behavioral strategies employed for chemotaxis have been described across phyla, but the sensorimotor basis of this phenomenon has seldom been studied in naturalistic contexts. Here, we examine how signals experienced during free olfactory behaviors are processed by first-order olfactory sensory neurons (OSNs) of the Drosophila larva. We find that OSNs can act as differentiators that transiently normalize stimulus intensity-a property potentially derived from a combination of integral feedback and feed-forward regulation of olfactory transduction. In olfactory virtual reality experiments, we report that high activity levels of the OSN suppress turning, whereas low activity levels facilitate turning. Using a generalized linear model, we explain how peripheral encoding of olfactory stimuli modulates the probability of switching from a run to a turn. Our work clarifies the link between computations carried out at the sensory periphery and action selection underlying navigation in odor gradients.


Relationship Between Gender and the Effectiveness of Montelukast: An Italian/Danish Register-Based Retrospective Cohort Study.
Rationale: Gender-related differences in asthma prevalence, pathophysiology and clinical features induced by sex steroids have been investigated, however, how gender influences response to asthma treatments in routine clinical practice have not yet been elucidated fully. This aspect is crucial for montelukast considering the jeopardization of asthmatic patients that benefit from this treatment and the existence of evidence of gender differences in leukotriene levels. Therefore, to fulfill this medical need, we investigated the role of gender on a set of montelukast' effectiveness surrogates in adults and pediatric patients with asthma. Methods: The study settings were Napoli 2 Local Health Unit (southern Italy) and the entire Danish territory. The study population was composed of adult and pediatric patients with asthma. Cumulative incidence curves, unadjusted and adjusted Cox regression were used as statistical models to compare aforementioned outcomes between genders. Results: Adult Italian male users of montelukast had a statistically lower persistence in montelukast treatment compared to female users. In the adjusted analyses, they had a higher hazard of montelukast' withdrawal (Hazard Ratio [HR] 1.07; 95% Confidence Interval [CI] 1.01-1.14), add-on/switch to a long-term treatment for asthma following montelukast withdrawal (HR 1.72; 95%CI 1.39-2.12), and rescue therapy with short-acting β2 agonist (HR 1.24; 95%CI 1.04-1.47). In the adult Danish cohort, we also found that male users had higher a hazard of rescue therapy with oral corticosteroids (HR 1.10; 95%CI 1.04-1.16). In the pediatric cohorts, no statistically significant differences were observed between genders for aforementioned outcomes. Conclusions: In adults, male gender was associated with increased hazards of montelukast discontinuation, add-on/switch to a long-term treatment for asthma following montelukast withdrawal, and rescue therapy with oral corticosteroids or short-acting β2 agonist when compared to the female gender. As expected, these associations were reversed or absent in pediatric patients.


[Treatment of adult men with congenital adrenal hyperplasia syndrome due to 21-hydroxylase deficiency].
Information about the treatment of males with congenital adrenal hyperplasia (CAH) is scarce and there are no therapeutical guidelines. The aim of this review is to provide a survey of the current data. An extensive literature research was performed in PubMed for relevant articles published in the last ten years. The aim in the treatment of adult male CAH patients is preservation of fertility, prevention of an addisonian crisis, blood pressure management, prevention of testicular adrenal rest tumors (TART), maintaining well-being and good quality of life, satisfactory sexual function and prevention of long-term side effects of gluco- and mineralocorticoid therapy. The change from paediatric to adult medicine should be handled in a transition outpatient clinic organized by paediatric and adult endocrinologists. Most studies have included only small numbers of patients. The steroid therapy is usually orientated on an individual basis; but, general guidelines are lacking. It is reported that fertility is often impaired and related to the occurrence of TART. Some of these tumors are responsive to altered glucocorticoid therapy. However, glucocorticoid-resistant TART have been described, and testis-sparing surgery seems to be a treatment option. A future system of regular follow-up visits and standardized therapy guidelines are essential to provide a better medical care and a higher quality of life for male patients with CAH.


