In search of the psychosis gene in people with Prader-Willi syndrome.
The two main causes of Prader-Willi syndrome (PWS) are a paternally derived deletion in the maternally imprinted 15q11-q13 region or UPD(15)mat. Both mechanisms result in a loss of the active paternal contribution to the region. The affective psychosis associated with PWS has been found to be mainly confined to the propositi with UPD(15)mat rather than to those with a deletion. This suggests that the psychosis may be related to the presence of two copies rather than a single copy of a gene or genes located in the distal half of the region which is paternally imprinted, but maternally active, and whose loss results in Angelman syndrome (AS). A large population-based study of PWS allowed the identification of 12 people with a 15q11-q13 deletion who had suffered psychotic episodes and four adults with UPD(15)mat who so far had not. When these people were investigated using microsatellite markers, the 12 with a deletion were found to have two maternally derived copies of a narrow region between D15S975 and D15S661 making them effectively disomic for these loci. Thus all of the people with psychosis had two active copies of any imprinted genes in the region while all non-psychotic people (including controls) had only one. Quantitative RT-PCR studies suggest that a lack of expression of FLJ33332, either as a result of or resulting in gene dysregulation, may be associated with psychosis in PWS.


Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/Akt signaling pathway.
Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood. Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 microA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats. Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex. These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.


First Report of Stem Canker on Cherry Caused by Phomopsis perniciosa in Shandong Peninsula, Eastern China.
Cherry is a main fruit tree species in Shandong Peninsula, which is one of the most important cherry-production areas of China. A stem canker disease was first noted in a 15-year-old cherry orchard in Yantai, Shandong Peninsula in May 2009. Canker and branch dieback were the main symptoms of the disease and cracks often appeared at the margins of sunken cankers, which exposed the wooden stem. In later stages from April to May, black pycnidia were observed on the surface of cankered bark and cirri containing α-conidia were extruded under wet conditions. Wooden tissue under the diseased bark was dark brown, in contrast to the healthy tissue that was yellowish green. On the basis of morphological characteristics, the pathogen was putatively identified as Phomopsis perniciosa (1). Pycnidia were smaller in naturally infected branches than when produced on potato dextrose agar (PDA) medium (180 to 365 × 65 to 226 μm). Cultures of the pathogen appeared creamy white with concentric rings on PDA at 25°C and a mass of α-conidia (5.75 to 11.13 × 2.08 to 3.46 μm) and β-conidia (31.24 to 34.68 × 1.45 to 1.82 μm) were produced within 3 weeks. Alpha-conidia were hyaline, fusiform-elliptic to oblong-elliptic, and biguttulate. Beta-conidia were hyaline and unicellular, filiformia, leviter arcuata vel hamata. Total DNA was extracted from three monoconidial isolates collected from different infected trees. The internal transcribed spacer (ITS) region was amplified using the universal primers ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-CCTCCGCTTATTGATATGC-3'). The ITS amplicons were sequenced (582 bp) from three isolates and no nucleotide variation was observed. BLAST analysis of the obtained ITS sequences showed that isolate 230101 had 99% homology with a Phomopsis sp. (GenBank Accession No. AB302248) isolated from fruit trees in Japan. The nucleotide sequence from isolate 230101 has been deposited in GenBank (Accession No. JF812647). Pathogenicity of the isolate was confirmed by inoculating branches of 3-year-old cherry trees with either conidia or hyphae. Inoculations were performed by making an incision with a sterile scalpel at the dissected area to expose the tissue under the bark. An agar plug (4 × 4 mm) containing 5-day-old cultured hyphae or 50 μl of a conidium suspension containing 106 α-conidia per ml was placed on each of the inoculation sites, wrapped with moist cheesecloth, and sealed with Parafilm. Control trees were treated similarly with sterile blocks of PDA or water, respectively. For each inoculation technique, five shoots were inoculated and the inoculation treatments were replicated three times. All inoculated and control trees were kept in a greenhouse and watered as needed. After 10 days, cankers and necrotic lesions developed on all shoots inoculated with P. perniciosa and the control trees did not display any symptoms. The same pathogen was reisolated from symptomatic branches. Phomopsis spp. are known to cause cankers and dieback of several woody hosts (2), but no reports have been found that the pathogen causes cherry canker and dieback in China. References: (1) P. K. Chi et al. Flora Fungorum Sinicorum-Phomopsis 34:127, 2007. (2) D. P. Weingartner and E. J. Klos. Phytopathology 65:105, 1975.


Activation, self-management, engagement, and retention in behavioral health care: a randomized clinical trial of the DECIDE intervention.
Given minority patients' unequal access to quality care, patient activation and self-management strategies have been suggested as a promising approach to improving mental health care. To determine whether the DECIDE (Decide the problem; Explore the questions; Closed or open-ended questions; Identify the who, why, or how of the problem; Direct questions to your health care professional; Enjoy a shared solution) intervention, an educational strategy that teaches patients to ask questions and make collaborative decisions with their health care professional, improves patient activation and self-management, as well as engagement and retention in behavioral health care. In this multisite randomized clinical trial performed from February 1, 2009, through October 9, 2011 (date of last follow-up interview), we recruited 647 English- or Spanish-speaking patients 18 to 70 years old from 13 outpatient community mental health clinics across 5 states and 1 US territory. A total of 722 patients were included in analyses of secondary outcomes. Three DECIDE training sessions delivered by a care manager vs giving patients a brochure on management of behavioral health. Primary outcomes were patient assessment of activation (Patient Activation Scale) and self-management (Perceived Efficacy in Patient-Physician Interactions). Secondary outcomes included patient engagement (proportion of visits attended of those scheduled) and retention (attending at least 4 visits in the 6 months after the baseline research assessment), collected through medical record review or electronic records. Patients assigned to DECIDE reported significant increases in activation (mean β = 1.74, SD = 0.58; P = .003) and self-management (mean β = 2.42, SD = 0.90; P = .008) relative to control patients, but there was no evidence of an effect on engagement or retention in care. The DECIDE intervention appears to help patients learn to effectively ask questions and participate in decisions about their behavioral health care, but a health care professional component might be needed to augment engagement in care. DECIDE appears to have promise as a strategy for changing the role of minority patients in behavioral health care. clinicaltrials.gov Identifier: NCT01226329


Cardiotoxic effects, or lack thereof, of anti-ErbB2 immunoagents.
This study investigated potential cardiotoxicity as exerted by Erbicin-derived-immunoagents (EDIAs), novel human anti-ErbB2 immunoagents engineered by fusion of a human anti-ErbB2 scFv, Erbicin, with either a human RNase or the Fc region of a human IgG1. EDIAs are strongly cytotoxic on ErbB2-positive cells in vitro and in vivo and bind to an epitope different from that of Herceptin, a humanized anti-ErbB2 mAb effective in the therapy of breast carcinoma, but cardiotoxic in a high percentage of cases. Toxicity and apoptosis were tested in vitro by 3-(4,5-dimethyl-2-thizolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), DNA fragmentation, and immunoblotting analyses. Echocardiography was measured in mice after treatment with each immunoagent. Cardiac fibrosis and detection of apoptosis were examined by Sirius red staining of collagen and TUNEL assay, respectively. EDIAs were found in vitro to have no adverse effects on cardiac cells for which Herceptin is severely toxic. In vivo studies on a mouse model showed that the EDIAs did not alter cardiac function, whereas Herceptin and doxorubicin, used as positive controls, significantly reduced the fractional shortening parameter. Cardiac fibrosis and apoptosis were not significantly affected in mice treated with EDIAs. Thus, EDIAs could fulfill the therapeutic need of patients ineligible for Herceptin treatment due to cardiac dysfunction.


