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Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool for the assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis, bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understanding the exact relationship between each MRI feature and local synovial pathobiology is critical to dissect disease pathogenesis as well as develop future predictive models., Methods: A systematic review was performed of the current published literature examining the relationship between MRI abnormalities and synovial pathobiology in patients with RA., Results: Eighteen studies were identified; most focused on validation of MRI as a tool to detect and quantify synovitis, with a significant relationship demonstrated. Additionally, from the limited data available, a critical role seems likely for synovial pathways, at least in driving joint damage. However, there was a lack of data examining the relationship between synovial pathobiology and bone marrow abnormalities and JSN., Conclusion: Although understanding the interrelationship of these disease biomarkers offers the potential to enhance the predictive validity of modern imaging with concomitant synovial pathobiological analysis, further studies integrating MRI with synovial tissue analysis in well-controlled cohorts at distinct disease stages before and after therapeutic intervention are required to achieve this.

Autism spectrum disorders (ASD) are neurodevelopmental disabilities characterized by severe impairment in social communication skills and restricted, repetitive behaviors. We have previously shown that a single transplantation of mesenchymal stem cells (MSC) into the cerebral lateral ventricles of BTBR autistic-like mice resulted in an improvement across all diagnostic criteria of ASD. We suggested that brain-derived neurotrophic factor (BDNF), a protein which supports the survival and regeneration of neurons secreted by MSC, largely contributed to the beneficial behavioral effect. In this study, we investigated the behavioral effects of transplanted MSC induced to secrete higher amounts of neurotrophic factors (NurOwn ® ), on various ASD-related behavioral domains using the BTBR mouse model of ASD. We demonstrate that NurOwn ® transplantation had significant advantages over MSC transplantation in terms of improving communication skills, one and six months following treatment, as compared to sham-treated BTBR mice. Furthermore, NurOwn ® transplantation resulted in reduced stereotypic behavior for as long as six months post treatment, compared to the one month improvement observed in the MSC treated mice. Notably, NurOwn ® treatment resulted in improved cognitive flexibility, an improvement that was not observed by MSC treatment. Both MSC and NurOwn ® transplantation induced an improvement in social behavior that lasted for six months. In conclusion, the present study demonstrates that a single transplantation of MSC or NurOwn ® have long-lasting benefits, while NurOwn ® may be superior to MSC treatment., (Copyright © 2017. Published by Elsevier B.V.)

Uncovering structural regularities and architectural topologies of cortical circuitry is vital for understanding neural computations. Recently, an experimentally constrained algorithm generated a dense network reconstruction of a ∼0.3-mm 3 volume from juvenile rat somatosensory neocortex, comprising ∼31,000 cells and ∼36 million synapses. Using this reconstruction, we found a small-world topology with an average of 2.5 synapses separating any two cells and multiple cell-type-specific wiring features. Amounts of excitatory and inhibitory innervations varied across cells, yet pyramidal neurons maintained relatively constant excitation/inhibition ratios. The circuit contained highly connected hub neurons belonging to a small subset of cell types and forming an interconnected cell-type-specific rich club. Certain three-neuron motifs were overrepresented, matching recent experimental results. Cell-type-specific network properties were even more striking when synaptic strength and sign were considered in generating a functional topology. Our systematic approach enables interpretation of microconnectomics 'big data' and provides several experimentally testable predictions.

Numerous animal species emit vocalizations in response to various social stimuli. The neural basis of vocal communication has been investigated in monkeys, songbirds, rats, bats, and invertebrates resulting in deep insights into motor control, neural coding, and learning. Mice, which recently became very popular as a model system for mammalian neuroscience, also utilize ultrasonic vocalizations (USVs) during mating behavior. However, our knowledge is lacking of both the behavior and its underlying neural mechanism. We developed a novel method for head-restrained male mice (HRMM) to interact with non-restrained female mice (NRFM) and show that mice can emit USVs in this context. We first recorded USVs in a free arena with non-restrained male mice (NRMM) and NRFM. Of the NRMM, which vocalized in the free arena, the majority could be habituated to also vocalize while head-restrained but only when a female mouse was present in proximity. The USVs emitted by HRMM are similar to the USVs of NRMM in the presence of a female mouse in their spectral structure, inter-syllable interval distribution, and USV sequence length, and therefore are interpreted as social USVs. By analyzing the vocalizations of NRMM, we established criteria to predict which individuals are likely to vocalize while head fixed based on the USV rate and average syllable duration. To characterize the USVs emitted by HRMM, we analyzed the syllable composition of HRMM and NRMM and found that USVs emitted by HRMM have a higher proportion of USVs with complex spectral representation, supporting previous studies showing that mice social USVs are context dependent. Our results suggest a way to study the neural mechanisms of production and control of social vocalization in mice using advanced methods requiring head fixation.