LASSO with cross-validation for genomic selection.
We used a least absolute shrinkage and selection operator (LASSO) approach to estimate marker effects for genomic selection. The least angle regression (LARS) algorithm and cross-validation were used to define the best subset of markers to include in the model. The LASSO-LARS approach was tested on two data sets: a simulated data set with 5865 individuals and 6000 Single Nucleotide Polymorphisms (SNPs); and a mouse data set with 1885 individuals genotyped for 10 656 SNPs and phenotyped for a number of quantitative traits. In the simulated data, three approaches were used to split the reference population into training and validation subsets for cross-validation: random splitting across the whole population; random sampling of validation set from the last generation only, either within or across families. The highest accuracy was obtained by random splitting across the whole population. The accuracy of genomic estimated breeding values (GEBVs) in the candidate population obtained by LASSO-LARS was 0.89 with 156 explanatory SNPs. This value was higher than those obtained by Best Linear Unbiased Prediction (BLUP) and a Bayesian method (BayesA), which were 0.75 and 0.84, respectively. In the mouse data, 1600 individuals were randomly allocated to the reference population. The GEBVs for the remaining 285 individuals estimated by LASSO-LARS were more accurate than those obtained by BLUP and BayesA for weight at six weeks and slightly lower for growth rate and body length. It was concluded that LASSO-LARS approach is a good alternative method to estimate marker effects for genomic selection, particularly when the cost of genotyping can be reduced by using a limited subset of markers.


4-Hydroxymethyl-substituted oxazolidinone synthesis by tetraarylphosphonium salt-catalyzed reactions of glycidols with isocyanates.
Preparation of 4-hydroxymethyl-substituted oxazolidinones including optically active ones, in which tetraarylphosphonium salts catalyze the reaction of glycidol with isocyanates effectively, is described. The neutral catalysis facilitates glycidol addition to isocyanates followed by intramolecular cyclization. Mechanistic studies suggest that hydrogen-bonding interactions with the catalyst play an important role in the reaction progress.


Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014--United States.
Since mid-2006, a licensed human papillomavirus (HPV) vaccine has been available and recommended by the Advisory Committee on Immunization Practices (ACIP) for routine vaccination of adolescent girls at ages 11 or 12 years. Two vaccines that protect against HPV infection are currently available in the United States. Both the quadrivalent (HPV4) and bivalent (HPV2) vaccines protect against HPV types 16 and 18, which cause 70% of cervical cancers; HPV4 also protects against HPV types 6 and 11, which cause 90% of genital warts. In 2011, the ACIP also recommended HPV4 for the routine vaccination of adolescent boys at ages 11 or 12 years. HPV vaccines can be safely co-administered with other routinely recommended vaccines, and ACIP recommends administration of all age-appropriate vaccines during a single visit. To assess progress with HPV vaccination coverage among adolescents aged 13-17 years, characterize adherence with recommendations for HPV vaccination by the 13th birthday, and describe HPV vaccine adverse reports received postlicensure, CDC analyzed data from the 2007-2013 National Immunization Survey-Teen (NIS-Teen) and national postlicensure vaccine safety data among females and males. Vaccination coverage with ≥1 dose of any HPV vaccine increased significantly from 53.8% (2012) to 57.3% (2013) among adolescent girls and from 20.8% (2012) to 34.6% (2013) among adolescent boys. Receipt of ≥1 dose of HPV among girls by age 13 years increased with each birth cohort; however, missed vaccination opportunities were common. Had HPV vaccine been administered to adolescent girls born in 2000 during health care visits when they received another vaccine, vaccination coverage for ≥1 dose by age 13 years for this cohort could have reached 91.3%. Postlicensure monitoring data continue to indicate that HPV4 is safe. Improving practice patterns so that clinicians use every opportunity to recommend HPV vaccines and address questions from parents can help realize reductions in vaccine-preventable infections and cancers caused by HPV.