The advantages of water immersion colonoscopy in ambulatory service.
The purpose of this prospective study was to compare patients' discomfort during water immersion (WI) colonoscopy without sedation or available on request, with that of patients during air insufflation (AI) colonoscopy with sedation, in the ambulatory setting. A prospective observational study was conducted in 100 patients who performed a colonoscopy between August 2015 and February 2016 in an Ambulatory Gastroenterology Center in Cluj-Napoca, Romania. They were divided into two branches A and B. Patients in Group A underwent a classic colonoscopy with AI and standard sedation (2 mg of midazolam and 50 mg of tramadol), while patients in Group B underwent an unsedated or on demand sedation colonoscopy with WI technique. The patients in group A presented a higher discomfort (statistically significant) compared to those in group B, and had also the median total discomfort score higher than those in group B. The patients in group A had also a higher discomfort score after examination. The total time of examination was the same in the two groups, but in group B the progression to cecum time was 3 minutes lower than for those in group A. A greater discomfort of the patient was correlated with the longer time required to reach the cecum. In conclusion, WI colonoscopy is superior to AI technique in reducing insertion pain, progression-to-cecum time, minimizing sedation requirements and also in the willingness to repeat the technique.


Early recovery of interhemispheric functional connectivity after corpus callosotomy.
To investigate whether interhemispheric functional connectivity (FC) recovers in the first year after total callosotomy. Eight epilepsy patients undergoing total callosotomy were recruited. Resting-state functional magnetic resonance imaging was acquired before and after surgery. The precallosotomy and postcallosotomy interhemispheric and intrahemispheric FC was analyzed by using graph theory and voxel-mirrored homotopic connectivity (VMHC). The seizure outcome was scored using the Engel surgical outcome scale. After callosotomy (mean postoperative interval = 4 months), the network density, average node degree, characteristic path length, and global efficiency of the whole interhemispheric networks were significantly decreased, compared to those in the precallosotomy networks. However, postcallosotomy interhemispheric FC and homotopic VMHC were not significantly reduced in bilateral frontal and temporal lobes. The network density and average node degree of the intrahemispheric networks were significantly increased. The characteristic path length and global efficiency of intrahemispheric networks were unchanged. The interhemispheric FC may be preserved or recover early within the first postoperative year after total callosotomy, particularly in the frontal and anterior temporal lobes.


Dirty money: an investigation into the hygiene status of some of the world's currencies as obtained from food outlets.
A total of 1280 banknotes were obtained from food outlets in 10 different countries (Australia, Burkina Faso, China, Ireland, the Netherlands, New Zealand, Nigeria, Mexico, the United Kingdom, and the United States), and their bacterial content was enumerated. The presence of bacteria on banknotes was found to be influenced by the material of the notes, and there was a strong correlation between the number of bacteria per square centimeter and a series of indicators of economic prosperity of the various countries. The strongest correlation was found with the "index of economic freedom," indicating that the lower the index value, the higher the typical bacterial content on the banknotes in circulation. Other factors that appear to influence the number of bacteria on banknotes were the age of the banknotes and the material used to produce the notes (polymer-based vs. cotton-based). The banknotes were also screened for the presence of a range of pathogens. It was found that pathogens could only be isolated after enrichment and their mere presence does not appear to be alarming. In light of our international findings, it is recommended that current guidelines as they apply in most countries with regard to the concurrent hygienic handling of foods and money should be universally adopted. This includes that, in some instances, the handling of food and money have to be physically separated by employing separate individuals to carry out one task each; whereas in other instances, it could be advantageous to handle food only with a gloved hand and money with the other hand. If neither of these precautions can be effectively implemented, it is highly recommended that food service personnel practice proper hand washing procedures after handling money and before handling food.


Paternal and maternal mutations in X-STRs: A GHEP-ISFG collaborative study.
The GHEP-ISFG organized a collaborative study to estimate mutation rates for the markers included in the Investigator Argus X-12 QS kit Qiagen. A total of 16 laboratories gathered data from 1,612 father/mother/daughter trios, which were used to estimate both maternal and paternal mutation rates, when pooled together with other already published data. Data on fathers and mothers' age at the time of birth of the daughter were also available for ∼93 % of the cases. Population analyses were computed considering the genetic information of a subset of 1,327 unrelated daughters, corresponding to 2,654 haplotypes from residents in several regions of five countries: Argentina, Brazil, Ecuador, Portugal and Spain. Genetic differentiation analyses between the population samples from the same country did not reveal signs of significant stratification, although results from Hardy-Weinberg and linkage disequilibrium tests indicated the need of larger studies for Ecuador and Brazilian populations. The high genetic diversity of the markers resulted in a large number of haplotype combinations, showing the need of huge databases for reliable estimates of their frequencies. It should also be noted the high number of new alleles found, many of them not included in the allelic ladders provided with the kit, as very diverse populations were analyzed. The overall estimates for locus specific average mutation rates varied between 7.5E-04 (for DXS7423) and 1.1E-02 (for DXS10135), the latter being a troublesome figure for kinship analyses. Most of the found mutations (∼92 %) are compatible with the gain or loss of a single repeat. Paternal mutation rates showed to be 5.2 times higher than maternal ones. We also found that older fathers were more prone to transmit mutated alleles, having this trend not been observed in the case of the mothers.