Introduction: Immunotherapy is a novel treatment for lung cancer. Pembrolizumab (Merck Sharp and Dohme, Kenilworth, NJ) is a monoclonal antibody against programmed cell death 1 that has been approved for use with NSCLC together with a companion diagnostic by Dako (Carpinteria, CA). Ventana's BenchMark XT (Ventana Medical Systems, Tucson, AZ) is a widely used immunohistochemical (IHC) platform. However, data on its reliability and reproducibility with the 22C3 antibody are scant., Methods: We performed a comprehensive calibration of 22C3 programmed cell death ligand 1 (PD-L1) staining on the BenchMark XT platform using Dako's prediluted 22C3 anti-PD-L1 primary antibody with two of Ventana's detection systems. Forty-one random cases of NSCLC were then independently evaluated by two pathologists. Each case was scored using Dako- or Ventana-stained slides. The scores obtained with the two 22C3 Ventana assays were compared with those obtained using the Dako 22C3 IHC platform., Results: The Dako IHC platform stratified eight, seven, and 26 cases as being strongly positive, weakly positive, and negative for PD-L1, respectively, whereas 36 of 41 cases (87.8%) had the same results with Ventana's UltraView 22C3 protocol (Pearson's correlation score 0.91, p < 0.0001). Moreover, 35 of 41 cases (85.3%) had the same results with Ventana's OptiView 22C3 protocol (Pearson's correlation score 0.89, p < 0.0001)., Conclusions: The results of this study demonstrate that the same PD-L1 IHC algorithm can be reliably applied to Ventana's BenchMark XT platform. Furthermore, we were able to detect all of the strongly positive cases with high interobserver and intraobserver agreement by using the Ventana platform. These findings suggest that the Ventana platform can be used to stratify patients for pembrolizumab-based immunotherapy., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We examined the mutagenic specificity of the widely used antibiotic ciprofloxacin (CPR), which displays weak to moderate mutagenic activity in several bacteria and generates short in-frame deletions in rpoB in Staphylococcus aureus To determine the spectrum of mutations in a system where any gene knockout would result in a recovered mutant, including frameshifts and both short and long deletions, we examined CPR-induced mutations in the thymidylate synthase-encoding thyA gene. Here, any mutation resulting in loss of thymidylate synthase activity generates trimethoprim (Trm) resistance. We found that deletions and insertions in all three reading frames predominated in the spectrum. They tend to be short deletions and cluster in two regions, one being a GC-rich region with potential extensive secondary structures. We also exploited the well-characterized rpoB-Rif(r) system in Escherichia coli to determine that cells grown in the presence of sublethal doses of CPR not only induced short in-frame deletions in rpoB, but also generated base substitution mutations resulting from induction of the SOS system. Some of the specific point mutations prominent in the spectrum of a strain that overproduces the dinB-encoded Pol IV were also present after growth in CPR. However, these mutations disappeared in CPR-treated dinB mutants, whereas the deletions remained. Moreover, CPR-induced deletions also occurred in a strain lacking all three SOS-induced polymerases. We discuss the implications of these findings for the consequences of overuse of CPR and other antibiotics., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Hardware implementation of artificial neural networks facilitates real-time parallel processing of massive data sets. Optical neural networks offer low-volume 3D connectivity together with large bandwidth and minimal heat production in contrast to electronic implementation. Here, we present a conceptual design for in-fiber optical neural networks. Neurons and synapses are realized as individual silica cores in a multi-core fiber. Optical signals are transferred transversely between cores by means of optical coupling. Pump driven amplification in erbium-doped cores mimics synaptic interactions. We simulated three-layered feed-forward neural networks and explored their capabilities. Simulations suggest that networks can differentiate between given inputs depending on specific configurations of amplification; this implies classification and learning capabilities. Finally, we tested experimentally our basic neuronal elements using fibers, couplers, and amplifiers, and demonstrated that this configuration implements a neuron-like function. Therefore, devices similar to our proposed multi-core fiber could potentially serve as building blocks for future large-scale small-volume optical artificial neural networks.

Foxp3(+) regulatory T cells in peripheral tissues (pT(regs)) are instrumental in limiting inflammatory responses to nonself antigens. Within the intestine, pT(regs) are located primarily in the lamina propria, whereas intraepithelial CD4(+) T cells (CD4(IELs)), which also exhibit anti-inflammatory properties and depend on similar environmental cues, reside in the epithelium. Using intravital microscopy, we show distinct cell dynamics of intestinal T(regs) and CD4(IELs) Upon migration to the epithelium, T(regs) lose Foxp3 and convert to CD4(IELs) in a microbiota-dependent manner, an effect attributed to the loss of the transcription factor ThPOK. Finally, we demonstrate that pT(regs) and CD4(IELs) perform complementary roles in the regulation of intestinal inflammation. These results reveal intratissue specialization of anti-inflammatory T cells shaped by discrete niches of the intestine., (Copyright © 2016, American Association for the Advancement of Science.)

Oral tolerance prevents pathological inflammatory responses to innocuous foreign antigens by peripheral regulatory T cells (pT(reg) cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure for the 'instruction' of naive CD4(+) T cells to differentiate into pT(reg) cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs were dispensable, while classical dendritic cells (cDCs) were critical, for pT(reg) cell induction and oral tolerance. CD11b(-) cDCs from the gut-draining lymph nodes efficiently induced pT(reg) cells and, conversely, loss of transcription factor IRF8-dependent CD11b(-) cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in the induction of pT(reg) cells and their redundancy during the development of oral tolerance.