American Academy of Orthopaedic Surgeons Clinical Practice Guideline Summary of Surgical Management of Osteoarthritis of the Knee.
The Surgical Management of Osteoarthritis of the Knee Evidence-Based Clinical Practice Guideline is based on a systematic review of published studies for surgical management of osteoarthritis of the knee in skeletally mature patients. This guideline contains 16 recommendations and seven options to assist orthopaedic surgeons and all qualified physicians with the surgical management of patients with osteoarthritis of the knee based on the best current available evidence. It is also intended to serve as an information resource for professional healthcare practitioners and developers of practice guidelines and recommendations. In addition to providing pragmatic practice recommendations, this guideline also highlights gaps in the literature and informs areas for future research and quality measure development.


Substance abuse and international travel.
Travel for both business and pleasure can be a risk factor for substance abuse problems, for clinical deterioration in those with chemical dependence, and for relapse when an addiction has been in remission. Sedatives, opioids and alcohol can complicate many of the physiologic adjustments mandated by modern jet travel, such as adaptation to different altitudes, climates, and time zones. Additionally, substances of abuse can result in a deterioration of many clinical conditions during travel, and they can precipitate other medical problems while underway, including motion sickness, heat-related illness and diarrheal disease. Drugs and alcohol are crucial factors in both serious accidents and legal difficulties while traveling. Finally, involvement with drugs as well as close and intimate liaison with drug abusers and their consorts has associated with it a high degree of risk for exposure to serious infectious diseases worldwide.


New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae: emergence and response in Europe.
Acquired carbapenemases confer extensive antibiotic resistance to Enterobacteriaceae and represent a public health threat. A novel acquired carbapenemase, New Delhi metallo-beta-lactamase 1 (NDM-1), has recently been described in the United Kingdom and Sweden, mostly in patients who had received care on the Indian subcontinent. We conducted a survey among 29 European countries (the European Union Member States, Iceland and Norway) to gather information on the spread of NDM-1-producing Enterobacteriaceae in Europe, on public health responses and on available national guidance on detection, surveillance and control. A total of 77 cases were reported from 13 countries from 2008 to 2010. Klebsiella pneumoniae was the most frequently reported species with 54%. Among 55 cases with recorded travel history, 31 had previously travelled or been admitted to a hospital in India or Pakistan and five had been hospitalised in the Balkan region. Possible nosocomial acquisition accounted for 13 of 77 cases. National guidance on NDM-1 detection was available in 14 countries and on NDM-1 control in 11 countries. In conclusion, NDM-1 is spreading across Europe, where it is frequently linked to a history of healthcare abroad, but also to emerging nosocomial transmission. National guidance in response to the threat of carbapenemase-producing Enterobacteriaceae is available in approximately half of the surveyed European countries. Surveillance of carbapenemase- producing Enterobacteriaceae must be enhanced in Europe and effective control measures identified and implemented.


Monoclonal antibodies binding to nuclear structures and axons in adult avian dorsal root ganglia.
Four monoclonal antibodies raised against embryonic chick dorsal root ganglia (5) recognize epitopes in neuronal and supporting cell nuclei, and in axons and contiguous cytoplasmic elements in some neurons of the adult chicken. Binding, analyzed at the ultrastructural level, is to reaction sites on the nuclear matrix, nucleolar complex, nuclear bodies, and filamentous elements in axons and some perikaryal regions.


Description of freshwater bacterial assemblages from the upper paraná river floodpulse system, Brazil.
Bacteria were identified from a large, seasonally flooded river (Paraná River, Brazil) and two floodplain habitats that were part of the same river system yet very different in nature: clearwater Garças Lagoon and the highly humic waters of Patos Lagoon. Bacterioplankton were collected during mid-summer (Jan. 2002) from water samples (2 l) filtered first through a 1.2-microm filter then a 0.2-microm membrane filter representing the particle-attached and free-living sub-communities, respectively. DNA was extracted from filters and purified and a 16S rRNA clone library established for each habitat. Over 300 clones were sequenced and checked for similarity to existing 16S sequences in GenBank using the BLAST algorithm with default parameters. Further classification of clones was done using a species "backbone" attachment followed by parsimony analysis. The majority (85%) of sequences, referred to here as operational taxonomic units (OTUs), were most similar to uncultured bacterium 16S sequences. OTUs from each Proteobacteria sub-phylum (alpha, beta, gamma, delta, epsilon) were present in the Upper Paraná River system, as well as members of the Bacteroidetes. The microbial assemblage from Patos Lagoon was least like other samples in that it had no Firmicutes present and was dominated by Actinobacteria. Verrucomicrobia OTUs were only found in the free-living assemblage. This study documents the presence of globally distributed phyla in Upper Paraná River and taxa unique to habitat and particle attachment.