Accuracy comparison of several common implicit solvent models and their implementations in the context of protein-ligand binding.
In this study several commonly used implicit solvent models are compared with respect to their accuracy of estimating solvation energies of small molecules and proteins, as well as desolvation penalty in protein-ligand binding. The test set consists of 19 small proteins, 104 small molecules, and 15 protein-ligand complexes. We compared predicted hydration energies of small molecules with their experimental values; the results of the solvation and desolvation energy calculations for small molecules, proteins and protein-ligand complexes in water were also compared with Thermodynamic Integration calculations based on TIP3P water model and Amber12 force field. The following implicit solvent (water) models considered here are: PCM (Polarized Continuum Model implemented in DISOLV and MCBHSOLV programs), GB (Generalized Born method implemented in DISOLV program, S-GB, and GBNSR6 stand-alone version), COSMO (COnductor-like Screening Model implemented in the DISOLV program and the MOPAC package) and the Poisson-Boltzmann model (implemented in the APBS program). Different parameterizations of the molecules were examined: we compared MMFF94 force field, Amber12 force field and the quantum-chemical semi-empirical PM7 method implemented in the MOPAC package. For small molecules, all of the implicit solvent models tested here yield high correlation coefficients (0.87-0.93) between the calculated solvation energies and the experimental values of hydration energies. For small molecules high correlation (0.82-0.97) with the explicit solvent energies is seen as well. On the other hand, estimated protein solvation energies and protein-ligand binding desolvation energies show substantial discrepancy (up to 10kcal/mol) with the explicit solvent reference. The correlation of polar protein solvation energies and protein-ligand desolvation energies with the corresponding explicit solvent results is 0.65-0.99 and 0.76-0.96 respectively, though this difference in correlations is caused more by different parameterization and less by methods and indicates the need for further improvement of implicit solvent models parameterization. Within the same parameterization, various implicit methods give practically the same correlation with results obtained in explicit solvent model for ligands and proteins: e.g. correlation values of polar ligand solvation energies and the corresponding energies in the frame of explicit solvent were 0.953-0.966 for the APBS program, the GBNSR6 program and all models used in the DISOLV program. The DISOLV program proved to be on a par with the other used programs in the case of proteins and ligands solvation energy calculation. However, the solution of the Poisson-Boltzmann equation (APBS program) and Generalized Born method (implemented in the GBNSR6 program) proved to be the most accurate in calculating the desolvation energies of complexes.


Design considerations and algorithms for partitioning optoelectronic multichip modules.
There is considerable interest in the development of optical interconnects for multichip modules (MCM's) to improve their performance. For effective utilization of the optical and electronic technologies, a methodology for partitioning the system is required. The key question to be answered is which technology should be used for each interconnect in a given netlist: optical or electronic. We introduce the computer-aided design approach for partitioning optoelectronic systems into optoelectronic MCM's. We first discuss the design trade-off issues in an optoelectronic system design, including speed, power dissipation, area, and diffraction limits for free-space optics. We then define a formulation for optoelectronic MCM partitioning and describe new algorithms for optimizing this partitioning based on the minimization of the power dissipation. The models for the algorithms are discussed in detail, and an example of a multistage interconnect network is given. Different results, with the number and size of chips being variable, are presented in which improvement for the system packaging has been observed when the partitioning algorithms are applied.


Achieving Nonenzymatic Blood Glucose Sensing by Uprooting Saturation.
The saturation of nonenzymatic blood glucose sensors at lower than normal blood glucose levels has blocked their practical applications. The mechanistic understanding of the saturation, however, has long been under debate. Employing cyclic voltammetry, amperometry, and FTIR with various electrolytes of varying concentrations, we were able to uproot the saturation cause. It was found to be related to the hydroxide ion concentration, which must be 11 times greater than that of the glucose concentration, contrary to the prior understanding. Together with the satisfactory sensitivity at high pH, nonenzymatic blood glucose sensing has finally been achieved, eliminating the usual problem of electrochemical current saturation as well as the need for enzyme found in the present technology.


Primary care quality indicators for children: measuring quality in UK general practice.
Child health care is an important part of the UK general practice workload; in 2009 children aged <15 years accounted for 10.9% of consultations. However, only 1.2% of the UK's Quality and Outcomes Framework pay-for-performance incentive points relate specifically to children. To improve the quality of care provided for children and adolescents by defining a set of quality indicators that reflect evidence-based national guidelines and are feasible to audit using routine computerised clinical records. Multi-step consensus methodology in UK general practice. Four-step development process: selection of priority issues (applying nominal group methodology), systematic review of National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) clinical guidelines, translation of guideline recommendations into quality indicators, and assessment of their validity and implementation feasibility (applying consensus methodology used in selecting QOF indicators). Of the 296 national guidelines published, 48 were potentially relevant to children in primary care, but only 123 of 1863 recommendations (6.6%) met selection criteria for translation into 56 potential quality indicators. A further 13 potential indicators were articulated after review of existing quality indicators and standards. Assessment of the validity and feasibility of implementation of these 69 candidate indicators by a clinical expert group identified 35 with median scores 8 on a 9-point Likert scale. However, only seven of the 35 achieved a GRADE rating >1 (were based on more than expert opinion). Producing valid primary care quality indicators for children is feasible but difficult. These indicators require piloting before wide adoption but have the potential to raise the standard of primary care for all children.


The FOXA1 transcriptional network coordinates key functions of primary human airway epithelial cells.
The differentiated functions of the human airway epithelium are coordinated by a complex network of transcription factors. These include the pioneer factors Forkhead box A1 and A2 (FOXA1 and FOXA2), which are well studied in several tissues, but their role in airway epithelial cells is poorly characterized. Here, we define the cistrome of FOXA1 and FOXA2 in primary human bronchial epithelial (HBE) cells by chromatin immunoprecipitation with deep-sequencing (ChIP-seq). Next, siRNA-mediated depletion of each factor is used to investigate their transcriptome by RNA-seq. We found that, as predicted from their DNA-binding motifs, genome-wide occupancy of the two factors showed substantial overlap; however, their global impact on gene expression differed. FOXA1 is an abundant transcript in HBE cells, while FOXA2 is expressed at low levels, and both these factors likely exhibit autoregulation and cross-regulation. FOXA1 regulated loci are involved in cell adhesion and the maintenance of epithelial cell identity, particularly through repression of genes associated with epithelial to mesenchymal transition (EMT). FOXA1 also directly targets other transcription factors with a known role in the airway epithelium such as SAM-pointed domain-containing Ets-like factor (SPDEF). The intersection of the cistrome and transcriptome for FOXA1 revealed enrichment of genes involved in epithelial development and tissue morphogenesis. Moreover, depletion of FOXA1 was shown to reduce the transepithelial resistance of HBE cells, confirming the role of this factor in maintaining epithelial barrier integrity.


Associations Between Anxiety Disorder Diagnoses and Body Mass Index Differ by Age, Sex and Race: A Population Based Study.
Few large studies have examined correlations between anxiety and body mass index (BMI) by gender or racial groups using clinical data. This study aimed to determine associations between diagnosed anxiety disorders and BMI, and evaluate whether observed associations varied by demographic characteristics. Data from the Rochester Epidemiology Project (REP) data linkage system were analyzed to examine associations between anxiety disorders and BMI among adults ages 18-85 residing in Olmsted County, MN in 2009 (n=103,557). Height and weight data were available for 75,958 people (73%). The international classification of underweight, overweight, and obesity by BMI was used. Population consisted of 56% females, 92.8% White individuals, with median age of 46 years. When adjusted for age, sex, and race, we observed a U-shaped association between anxiety and BMI group. Underweight and obese individuals were more likely to have an anxiety diagnosis compared to normal weight individuals. Stratification by sex yielded a U-shaped association between anxiety and BMI only in women. Stratification by race showed a U-shaped association between anxiety and BMI only in the White population. Anxiety was significantly associated only with obesity in the Black population. Anxiety was not associated with a BMI category in Asian or Hispanic groups. Among elderly group, there is inverse correlation between anxiety and obesity. Our results suggest that anxiety may have heterogeneous associations with BMI in the population. Further research on potential mechanisms contributing to these findings will help direct efforts in anxiety and obesity management across diverse population groups.