CD4(+) T cells differentiate into phenotypically distinct T helper cells upon antigenic stimulation. Regulation of plasticity between these CD4(+) T-cell lineages is critical for immune homeostasis and prevention of autoimmune disease. However, the factors that regulate lineage stability are largely unknown. Here we investigate a role for retinoic acid (RA) in the regulation of lineage stability using T helper 1 (Th1) cells, traditionally considered the most phenotypically stable Th subset. We found that RA, through its receptor RARα, sustains stable expression of Th1 lineage specifying genes, as well as repressing genes that instruct Th17-cell fate. RA signaling is essential for limiting Th1-cell conversion into Th17 effectors and for preventing pathogenic Th17 responses in vivo. Our study identifies RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1-cell fate and defines an additional pathway for the development of Th17 cells., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: CD4 T cells with features of both T-helper-type 1 (Th1) and 17 (Th17) cells have been implicated in several autoimmune diseases suggesting that plasticity among CD4 T-cell lineages is potentially pathogenic. However, the factors that regulate T-cell lineage stability are largely unknown. Retinoic acid (RA) is synthesised at sites of inflammation. We hypothesised that retinoic acid, a profound epigenetic modifier, could regulate T-cell lineage stability., Methods: We used a mouse model in which retinoic acid signalling is specifically ablated within the T-cell compartment through overexpression of a dominant negative retinoic acid receptor α (RARα) (dnRARα mice) to investigate its role in the regulation of Th1 lineage stability. Genome-wide ChIP-seq analysis was done to identify RARα targets. In parallel, we performed global mapping of regulatory regions, termed enhancers, to gain mechanistic insight into retinoic acid regulation of T-cell fate. The in-vivo relevance of our findings was determined in a model of oral antigen-induced intestinal inflammation., Findings: We found that retinoic acid is crucial for maintenance of the Th1 lineage. Abrogation of retinoic acid signalling in Th1 cells resulted in loss of T-bet expression and STAT4 activity. Th1 cells from dnRARα mice showed enhanced plasticity with the emergence of hybrid Th1-Th17 and Th17 effector cells. Global analysis of RARα binding and enhancer mapping revealed that RA-RARα directly regulated enhancer activity at Th1 lineage defining genes while repressing genes that regulate Th17 cell fate. Retinoic acid inhibition of Th1 plasticity was essential for maintaining appropriate Th cell responses in vivo and preventing autoimmune intestinal inflammation., Interpretation: Our study has identified RA-RARα as a key component of the regulatory network governing maintenance and plasticity of Th1 cells and defines a new pathway for the development of pathogenic Th17 cells. Retinoids might be novel therapeutic agents for Th17-associated autoimmune diseases., Funding: Wellcome Trust., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: We assessed the impact of unemployment benefit programs on the health of the unemployed., Methods: We linked US state law data on maximum allowable unemployment benefit levels between 1985 and 2008 to individual self-rated health for heads of households in the Panel Study of Income Dynamics and implemented state and year fixed-effect models., Results: Unemployment was associated with increased risk of reporting poor health among men in both linear probability (b=0.0794; 95% confidence interval [CI]=0.0623, 0.0965) and logistic models (odds ratio=2.777; 95% CI=2.294, 3.362), but this effect is lower when the generosity of state unemployment benefits is high (b for interaction between unemployment and benefits=-0.124; 95% CI=-0.197, -0.0523). A 63% increase in benefits completely offsets the impact of unemployment on self-reported health., Conclusions: Results suggest that unemployment benefits may significantly alleviate the adverse health effects of unemployment among men.

Workplace violence is an enormous problem worldwide; incidents where the perpetrator is a current or former employee are an important dimension. This large cross-sectional survey examined the prevalence of this problem among a U.S. state government unionized public sector workforce. Using participatory action research methods, we conducted a web-based survey of members of that workforce from a single northeast U.S. state, receiving 11,874 completed surveys (response rate: 71.8%). Overall, 10.0% of the respondents indicated that they had been bullied at work during the prior 6 months, with 71.9% of those who reported regular bullying identifying the perpetrator as a supervisor and/or top management. The prevalence of bullying was similar to the rates reported in Europe and Scandinavia (5%-30%). Those reports also identified the person(s) responsible for the behavior as being predominantly of higher status within the organization.

Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. Here, we report the synthesis of a functional 272,871-base pair designer eukaryotic chromosome, synIII, which is based on the 316,617-base pair native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, transfer RNAs, transposons, and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling. SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in a-mater derivatives resulting from loss of the MATα allele on synIII. The complete design and synthesis of synIII establishes S. cerevisiae as the basis for designer eukaryotic genome biology.

Differentiating bipolar from recurrent unipolar depression is a major clinical challenge. In 18 healthy females and 36 females in a depressive episode--18 with bipolar disorder type I, 18 with recurrent unipolar depression--we applied pattern recognition analysis using subdivisions of anterior cingulate cortex (ACC) blood flow at rest, measured with arterial spin labelling. Subgenual ACC blood flow classified unipolar v. bipolar depression with 81% accuracy (83% sensitivity, 78% specificity).

GABAergic granule cells (GCs) regulate, via mitral cells, the final output from the olfactory bulb to piriform cortex and are central for the speed and accuracy of odour discrimination. However, little is known about the local circuits in which GCs are embedded and how GCs respond during functional network activity. We recorded inhibitory and excitatory currents evoked during a single sniff-like odour presentation in GCs in vivo. We found that synaptic excitation was extensively activated across cells, whereas phasic inhibition was rare. Furthermore, our analysis indicates that GCs are innervated by a persistent firing of deep short axon cells that mediated the inhibitory evoked responses. Blockade of GABAergic synaptic input onto GCs revealed a tonic inhibitory current mediated by furosemide-sensitive GABA(A) receptors. The average current associated with this tonic GABAergic conductance was 3-fold larger than that of phasic inhibitory postsynaptic currents. We show that the pharmacological blockage of tonic inhibition markedly increased the occurrence of supra-threshold responses during an odour-stimulated sniff. Our findings suggest that GCs mediate recurrent or lateral inhibition, depending on the ambient level of extracellular GABA.