Safety, Threat, and Stress in Intergroup Relations: A Coalitional Index Model.
Contact between people from different groups triggers specific individual- and group-level responses, ranging from attitudes and emotions to welfare and health outcomes. Standard social psychological perspectives do not yet provide an integrated, causal model of these phenomena. As an alternative, we describe a coalitional perspective. Human psychology includes evolved cognitive systems designed to garner support from other individuals, organize and maintain alliances, and measure potential support from group members. Relations between alliances are strongly influenced by threat detection mechanisms, which are sensitive to cues that express that one's own group will provide less support or that other groups are dangerous. Repeated perceptions of such threat cues can lead to chronic stress. The model provides a parsimonious explanation for many individual-level effects of intergroup relations and group-level disparities in health and well-being. This perspective suggests new research directions aimed at understanding the psychological processes involved in intergroup relations.


Transcriptome sequencing of different narrow-leafed lupin tissue types provides a comprehensive uni-gene assembly and extensive gene-based molecular markers.
Narrow-leafed lupin (NLL; Lupinus angustifolius L.) is an important grain legume crop that is valuable for sustainable farming and is becoming recognized as a human health food. NLL breeding is directed at improving grain production, disease resistance, drought tolerance and health benefits. However, genetic and genomic studies have been hindered by a lack of extensive genomic resources for the species. Here, the generation, de novo assembly and annotation of transcriptome datasets derived from five different NLL tissue types of the reference accession cv. Tanjil are described. The Tanjil transcriptome was compared to transcriptomes of an early domesticated cv. Unicrop, a wild accession P27255, as well as accession 83A:476, together being the founding parents of two recombinant inbred line (RIL) populations. In silico predictions for transcriptome-derived gene-based length and SNP polymorphic markers were conducted and corroborated using a survey assembly sequence for NLL cv. Tanjil. This yielded extensive indel and SNP polymorphic markers for the two RIL populations. A total of 335 transcriptome-derived markers and 66 BAC-end sequence-derived markers were evaluated, and 275 polymorphic markers were selected to genotype the reference NLL 83A:476 × P27255 RIL population. This significantly improved the completeness, marker density and quality of the reference NLL genetic map.


Activity of penicillin and novobiocin against bovine mastitis pathogens.
Penicillin (P), novobiocin (N), and both (P-N) were evaluated in vitro against 143 clinical isolates of bovine mastitis, including, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis. Greater antistaphylococcal activities were demonstrated with N alone and P-N than with P alone. Streptococcus spp were more susceptible to P alone than to N alone, and the effectiveness of P-N corresponded with that of P alone. In vitro, P-N had a wider spectrum of antibacterial activity than did either P or N. Similar results were also obtained in vivo, using the mouse protection test. The P-N gave a greater protection rate in mice experimentally infected with S aureus and Str agalactiae than did P or N.


[Role of gamasids in the epizootiology of tularemia].
10 strains of Francisella tularensis were isolated from 4 species of gamasid mites, Laelaps muris, L. multispinosus, Hyperlaelaps amphibius and Haemolaelaps glasgowi, in natural nidi of tularemia in the Tumen district. Under experimental conditions L. muris is often infected with tularemia agent on sick animals but preserves it at an indoor temperature not more than a week and does not transmit it transovarially. Haemogamasus ambulans preserve the agent within the same period. L. muris and Hirstionyssus isabellinus do not transmit the tularemia agent to healthy animals through a bite.