Hippocampal and Cerebral Blood Flow after Exercise Cessation in Master Athletes.
While endurance exercise training improves cerebrovascular health and has neurotrophic effects within the hippocampus, the effects of stopping this exercise on the brain remain unclear. Our aim was to measure the effects of 10 days of detraining on resting cerebral blood flow (rCBF) in gray matter and the hippocampus in healthy and physically fit older adults. We hypothesized that rCBF would decrease in the hippocampus after a 10-day cessation of exercise training. Twelve master athletes, defined as older adults (age ≥ 50 years) with long-term endurance training histories (≥15 years), were recruited from local running clubs. After screening, eligible participants were asked to cease all training and vigorous physical activity for 10 consecutive days. Before and immediately after the exercise cessation period, rCBF was measured with perfusion-weighted MRI. A voxel-wise analysis was used in gray matter, and the hippocampus was selected a priori as a structurally defined region of interest (ROI), to detect rCBF changes over time. Resting CBF significantly decreased in eight gray matter brain regions. These regions included: (L) inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, (R) cerebellar tonsil, lingual gyrus, precuneus, and bilateral cerebellum (FWE p < 0.05). Additionally, rCBF within the left and right hippocampus significantly decreased after 10 days of no exercise training. These findings suggest that the cerebrovascular system, including the regulation of resting hippocampal blood flow, is responsive to short-term decreases in exercise training among master athletes. Cessation of exercise training among physically fit individuals may provide a novel method to assess the effects of acute exercise and exercise training on brain function in older adults.


Put Your Imperfections Behind You: Temporal Landmarks Spur Goal Initiation When They Signal New Beginnings.
People often fail to muster the motivation needed to initiate goal pursuit. Across five laboratory experiments, we explored occasions when people naturally experience enhanced motivation to take actions that facilitate goal pursuit and why certain dates are more likely to spur goal initiation than others. We present causal evidence that emphasizing a temporal landmark denoting the beginning of a new time period increases people's intentions to initiate goal pursuit. In addition, we propose and show that people's strengthened motivation to begin pursuing their aspirations following such temporal landmarks originates in part from the psychological disassociation these landmarks induce from a person's past, imperfect self.


A Ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase.
Ribonucleotide reductase plays a central role in cell proliferation by supplying deoxyribonucleotide precursors for DNA synthesis and repair. The holoenzyme is a protein tetramer that features two large (hRRM1) and two small (hRRM2 or p53R2) subunits. The small subunit contains a di-iron cluster/tyrosyl radical cofactor that is essential for enzyme activity. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP) is a new, potent ribonucleotide reductase inhibitor currently in phase II clinical trials for cancer chemotherapy. Ferric chloride readily reacts with Triapine to form an Fe(III)-(3-AP) complex, which is reduced to Fe(II)-(3-AP) by DTT. Spin-trapping experiments with 5,5-dimethyl-1-pyrroline-N-oxide prove that Fe(II)-(3-AP) reduces O2 to give oxygen reactive species (ROS). In vitro activity assays show that Fe(II)-(3-AP) is a much more potent inhibitor of hRRM2/hRRM1 and p53R2/hRRM1 than Triapine. Electron paramagnetic resonance measurements on frozen solutions of hRRM2 and p53R2 show that their tyrosyl radicals are completely quenched by incubation with Fe(II)-(3-AP). However, the enzyme activity is maintained in protein samples supplemented with catalase alone or in combination with superoxide dismutase. Furthermore, catalase alone or in combination with superoxide dismutase markedly decreases the antiproliferative effect of Triapine in cytotoxicity assays. These results indicate that Triapine-induced inhibition of ribonucleotide reductase is caused by ROS. We suggest that ROS may ultimately be responsible for the pharmacologic effects of Triapine in vivo.


Metabolomic signatures of low birthweight: Pathways to insulin resistance and oxidative stress.
Several studies suggest that low birthweight resulting from restricted intrauterine growth can leave a metabolic footprint which may persist into adulthood. To investigate this, we performed metabolomic profiling on 5036 female twins, aged 18-80, with weight at birth information available from the TwinsUK cohort and performed independent replication in two additional cohorts. Out of 422 compounds tested, 25 metabolites associated with birthweight in these twins, replicated in 1951 men and women from the Hertfordshire Cohort Study (HCS, aged 66) and in 2391 men and women from the North Finland Birth 1986 cohort (NFBC, aged 16). We found distinct heterogeneity between sexes and, after adjusting for multiple tests and heterogeneity, two metabolites were reproducible overall (propionylcarnitine and 3-4-hydroxyphenyllactate). Testing women only, we found other metabolites associated with lower birthweight from the meta-analysis of the three cohorts (2-hydroxy-butyric acid and γ-glutamylleucine). Higher levels of all these metabolites can be linked to insulin resistance, oxidative stress or a dysfunction of energy metabolism, suggesting that low birthweight in both twins and singletons are having an impact on these pathways in adulthood.


Clinical leadership as an integral curriculum thread in pre-registration nursing programmes.
In recent years there has been a growth in leadership development frameworks in health for the existing workforce. There has also been a related abundance of leadership programmes developed specifically for qualified nurses. There is a groundswell of opinion that clinical leadership preparation needs to extend to preparatory programmes leading to registration as a nurse. To this end a doctoral research study has been completed that focused specifically on the identification and verification of the antecedents of clinical leadership (leadership and management) so they can shape the curriculum content and the best way to deliver the curriculum content as a curriculum thread. To conceptualise how the curriculum content, identified and verified empirically, can be structured within a curriculum thread and to contribute to the discussion on effective pedagogical approaches and educational strategies for learning and teaching of clinical leadership. A multi-method design was utilised in the research in Australia. Drawing on core principles in critical social theory, an integral curriculum thread is proposed for pre-registration nursing programmes that identifies the antecedents of clinical leadership; the core concepts, together with the continuum of enlightenment, empowerment, and emancipation. The curriculum content, the effective pedagogical approaches and the educational strategies are supported theoretically and we believe this offers a design template for action and a way of thinking about this important aspect of preparatory nursing education. Moreover, we hope to have created a process contributing to a heighten sense of awareness in the nursing student (and other key stakeholders) of the what, how and when of clinical leadership for a novice registered nurse. The next stage is to further test through research the proposed integral curriculum thread.