Workplace violence, a dangerous and complex occupational hazard in the modern health care work environment, presents challenges for nurses, other health care employees, management, labor unions, and regulators. Violence from patients, visitors, and coworkers is often tolerated and explained as part of the job in the fast-paced, stressful health care delivery workplace. Addressing violence in health care requires very purposeful organizational processes conducted by very specific organizational structures. The strength of the scientific evidence for workplace violence prevention strategies is well past the "emerging" evidence stage but has not achieved the "unequivocal" stage. It is unlikely that workplace violence interventions will be tested using randomized controlled experimental conditions. Consequently, educated and aware nurses often provide key leadership for organizations undertaking the development of workplace violence prevention programs, but must do so using local evidence generated at the facility level. In some cases, tools such as state regulations and federal workplace safety policies provide important impetus and support for nurses and hospitals undertaking these transformational programs. This article provides background information about workplace violence and offers a framework for developing comprehensive workplace violence prevention programs built on the existing scientific evidence, regulatory guidance, and locally generated practice evidence.

The Occupational Health Internship Program (OHIP) was initiated in 2003 to recruit a new, diverse generation of occupational safety and health (OSH) professionals and to advance OSH within union and community-based initiatives. It retains the principles of the original OCAW/Montefiore internship program while adapting to the changed landscape of the 21st-century workplace. Case studies of OHIP projects illustrate how students have contributed to key OSH policies-to regulate silica exposure among construction workers, apply principles of green chemistry with Vietnamese nail salon workers, and integrate OSH into "green" jobs in the recycling industry. They have supported innovative campaigns with immigrant workers in contingent jobs-from taxi drivers to warehouse workers. The students, in turn, have been inspired to enter the OSH arena as professionals and worker advocates with the potential to contribute new energy to an OSH movement.

Introduction: During human immunodeficiency virus (HIV) infection a dysfunction of polymorphonuclear (PMN) cells has been described including a progressively altered superoxide production as disease progression. The NADPH oxidase has been described as a major source of superoxide. The neutrophil NADPH oxidase comprises a plasma membrane-bound cytochrome b558 (which is a heterodimer of one p22-phox and one gp91-phox subunit) and cytosolic subunits, namely p47-phox, p67-phox and p40-phox. During neutrophil activation in response to various agonists, the cytosolic subunits translocate to and associate with the cytochrome b558, a process that results in oxidase activation. Therefore, an altered superoxide production could be a consequence of abnormal distribution or translocation of NADPH oxidase components in response to HIV infection., Material and Methods: We used several strategies including: confocal microscopy, subcellular fractionation and sucrose gradients, to analyze the cellular distribution of two of the NADPH oxidase components (p22-phox and p47-phox)., Results: We observed that in resting cells, a substantial proportion of p22-phox from HIV positive patients is distributed in regions close to the cytoplasmic membrane, sediment in high density sucrose fractions and is located in the cytoplasmic insoluble fraction. Additionally, a diffuse cytosolic distribution of p47-phox was observed in neutrophils from HIV infected patients. The results demonstrate an inappropriate cell distribution of NADPH-complex in PMN from HIV positive patients.

Background: The willingness of healthcare workers to risk their lives for a patient with a potentially fatal, communicable disease is a major concern, especially during a pandemic where the need for adequate staffing is crucial and where the public atmosphere might enhance anxiety and fear of exposure., Objective: To examine the relationships between the willingness of healthcare workers to risk their lives for a patient with a potentially fatal A/H1N1 flu, and knowledge of personal protection against infection, and trust in colleagues, workplace preparedness and the effectiveness of safety measures, during the winter A/H1N1 pandemic in Israel., Materials and Methods: A questionnaire was distributed to healthcare workers in 21 hospitals in Israel between 26 November 2009 and 10 December 2009 (the peak of the winter A/H1N1 flu outbreak). The questionnaire was completed by 1147 healthcare workers., Results: Willingness to risk one's life for a patient was significantly lower in females, respondents of younger age (18-24 years), administrative staff, and those with a non-academic education, as well as among those with a less knowledge about safety measures and among those with less trust in colleagues, in work place preparedness, and in the effectiveness of safety measures., Conclusions: Willingness to risk one's life for a patient is related to knowledge of safety measures, and trust in colleagues and work place preparedness. Education programs to enhance trust in colleagues, improve work place preparedness, and safety measures are recommended, especially for healthcare workers who are young, inexperienced, female, or administrative staff.

Intraaortic balloon pump insertion is traditionally performed through the femoral artery in the groin. However, this restricts the patient to bed rest, and prolonged implantation can be associated with infections in the groin crease. We describe a technique of insertion of a balloon pump through the subclavian artery, which allows the patient to ambulate. This technique can also be performed under local anesthesia in the cardiac catheterization laboratory., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

It is well known that neural activity exhibits variability, in the sense that identical sensory stimuli produce different responses, but it has been difficult to determine what this variability means. Is it noise, or does it carry important information-about, for example, the internal state of the organism? Here we address this issue from the bottom up, by asking whether small perturbations to activity in cortical networks are amplified. Based on in vivo whole-cell patch-clamp recordings in rat barrel cortex, we find that a perturbation consisting of a single extra spike in one neuron produces approximately 28 additional spikes in its postsynaptic targets. We also show, using simultaneous intra- and extracellular recordings, that a single spike in a neuron produces a detectable increase in firing rate in the local network. Theoretical analysis indicates that this amplification leads to intrinsic, stimulus-independent variations in membrane potential of the order of +/-2.2-4.5 mV-variations that are pure noise, and so carry no information at all. Therefore, for the brain to perform reliable computations, it must either use a rate code, or generate very large, fast depolarizing events, such as those proposed by the theory of synfire chains. However, in our in vivo recordings, we found that such events were very rare. Our findings are thus consistent with the idea that cortex is likely to use primarily a rate code.

An engineered variant of the protease subtilisin from Bacillus amyloliquefaciens, in which the D32A mutation renders the enzyme's activity dependent on the presence of certain small anions such as fluoride or azide, has been produced. This modified enzyme has applications as an azide or fluoride-triggered expression-purification tool. We report activity measurements showing that the enzyme is activated more than 3000-fold by azide and describe the 1.8 A resolution structure of an inactive form (by replacing the catalytic nucleophile Ser 221 with alanine) of the protease, in complex with azide and with a substrate that spans the active site. Both enzyme and substrate have been engineered to increase their stability and the affinity of their interaction. The substrate is based on a stabilized subtilisin prodomain, extended across the active site by the addition of four residues at its C-terminus. In the crystal structure, the substrate is well-ordered across the active site, and the azide anion is observed bound adjacent to Ala 32. The structures of the substrate complex in three different crystals (anion-free, fluoride-soaked, and azide-soaked) are compared. These structures provide extensive information for understanding subtilisin's substrate binding and catalytic mechanism, and for the development of biotechnology tools based on anion-activated proteolysis. The mechanism of anion-dependent proteolysis appears to be a slight modification of the accepted charge-relay mechanism for serine proteases.

Synaptic information efficacy (SIE) is a statistical measure to quantify the efficacy of a synapse. It measures how much information is gained, on the average, about the output spike train of a postsynaptic neuron if the input spike train is known. It is a particularly appropriate measure for assessing the input-output relationship of neurons receiving dynamic stimuli. Here, we compare the SIE of simulated synaptic inputs measured experimentally in layer 5 cortical pyramidal neurons in vitro with the SIE computed from a minimal model constructed to fit the recorded data. We show that even with a simple model that is far from perfect in predicting the precise timing of the output spikes of the real neuron, the SIE can still be accurately predicted. This arises from the ability of the model to predict output spikes influenced by the input more accurately than those driven by the background current. This indicates that in this context, some spikes may be more important than others. Lastly we demonstrate another aspect where using mutual information could be beneficial in evaluating the quality of a model, by measuring the mutual information between the model's output and the neuron's output. The SIE, thus, could be a useful tool for assessing the quality of models of single neurons in preserving input-output relationship, a property that becomes crucial when we start connecting these reduced models to construct complex realistic neuronal networks.

Problem: Federal policy recommends environmental strategies as part of a comprehensive workplace violence program in healthcare and social services. The purpose of this project was to contribute specific, evidence-based guidance to the healthcare and social services employer communities regarding the use of environmental design to prevent violence., Method: A retrospective record review was conducted of environmental evaluations that were performed by an architect in two Participatory Action Research (PAR) projects for workplace violence prevention in 2000 and, in the second project in 2005. Ten facility environmental evaluation reports along with staff focus group reports from these facilities were analyzed to categorize environmental risk factors for Type II workplace violence., Results: Findings were grouped according to their impact on access control, the ability to observe patients (natural surveillance), patient and worker safety (territoriality), and activity support., Discussion: The environmental assessment findings reveal design and security issues that, if corrected, would improve safety and security of staff, patients, and visitors and reduce fear and unpredictability., Impact on Industry: Healthcare and social assistance employers can improve the effectiveness of violence prevention efforts by including an environmental assessment with complementary hazard controls.

Aim: Recently, the clinical significance of aprotinin-induced renal dysfunction and other end-organ complications in patients undergoing cardiac surgery has engendered substantial controversy. Therefore, we assessed the effect of aprotinin on end-organ complications in patients undergoing cardiac surgery., Methods: Data of 674 patients (mean age 65.4 +/- 11.0 years, 457 males) undergoing cardiac surgery between January 1 and December 31, 2005 at Semmelweis University were used for the analyses. Preoperative, intraoperative and postoperative clinical and surgical variables were recorded. Patients administered aprotinin received the drug either as a low-dose regimen, a loading dose of 1 million kallikrein-inhibitor units (KIU), 1 million KIU in pump, and 1 million KIU post pump (or continuous infusion of 0.25 million KIU per hour); or a high-dose regimen, a loading dose of 2 million KIU, 2 million KIU in pump, and 2 million KIU post pump (or continuous infusion of 0.5 million KIU per hour). The outcomes were renal complications defined as a 25% reduction in postoperative calculated creatinine clearance compared to the preoperative baseline or renal failure requiring dialysis; and the composite of renal, cardiovascular and cerebrovascular complications and all-cause mortality., Results: Patients underwent coronary artery bypass surgery (63%), valvular (27%) or a combination (5%) and surgery on the ascending aorta (5%). There were 550 patients (81.6%) who received aprotinin treatment. In multivariate regression analyses when the relation between high or low dose aprotinin compared to no aprotinin was evaluated, the likelihood of renal complications [high dose: odds ratio (OR)=1.4, 95% confidence interval (CI), 0.6-3.0, P=0.4; low dose: OR=1.2, 95%CI, 0.7-2.3, p=0.5], and the composite outcome variable (high dose: OR=1.6, 95%CI, 0.8-3.4, P=0.2; low dose: OR=1.3, 95%CI, 0.7-2.3, P=0.4) were not significantly increased., Conclusion: Our analysis suggests that aprotinin use in either a high or low dose regimen was not associated with an increase in adverse end-organ complications.