Mental health consumer involvement in occupational therapy education in Australia and Aotearoa New Zealand.
Recovery-oriented practice policies and occupational therapy education accreditation standards require that consumers are engaged in the design, delivery and evaluation of curricula. This consumer involvement (sometimes referred to as service-user involvement or patient involvement in other contexts) should go beyond consumers simply 'telling their stories' to more meaningful collaboration in curricula. This study was designed to map the current patterns of consumer involvement in occupational therapy programs across Australia and Aotearoa New Zealand. A survey was distributed to all occupational therapy programs across Australia and Aotearoa New Zealand. The survey included questions related to: (a) perceived enablers and barriers to consumer involvement in education; (b) organisational structures and support; (c) ways in which consumer are involved in the design, delivery and evaluation of curricula; (d) access to remuneration for consumers; (e) overall ratings of the level of consumer involvement in curricula; and (f) academic confidence in working with consumers. Usable responses were received for 23 programs from 19 universities (83% response rate). Every program reported some consumer involvement in the curriculum. Consumer participation tended to be mainly focussed on curriculum delivery with less frequent involvement in curriculum design or evaluation. The most common barrier to consumer involvement in curricula was 'funding/remuneration for consumers' and the most common enabler of consumer involvement was 'positive attitudes of teaching staff'. In comparison to previous reports, consumer involvement in occupational therapy curricula has increased over the past decade. However, ongoing effort is required to support true collaboration in all aspects of curriculum design, delivery and evaluation. While this will require attention and effort from academic teams, changes at a university level to establish systems to engage and effectively remunerate consumers for their involvement (especially in design and evaluation elements) are also required.


Introduction of a new mobile-bearing total knee prosthesis: minimum three year follow-up of an RCT comparing it with a fixed-bearing device.
As part of the step-wise validation of a new prosthesis (TMK), we previously published the 1 year results of a randomised controlled trial in patients undergoing bilateral knee replacement [Price A., Rees J., Beard D., Juszczak E. et al. A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis. JBJS B 2003;85-B-1:62-7.]. Forty patients had the new mobile-bearing prosthesis implanted in one knee and an established fixed-bearing device in the other (AGC). We now report the 3 year status of these patients and, in addition, review a separate multi-centre cohort of 172 patients who had undergone unilateral arthroplasty with the TMK. No significant differences were found in outcome (American Knee Society Score and Oxford Knee Score) between the two prostheses. The greater incidence of "clicking" in the mobile-bearing knee, reported in the previous review, persisted (TMK=48%, AGC=30%). The presence of this mechanical noise was found to have no relationship with outcome in either of the prostheses. The unilateral cohort study showed an acceptable complication rate for the new prosthesis, although some patients reported subjective instability. The method of controlled introduction of the TMK, of which this constitutes a further step, has allowed us to assess the significance of a reported problem (clicking) and to provide scientific data from which other surgeons can decide about use of the implant.


The tree that hides the forest: cryptic diversity and phylogenetic relationships in the Palaearctic vector Obsoletus/Scoticus Complex (Diptera: Ceratopogonidae) at the European level.
Culicoides obsoletus is an abundant and widely distributed Holarctic biting midge species, involved in the transmission of bluetongue virus (BTV) and Schmallenberg virus (SBV) to wild and domestic ruminants. Females of this vector species are often reported jointly with two morphologically very close species, C. scoticus and C. montanus, forming the Obsoletus/Scoticus Complex. Recently, cryptic diversity within C. obsoletus was reported in geographically distant sites. Clear delineation of species and characterization of genetic variability is mandatory to revise their taxonomic status and assess the vector role of each taxonomic entity. Our objectives were to characterize and map the cryptic diversity within the Obsoletus/Scoticus Complex. Portion of the cox1 mitochondrial gene of 3763 individuals belonging to the Obsoletus/Scoticus Complex was sequenced. Populations from 20 countries along a Palaearctic Mediterranean transect covering Scandinavia to Canary islands (North to South) and Canary islands to Turkey (West to East) were included. Genetic diversity based on cox1 barcoding was supported by 16S rDNA mitochondrial gene sequences and a gene coding for ribosomal 28S rDNA. Species delimitation using a multi-marker methodology was used to revise the current taxonomic scheme of the Obsoletus/Scoticus Complex. Our analysis showed the existence of three phylogenetic clades (C. obsoletus clade O2, C. obsoletus clade dark and one not yet named and identified) within C. obsoletus. These analyses also revealed two intra-specific clades within C. scoticus and raised questions about the taxonomic status of C. montanus. To our knowledge, our study provides the first genetic characterization of the Obsoletus/Scoticus Complex on a large geographical scale and allows a revision of the current taxonomic classification for an important group of vector species of livestock viruses in the Palaearctic region.


Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy.
Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes. Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days. In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials. Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.


The Effect of B-Pyracin and the Lactobacillus casei Factor Upon Hemoglobin Regeneration Following Hemorrhage.
In severe experimental hemorrhagic anemia in hens, the injection of beta-pyracin and Lactobacillus casei factor, alone and in combination, was found to hasten the regeneration of hemoglobin. When these factors were administered together, however, the rise in hemoglobin was much more rapid and the level reached was higher than in the lots administered the factors alone. The hemoglobin levels in the control lots rose above the "pre-bleeding" values and then began an almost immediate decline to approximately the original level. In the lots receiving beta-pyracin and Lactobacillus casei factor, alone or in combination, the hemoglobin levels also rose above the "pre-bleeding" values but were maintained for some time after injections were discontinued before declining to the original values.


AFLP and SSR polymorphism in a Coffea interspecific backcross progeny [( C. heterocalyx x C. canephora) x C. canephora].
An interspecific cross (BC 1) involving a species with one of the largest genomes in the Coffea genus [ Coffea heterocalyx (HET), qDNA = 1.74 pg] and a species with a medium-sized genome [ Coffea canephora (CAN), qDNA = 1.43 pg] was studied using two types of molecular markers, AFLP and SSR. One hundred and eighty eight AFLP bands and 34 SSR primer pairs were suitable for mapping. The total map length was 1,360 cM with 190 loci distributed in 15 linkage groups. The results were compared to those obtained previously on an interspecific BC 1 progeny involving a species with a medium-sized genome ( Coffea liberica var dewevrei, DEW) and a species with one of the smallest genomes ( Coffea pseudozanguebariae, PSE). They are discussed relative to three main points: (1) the relevance of the different marker types, (2) the genomic distribution of AFLP and SSR markers, and (3) the relation between AFLP polymorphism and genome size.


[Organ-preserving interventions in combined therapy of children and adolescents with osteosarcoma].
An analyzed cohort consists of 50 pediatric patients with osteosarcoma receiving combined therapy in N. N. Petrov Research Institute for Oncology (1999-2010). Thirty nine of them had localized disease, 11 patients had distant metastases. The treatment scheme included neoadjuvant therapy with cisplatin and doxorubicin, surgical treatment and adjuvant therapy depended on initial response and could include cisplatin, doxorubicin, high-dose methotrexate, ifosfamide, etoposide. Four-year overall and relapse-free survival in children with localized disease was 74.3% and 69.2% accordingly. In 62% of patients were performed organ-preserving surgical interventions, in 22 patients was performed endoprosthetics, in 4 patients the defect was replaced by a bone autograft on a vascular bundle. The effectiveness of initial treatment and secondary endoprosthetics were analyzed. Six patients with lung metastases received normotermic lung chemoperfusion, 4 of them are alive and disease-free for 8 to 24 months.


Components of switching intentional set.
Despite the intuition that we can shift cognitive set on instruction, some behavioral studies have suggested that set shifting might only be accomplished once we engage in performance of the new task. It is possible that set switching consists of more than one component cognitive process and that the component processes might segregated in time. We recorded event-related potentials (ERPs) during two set-switching tasks to test whether different component processes were responsible for (i) set initiation and reconfiguration when presented with the instruction to switch, and (ii) the implementation of the new set once subjects engaged in performing the new task. The response switching (RS) task required shifts of intentional set; subjects selected between responses according to one of two conflicting intentional sets. The results demonstrated the existence of more than one constituent process. Some of the processes were linked to the initiation and reconfiguration of the set prior to actual performance of the new task. Other processes were time locked to performance of new task items. Set initiation started with modulation of medial frontal ERPs and was followed by modulation over parietal electrodes. Implementation of intentional set was associated with modulation of response-related ERPs.


Raman spectroscopic study of bacterial endospores.
Endospores and endospore-forming bacteria were studied by Raman spectroscopy. Raman spectra were recorded from Bacillus licheniformis LMG 7634 at different steps during growth and spore formation, and from spore suspensions obtained from diverse Bacillus and Paenibacillus strains cultured in different conditions (growth media, temperature, peroxide treatment). Raman bands of calcium dipicolinate and amino acids such as phenylalanine and tyrosine are more intense in the spectra of sporulating bacteria compared with those of bacteria from earlier phases of growth. Raman spectroscopy can thus be used to detect sporulation of cells by a characteristic band at 1,018 cm(-1) from calcium dipicolinate. The increase in amino acids could possibly be explained by the formation of small acid-soluble proteins that saturate the endospore DNA. Large variations in Raman spectra of endospore suspensions of different strains or different culturing conditions were observed. Next to calcium dipicolinate, tyrosine and phenylalanine, band differences at 527 and 638 cm(-1) were observed in the spectra of some of the B. sporothermodurans spore suspensions. These bands were assigned to the incorporation of cysteine residues in spore coat proteins. In conclusion, Raman spectroscopy is a fast technique to provide useful information about several spore components.


The effect of a membrane-mimicking environment on the interactions of Cu2+ with an amyloidogenic fragment of chicken prion protein.
Prion proteins (PrP) from different species have the ability to tightly bind Cu2+ ions. Copper coordination sites are located in the disordered and flexible N-terminal region which contains several His anchoring sites. Among them, two His residues are found in the so called amyloidogenic PrP region which is believed to play a key role in the process leading to oligomer and fibril formation. Both chicken and human amyloidogenic regions have a hydrophobic C-terminal region rich in Ala and Val amino acids. Recent findings revealed that this domain undergoes random coil to α-helix structuring upon interaction with membrane models. This interaction might strongly impact metal binding abilities either in terms of donor sets or affinity. In this study we investigated Cu2+ interaction with an amyloidogenic fragment, chPrP105-140, derived from chicken prion protein (chPrP), in different solution environments. The behavior of the peptide and its metal complexes was analyzed in water and in the presence of negative and positive charged membrane mimicking environments formed by sodium dodecyl sulfate (SDS) and dodecyl trimethyl ammonium chloride (DTAC) micelles. The metal coordination sphere, the metal binding affinity and stoichiometry were evaluated by combining spectroscopic and potentiometric methods. Finally we compare copper(ii) interactions with human and chicken amyloidogenic fragments. Our results indicate that the chicken amyloidogenic fragment is a stronger copper ligand than the human amyloidogenic fragment.


Kinesio Taping for pain control during labor: Protocol of a randomized, controlled trial.
This study protocol will evaluate the effectiveness and safety during labor and delivery of the Kinesio Taping bandage for pain sensation, satisfaction of patients, and obstetric and neonatal outcomes. A randomized controlled trial with 60 participants divided into two groups will be conducted. The intervention group will receive bandage application on the vertebral regions corresponding to uterine dermatomes - from T10 to L1 and from S2 to S4. The control group will receive bandage application away from uterine dermatomes, from T1 to T4. The primary endpoint is pain during labor. Secondary endpoints are perinatal outcomes and patient satisfaction with the bandage and with her labor. Pain levels will be evaluated on an hourly basis during labor, and intention-to-treat analysis will be performed. Risk ratios and 95% confidence intervals will be calculated. Findings on effectiveness of pain control with no adverse effects to both the mother and neonate are the first step in evaluating the systematic use of Kinesio Taping during labor. Since self-control may affect birthing experience satisfaction, discovering new alternatives for pain control may allow for a better experience.


Use of information and communication technology to provide health information: what do older migrants know, and what do they need to know?
Governments and businesses are increasingly using the internet and mobile telephones to disseminate information about services and products. However, not all population groups have the resources and capabilities to support equality of access to and use of these technologies. While Australia's ageing population receives attention in a wide variety of literatures, the ageing migrant population has received very little attention in relation to understanding their place in the 'digital divide'. It is not known how this group gathers information used in everyday living, or what role the internet or mobile phones plays within this. At a time when the population is ageing and there is an increasing use of the internet to deliver services and information, there is little research on the effects of ethnicity, migration, socio-economic status, education or gender of older people on the use of information and communication technology (ICT). Addressing this should be a priority in Australia, which has an old and ageing population that includes many post-war migrants from non-English speaking European countries. To analyse the views of older migrants living in South Australia with respect to their current information sources, their use of ICT and any barriers and enablers to future use of ICT for accessing health information. A qualitative study employing eight focus groups involving 43 older Italian and Greek migrants living in the community in metropolitan or regional settings in South Australia. Interviews were held and audio-recorded and the English language components transcribed. Transcriptions were analysed manually using a grounded theory approach. Older migrants do not use ICT to a great extent to access information in their everyday lives, with many expressing no interest in learning how to do so. However, they access the information they need to function in society with a desired quality of life from multiple sources by various means. Sources include electronic and print media from Australia and their home countries, family and acquaintances, government departments or service providers. Many expressed a preference for receiving information as printed material or directly from another person. Governments or primary healthcare organisations planning to make health information solely available via ICT should be aware that doing so may lead to an increase in 'information exclusion' and the formation of functional knowledge deficits for older migrants. At the moment at least, our participants do not perceive any functional knowledge deficits as they engage multiple sources to access the information they need for everyday life. We recommend that governments and healthcare organisations evaluate the appropriateness of using ICT to directly provide information to older migrants and consider non-digital means or the engagement of 'information brokers' when communicating with groups identified as low or non-users of ICT.