The hyperpolarization-activated cation current I(h) exhibits a steep gradient of channel density in dendrites of pyramidal neurons, which is associated with location independence of temporal summation of EPSPs at the soma. In striking contrast, here we show by using dendritic patch-clamp recordings that in cerebellar Purkinje cells, the principal neurons of the cerebellar cortex, I(h) exhibits a uniform dendritic density, while location independence of EPSP summation is observed. Using compartmental modeling in realistic and simplified dendritic geometries, we demonstrate that the dendritic distribution of I(h) only weakly affects the degree of temporal summation at the soma, while having an impact at the dendritic input location. We further analyze the effect of I(h) on temporal summation using cable theory and derive bounds for temporal summation for any spatial distribution of I(h). We show that the total number of I(h) channels, not their distribution, governs the degree of temporal summation of EPSPs. Our findings explain the effect of I(h) on EPSP shape and temporal summation, and suggest that neurons are provided with two independent degrees of freedom for different functions: the total amount of I(h) (controlling the degree of temporal summation of dendritic inputs at the soma) and the dendritic spatial distribution of I(h) (regulating local dendritic processing).

In 1994, the Food and Drug Administration Office of Women's Health (FDA-OWH) was created to provide leadership and policy direction for the Agency regarding issues of women's health. Within its first year, the FDA-OWH established a science program for women's health research, promoting the development of sound policy and regulation. In a little over a decade, the program has provided approximately 14 million dollars to fund more than 100 women's health research studies covering a broad range of health topics affecting women across their lifespan. Some studies, such as those elucidating drug effects on QT prolongation in women and drug-dietary supplement interaction, have had significant influence on regulatory decisions. Other studies have provided sound scientific data on sex and gender differences supporting FDA guidelines to protect women's health. This paper describes the science program at the FDA-OWH, providing examples of how funded research impacts regulatory policy.

Objective: Previously, we reported that opiate users enrolled in methadone treatment made 'risky' choices on a decision-making task following a loss of points compared with heroin users and healthy volunteers. One possible explanation for this behaviour is that methadone users were less sensitive to punishment on immediately preceding unsuccessful trials., Methods: We sought to explore this finding from a neural perspective by performing a post hoc analysis of data from a previous [see text] positron emission tomography study. We restricted the analysis to the opiate groups and controls, assessing differences between opiate users on methadone and those on heroin., Results: We found significant over-activation in the lateral orbitofrontal cortex (OFC) in methadone users compared with both heroin users and controls concomitant with the greatest overall tendency to 'play risky'. Heroin users showed significant under-activation in this area compared with the other two groups whilst exhibiting the greatest overall tendency to 'play safe'. Correlational analysis revealed that abnormal task-related activation of the left OFC was associated with the dose of methadone in methadone users and with the duration of intravenous heroin use in heroin users. 'Playing safe' following a loss of points was also negatively correlated with the activation of pregenual anterior cingulate and insula cortex in controls, but not in opiate users., Conclusion: Our findings suggest that the interplay between processes involved in integrating penalty information for the purpose of response selection may be altered in opiate users. This change was reflected differentially in task-related pattern of OFC activation depending on the opiate used.

Cognitive function was assessed in chronic drug users on neurocognitive measures of executive and memory function. Current amphetamine users were contrasted with current opiate users, and these two groups were compared with former users of these substances (abstinent for at least one year). Four groups of participants were recruited: amphetamine-dependent individuals, opiate-dependent individuals, former users of amphetamines, and/or opiates and healthy non-drug taking controls. Participants were administered the Tower of London (TOL) planning task and the 3D-IDED attentional set-shifting task to assess executive function, and Paired Associates Learning and Delayed Pattern Recognition Memory tasks to assess visual memory function. The three groups of substance users showed significant impairments on TOL planning, Pattern Recognition Memory and Paired Associates Learning. Current amphetamine users displayed a greater degree of impairment than current opiate users. Consistent with previous research showing that healthy men are performing better on visuo-spatial tests than women, our male controls remembered significantly more paired associates than their female counterparts. This relationship was reversed in drug users. While performance of female drug users was normal, male drug users showed significant impairment compared to both their female counterparts and male controls. There was no difference in performance between current and former drug users. Neither years of drug abuse nor years of drug abstinence were associated with performance. Chronic drug users display pronounced neuropsychological impairment in the domains of executive and memory function. Impairment persists after several years of drug abstinence and may reflect neuropathology in frontal and temporal cortices.

Reinforcing properties of psychoactive substances are considered to be critically involved in the development and maintenance of substance dependence. While accumulating evidence suggests that the sensitivity to reinforcement values may generally be altered in chronic substance users, relatively little is known about the influence reinforcing feedback exerts on ongoing decision-making in these individuals. Decision-making was investigated using the Cambridge Risk Task, in which there is a conflict between an unlikely large reward option and a likely small reward option. Responses on a given trial were analyzed with respect to the outcome on the previous trial, providing a measure of the impact of prior feedback in modulating behavior. Five different groups were compared: (i) chronic amphetamine users, (ii) chronic opiate users in methadone maintenance treatment (MMT), (iii) chronic users of illicit heroin, (iv) ex-drug users who had been long-term amphetamine / opiate users but were abstinent from all drugs of abuse for at least 1 year and (v) matched controls without a history of illicit substance use. Contrary to our predictions, choice preference was modified in response to feedback only in opiate users enrolled in MMT. Following a loss, the MMT opiate group chose the likely small reward option significantly less frequently than controls and heroin users. Our results suggest that different opiates are associated with distinctive behavioral responses to feedback. These findings are discussed with respect to the different mechanisms of action of heroin and methadone. Neuropsychopharmacology (2005) 30, 2115-2124. doi:10.1038/sj.npp.1300812; published online 6 July 2005.