Transferring patient care: patterns of synchronous bidisciplinary communication between physicians and nurses during handoffs in a critical care unit.
The transfer of patient care from one health care worker to another involves communication in high-pressure contexts that are often vulnerable to error. This research project captured current practices for handoffs during the critical care stage of surgical recovery in a hospital setting. The objective was to characterize information flow during transfer and identify patterns of communication between nurses and physicians. Observations were used to document communication exchanges. The data were analyzed qualitatively according to the types of information exchanged and verbal behavior types. Reporting and questions were the most common verbal behaviors, and retrospective medical information was the focus of information exchange. The communication was highly interactive when discussing patient status and future care plans. Nurses proactively asked questions to capture a large proportion of the information they needed. Findings reflect positive and constructive patterns of communication during handoffs in the observed hospital unit.


The Community Health Applied Research Network (CHARN) Data Warehouse: a Resource for Patient-Centered Outcomes Research and Quality Improvement in Underserved, Safety Net Populations.
The Community Health Applied Research Network, funded by the Health Resources and Services Administration, is a research network comprising 18 Community Health Centers organized into four Research Nodes (each including an academic partner) and a data coordinating center. The network represents more than 500,000 diverse safety net patients across 11 states. The primary objective of this paper is to describe the development and implementation process of the CHARN data warehouse. The methods involved regulatory and governance development and approval, development of content and structure of the warehouse and processes for extracting the data locally, performing validation, and finally submitting data to the data coordinating center. Version 1 of the warehouse has been developed. Tables have been added, the population and the years of electronic health records (EHR) have been expanded for Version 2. It is feasible to create a national, centralized data warehouse with multiple Community Health Center partners using different EHR systems. It is essential to allow sufficient time: (1) to develop collaborative, trusting relationships among new partners with varied technology, backgrounds, expertise, and interests; (2) to complete institutional, business, and regulatory review processes; (3) to identify and address technical challenges associated with diverse data environments, practices, and resources; and (4) to provide continuing data quality assessments to ensure data accuracy.


Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region.


Contextual role of E2F1 in suppression of melanoma cell motility and invasiveness.
The general transcription factor E2F1 reportedly functions in a protumorigenic manner in several cancer models. We show that the genetic context of cancer cells influence E2F1's role to impede the protumorigenic role. Thirty to fifty percent of melanoma patients carry mutant BRAF with about 90% of mutant BRAF melanomas being V600E mutation. Tissue microarrays from melanoma patients were used to establish an association between E2F1 and BRAFV600E . We show for the first time that low E2F1 levels in BRAFV600E melanomas are associated with lymph node metastasis. Genetic manipulation of E2F1 in BRAFV600E and BRAFwt cells were used to determine its role in malignant melanoma progression by examining effects on migration and invasion. E2F1-mediated negative regulation of myosin light chain kinase (MYLK) increased migration and invasion in BRAFV600E cells by phosphorylating myosin light chain and increased stress fiber formation. We show that E2F1 inhibits extracellular signal-regulated kinase (ERK) activation in BRAFV600E cells and provide evidence for a negative feedback loop between E2F1 and ERK in these cells. This study shows for the first time that E2F1 has a cancer protective role in oncogenic BRAF-activated melanoma cells and that loss of E2F1 can allow disease progression through a novel mechanism of E2F1-mediated MYLK regulation. This study has implications for oncogenic BRAF-activated tumors and resistance to targeted oncogenic BRAF therapy.


Signaling pathways required for macrophage scavenger receptor-mediated phagocytosis: analysis by scanning cytometry.
Scavenger receptors are important components of the innate immune system in the lung, allowing alveolar macrophages to bind and phagocytose numerous unopsonized targets. Mice with genetic deletions of scavenger receptors, such as SR-A and MARCO, are susceptible to infection or inflammation from inhaled pathogens or dusts. However, the signaling pathways required for scavenger receptor-mediated phagocytosis of unopsonized particles have not been characterized. We developed a scanning cytometry-based high-throughput assay of macrophage phagocytosis that quantitates bound and internalized unopsonized latex beads. This assay allowed the testing of a panel of signaling inhibitors which have previously been shown to target opsonin-dependent phagocytosis for their effect on unopsonized bead uptake by human in vitro-derived alveolar macrophage-like cells. The non-selective scavenger receptor inhibitor poly(I) and the actin destabilizer cytochalasin D were used to validate the assay and caused near complete abrogation of bead binding and internalization, respectively. Microtubule destabilization using nocodazole dramatically inhibited bead internalization. Internalization was also significantly reduced by inhibitors of tyrosine kinases (genistein and herbimycin A), protein kinase C (staurosporine, chelerythrine chloride and Gö 6976), phosphoinositide-3 kinase (LY294002 and wortmannin), and the JNK and ERK pathways. In contrast, inhibition of phospholipase C by U-73122 had no effect. These data indicate the utility of scanning cytometry for the analysis of phagocytosis and that phagocytosis of unopsonized particles has both shared and distinct features when compared to opsonin-mediated phagocytosis.


In the adult hippocampus, chronic nerve growth factor deprivation shifts GABAergic signaling from the hyperpolarizing to the depolarizing direction.
GABA, the main inhibitory transmitter in adulthood, early in postnatal development exerts a depolarizing and excitatory action. This effect, which results from a high intracellular chloride concentration ([Cl(-)](i)), promotes neuronal growth and synaptogenesis. During the second postnatal week, the developmental regulated expression of the cation-chloride cotransporter KCC2 accounts for the shift of GABA from the depolarizing to the hyperpolarizing direction. Changes in chloride homeostasis associated with high [Cl(-)](i) have been found in several neurological disorders, including temporal lobe epilepsy. Here, we report that, in adult transgenic mice engineered to express recombinant neutralizing anti-nerve growth factor antibodies (AD11 mice), GABA became depolarizing and excitatory. AD11 mice exhibit a severe deficit of the cholinergic function associated with an age-dependent progressive neurodegenerative pathology resembling that observed in Alzheimer patients. Thus, in hippocampal slices obtained from 6-month-old AD11 (but not wild-type) mice, the GABA(A) agonist isoguvacine significantly increased the firing of CA1 principal cells and, at the network level, the frequency of multiunit activity recorded with extracellular electrodes. In addition, in AD11 mice, the reversal of GABA(A)-mediated postsynaptic currents and of GABA-evoked single-channel currents were positive with respect to the resting membrane potential as estimated in perforated patch and cell attached recordings, respectively. Real-time quantitative reverse transcription-PCR and immunocytochemical experiments revealed a reduced expression of mRNA encoding for Kcc2 and of the respective protein. This novel mechanism may represent a homeostatic response that counterbalances within the hippocampal network the Alzheimer-like neurodegenerative pathology found in AD11 mice.