The level of substance misuse in Britain has fluctuated over recent centuries, reaching its nadir in the early twentieth century. Since then, the trends for alcohol and drug abuse (though not for tobacco consumption) have risen steadily. British physicians have played a major role in the emergence of the addiction concept, from the initial challenge to Galen's theories to the now widely adopted Alcohol Dependence Syndrome. While treatment has been influenced by contemporary attitudes, it has been generally underpinned by pragmatism and has avoided the punitive responses seen in other parts of the world.

Knowledge of the site of action potential initiation is essential for understanding how synaptic input is converted into neuronal output. Previous studies have shown that the lowest-threshold site for initiation of action potentials is in the axon. Here we use recordings from visualized rat cerebellar Purkinje cell axons to localize the site of initiation to a well-defined anatomical structure: the first node of Ranvier, which normally forms at the first axonal branch point.

One of the central questions in neuroscience is how particular tasks, or computations, are implemented by neural networks to generate behavior. The prevailing view has been that information processing in neural networks results primarily from the properties of synapses and the connectivity of neurons within the network, with the intrinsic excitability of single neurons playing a lesser role. As a consequence, the contribution of single neurons to computation in the brain has long been underestimated. Here we review recent work showing that neuronal dendrites exhibit a range of linear and nonlinear mechanisms that allow them to implement elementary computations. We discuss why these dendritic properties may be essential for the computations performed by the neuron and the network and provide theoretical and experimental examples to support this view.

We provide a functional measure, the synaptic information efficacy (SIE), to assess the impact of synaptic input on spike output. SIE is the mutual information shared by the presynaptic input and postsynaptic output spike trains. To estimate SIE we used a method based on compression algorithms. This method detects the effect of a single synaptic input on the postsynaptic spike output in the presence of massive background synaptic activity in neuron models of progressively increasing realism. SIE increased with increases either in time locking between the input synapse activity and the output spike or in the average number of output spikes. SIE depended on the context in which the synapse operates. We also measured SIE experimentally. Systematic exploration of the effect of synaptic and dendritic parameters on the SIE offers a fresh look at the synapse as a communication device and a quantitative measure of how much the dendritic synapse informs the axon.

Diagnosis of myocardial ischemia requires integration of ECG, pulmonary artery pressures, and TEE data. ST depression of 1 mV or elevation of 2 mV remains the mainstay of diagnosis of ischemia. Increases of pulmonary artery pressures of 5 mm Hg are common but not reliably diagnostic of ischemia. Transesophageal echocardiography is the most sensitive monitor of ischemia, where the spectra of SWMA evolve. Diastolic dysfunction (elevations in LVEDP) is a more sensitive marker of ischemia, but requires measurement of several Doppler patterns. After diagnosis, treatment should include optimization of hemodynamics (beginning with beta-blockers and nitrates), anesthesia, and oxygen-carrying capacity (e.g., normothermia, oxygen saturation, hematocrit more than 28%).

A previously published study recommended the daily use of visible smoke to test for negative air pressure in isolation rooms occupied by potentially infectious tuberculosis cases. Continuous monitoring devices were found to have poor reliability. Findings from our survey of engineering controls in acute-care hospitals within New York State support this recommendation.

Objectives: To compare self-reporting of pain by cognitively impaired (CI) older adults living in the community with reports of their caregivers; to identify the factors associated with differences in agreement; and to identify those pain assessment tools that are most useful to nonprofessional caregivers., Design: Prospective observational cohort of patients with dementia and their caregivers., Setting: In-home assessments of community-dwelling CI older adults and family members, adult foster care providers, or aides in residential care facilities. All CI subjects were enrolled in a Program for All-inclusive Care of the Elderly program (ElderPlace) in Portland, Oregon., Participants: A total of 156 CI adults and their caregivers., Methods: Standardized pain assessment instruments were administered to the CI subjects and their caregivers in the subject's home by trained research assistants between June and October 1998. CI subjects were assessed with the Nonverbal Visual Analog scale ("line"), the Faces Pain Scale ("faces"), and the Philadelphia Pain Intensity Scale (PIS). Research assistants observed pain behaviors in the CI subjects using the Hospice Approach Discomfort Scale. The CI subject's caregivers completed the "line," "faces," PIS, and Cornell Scale for Depression in Dementia. A baseline Mini-Mental State Exam, Functional Assessment Stage Test, and Geriatric Depression Scale were performed on all CI subjects by ElderPlace medical, nursing, or social work staff., Results: The mean age of the CI subjects was 83, and 83% were women. The mean Mini-Mental State Exam score was 15.7. One-third of the CI subjects were unable to complete any of the three pain assessment tools. Of the 104 subjects completing at least one tool, 13 (12.5%) reported no pain and 91 (87.5%) reported some pain. Sixteen (10%) of the subjects were depressed as measured with the GDS or Cornell instrument. In 70 of the 104 subjects (67%) able to complete any tool, the caregiver and CI subject agreed as to the level of pain experienced by the CI subject. The number of tools completed by the CI subjects decreased with increased cognitive impairment. The Pain Intensity Scale was the tool most likely to be completed by both CI subjects and caregivers. The means of test scores were not significantly different for the paired groups of CI subject and caregiver, and the nonparametric correlation of each tool was significant: "faces" (Spearman's rho (p) = .417); "line" (p = .420); and PIS (p = .452). The Hospice Approach Discomfort Scale did not correlate well with other tools. The Pain Intensity Scale seems to be more useful than other pain assessment tools in assessing pain in cognitively impaired patients and can be used by nonprofessional caregivers in a community-based care setting.

Objective: To delineate associations between preoperative risk factors and clinical processes of care and perioperative glucose tolerance in patients managed on a fast-track cardiac surgery clinical pathway with prebypass methylprednisolone administration., Design: Retrospective sequential cohort study., Setting: University-affiliated Department of Veterans Affairs medical center., Participants: Fast-track patients (n = 293; n = 72 low-dose methylprednisolone [100-125 mg]; n = 221 moderate-dose methylprednisolone [500 mg]) plus pre-fast-track patients (n = 258; no methylprednisolone) undergoing cardiac surgery with cardiopulmonary bypass., Interventions: None., Measurements and Main Results: Multivariate linear regression was used to model the association of 17 preoperative risk and intraoperative process-of-care variables with serum glucose concentration on arrival in the intensive care unit. Preoperative serum glucose concentrations were not significantly different among the pre-fast-track, fast-track with low-dose methylprednisolone, and fast-track with moderate-dose methylprednisolone cohorts (129 +/- 54, 137 +/- 55, 127 +/- 46 mg/dL [mean +/- SD]). Postoperative serum glucose concentrations were significantly different (171 +/- 58, 223 +/- 56, 250 +/- 75 mg/dL; p < 0.03, for all pairwise comparisons). Using backward elimination from the full 17-variable multivariate model (R-square = 0.63), 4 variables remained significant (all p < 0.0001; R-square = 0.60): (1) Preoperative diabetes status (adjusted mean post-operative glucose level, mg/dL; [95% confidence interval (CI)]): no treatment, 193 (188-199); oral agent, 276 (262-291); insulin requiring, 301 (283-320); (2) steroid group: pre-fast-track, 201 (195-209), fast-track with low-dose methylprednisolone, 271 (256-287); fast-track with moderate-dose methylprednisolone, 295 (284-306); (3) volume of glucose-containing cardioplegia (beta coefficient, 95% CI): 2.22% (1.37-3.10) increase per 100 mL; and (4) intraoperative epinephrine infusion: none, 231 (224-239); yes, 276 (264-288). No significant interactions were identified. No significant effect of opioid dose was observed., Conclusion: At this institution, implementation of the fast-track pathway was associated with a deterioration of glucose tolerance. Preoperative diabetes, pre-cardiopulmonary bypass administration of steroids, volume of glucose-containing cardioplegia solution administered, and use of epinephrine infusions were significantly associated multivariate factors.

Our understanding of the function of dendrites has been greatly enriched by an inspiring dialogue between theory and experiments. Rather than functionally ignoring dendrites, representing neurons as single summing points, we have realized that dendrites are electrically and chemically distributed nonlinear units and that this has important consequences for interpreting experimental data and for the role of neurons in information processing. Here, we examine the route to unraveling some of the enigmas of dendrites and highlight the main insights that have been gained. Future directions are discussed that will enable theory and models to keep shedding light on dendrites, where the most fundamental input-output adaptive processes take place.

Objectives: To evaluate whether terminal care was consistent with Physician Orders for Life-Sustaining Treatment (POLST), a preprinted and signed doctor's order specifying treatment instructions in the event of serious illness for CPR, levels of medical intervention, antibiotics, IV fluids, and feeding tubes., Design: Retrospective chart review., Setting: ElderPlace, a Program of All-Inclusive Care for the Elderly (PACE) site in Portland, Oregon., Participants: All ElderPlace participants who died in 1997 were eligible (n = 58). Reasons for exclusion were no POLST (1), missing POLST (1), and insufficient documentation of care (2)., Measurements: POLST instructions for each participant and whether or not each of the treatments addressed by the POLST was administered in the final 2 weeks of life., Results: The POLST specified "do not resuscitate" for 50 participants (93%); CPR use was consistent with these instructions for 49 participants (91%). "Comfort care" was the designated level of medical intervention in 13 cases, "limited interventions" in 18, "advanced interventions" in 18, and "full interventions" in 5. Interventions administered were at the level specified in 25 cases (46%); at a less invasive level in 18 (33%), and at a more invasive level in 11 (20%). Antibiotic administration was consistent with POLST instructions for 86% of 28 subjects who had infections in the last 2 weeks of life, and less invasive for 14%. Care matched POLST instructions in 84% of cases for IV fluids and 94% for feeding tubes., Conclusions: POLST completion in ElderPlace exceeds reported advance directive rates. Care matched POLST instructions for CPR, antibiotics, IV fluids, and feeding tubes more consistently than previously reported for advance directive instructions. Medical intervention level was consistent with POLST instructions for less than half the participants, however. We conclude that the POLST is effective for limiting the use of some life-sustaining interventions, but that the factors that lead physicians to deviate from patients' stated preferences merit further investigation.