Occlusive IOLs for intractable diplopia demonstrate a novel near-infrared window of transmission for SLO/OCT imaging and clinical assessment.
Occlusive intraocular lens (IOL) implantation is an effective therapeutic option in patients with intractable diplopia, visual confusion, and unsightly leukocoria. However, their use has been restricted by concerns that inability to visualize the retina may prevent the diagnosis of important posterior pole diseases. In this study, transmission spectra of occlusive IOLs were defined as a basis for acquiring scanning laser ophthalmoscopy/optical coherence tomography (SLO/OCT) images. Fifteen IOLs of three designs were examined: black small and large PMMA and black Lotus (Morcher GmbH, Stuttgart, Germany). Each IOL was placed between a broad-spectrum white light source and a spectroradiometer, to generate transmission spectra for each lens and determine the cutoff wavelength. Transmission in the near-infrared (NIR) range was confirmed with an 850-nm LED. A model eye was implanted with occlusive IOLs, and SLO/OCT scans were acquired with seven clinical SLO/OCT imaging systems. Occlusive IOLs demonstrated high levels of transmission of NIR light. It was determined that most SLO/OCT scanners would achieve 99% to 100% transmission at their operational wavelengths of NIR light. Furthermore, all clinical SLO/OCT imaging systems were capable of imaging fine retinal features without attenuation through occlusive IOLs in a model eye. In this study, a novel NIR window of high-level transmission was identified across the occlusive IOLs with applications to SLO/OCT imaging and NIR-based clinical assessment. The ability to acquire high-quality SLO/OCT scans to detect posterior pole disease may fundamentally change the current view on occlusive IOLs and encourage their use in patients with intractable diplopia.


Microelectrode voltammetry of multi-electron transfers complicated by coupled chemical equilibria: a general theory for the extended square scheme.
A very general and simple theoretical solution is presented for the current-potential-time response of reversible multi-electron transfer processes complicated by homogeneous chemical equilibria (the so-called extended square scheme). The expressions presented here are applicable regardless of the number of electrons transferred and coupled chemical processes, and they are particularized for a wide variety of microelectrode geometries. The voltammetric response of very different systems presenting multi-electron transfers is considered for the most widely-used techniques (namely, cyclic voltammetry, square wave voltammetry, differential pulse voltammetry and steady state voltammetry), studying the influence of the microelectrode geometry and the number and thermodynamics of the (electro)chemical steps. Most appropriate techniques and procedures for the determination of the 'interaction' between successive transfers are discussed. Special attention is paid to those situations where homogeneous chemical processes, such as protonation, complexation or ion association, affect the electrochemical behaviour of the system by different stabilization of the oxidation states.


A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK.
Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults. Estimate the cost-effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX). A 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed-treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression-Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed. LDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by £5 and £200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost-effectiveness for LDX vs. MPH-ER and ATX at a threshold of £20,000 per QALY was 61% and 80%, respectively. From the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH-ER.


Symmetric inertial confinement fusion implosions at ultra-high laser energies.
Indirect-drive hohlraum experiments at the National Ignition Facility have demonstrated symmetric capsule implosions at unprecedented laser drive energies of 0.7 megajoule. One hundred and ninety-two simultaneously fired laser beams heat ignition-emulate hohlraums to radiation temperatures of 3.3 million kelvin, compressing 1.8-millimeter-diameter capsules by the soft x-rays produced by the hohlraum. Self-generated plasma optics gratings on either end of the hohlraum tune the laser power distribution in the hohlraum, which produces a symmetric x-ray drive as inferred from the shape of the capsule self-emission. These experiments indicate that the conditions are suitable for compressing deuterium-tritium-filled capsules, with the goal of achieving burning fusion plasmas and energy gain in the laboratory.


Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature.
Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients. Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study. Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study. By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young. Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance. This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore.


Evaluation of the atherogenic tendency of lipids and lipoprotein content and their relationships with oxidant-antioxidant system in patients with psoriasis.
Psoriasis is a common chronic and recurrent inflammatory skin disease that can occur due to abnormalities in essential fatty acid metabolism, lymphokine secretion, free radical generation, lipid peroxidation and eicosanoid metabolism, and has been associated with increased frequency of cardiovascular events. The current study was designed to evaluate plasma lipids, susceptibility of LDL to oxidation and oxidant-antioxidant status and their relationships in patients with psoriasis. The study group included 35 patients with psoriasis (18 females and 17 males), and 35 sex- and age-matched healthy volunteers (16 females and 19 males). From blood samples, their lipids, lipoproteins, acute phase reactants, lipid peroxidation products [lipid hydroperoxide (LHP) and malondialdehyde (MDA)], antioxidant enzymes [glutathione peroxidase (GSH-Px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT)], total antioxidant status (TAS) and autoantibodies against oxidized low-density lipoprotein (AuAb-oxLDL) levels were determined. Moreover, the susceptibility of copper-induced in vitro oxidation of LDL was examined. The mean levels of atherogenic lipids (total cholesterol [TC], triacylglycerol [TG] and LDL cholesterol [LDL-C]), acute-phase reactants (CRP, ESR, PMNLs, ceruloplasmin and fibrinogen) and lipid peroxidation products, AuAb-oxLDL levels in patients with psoriasis were found to be significantly higher than those of healthy subjects. On the other hand, TAS and antioxidant enzyme activities (CAT, SOD and GSH-Px in erythrocyte and SOD in plasma) were significantly lower when compared to healthy subjects. The lag times [t(lag)], a measure of resistance to oxidation of LDL, were also lower. The levels of AuAb-oxLDL in patients were correlated with TC, LDL-C, plasma LHP, erythrocyte MDA, oxidized LDL-MDA (oxLDL-MDA), fibrinogen, CRP, PMNL levels and plasma SOD activities (r = 0.69, P < 0.01; r = 0.64, P < 0.01; r = 0.38, P < 0.05; r = 0.65, P < 0.01; r = 0.34, P < 0.05; r = 0.34, P < 0.05; r = 0.53, P < 0.01, r = 0.34, P < 0.05; r = -0.67, P < 0.01, respectively). On the other hand, t(lag) was correlated negatively with the levels of VLDL-TG, VLDL-TC and LDL-TG but positively correlated with the levels of TAS in psoriatics (r = -0.49, P < 0.01; r = -0.49, P < 0.01, r = -0.65, P < 0.05; r = 0.37, P < 0.05). It was concluded that the psoriatic patients could be considered as a group with an increased atherosclerotic risk because of increased oxidant stress, decreased antioxidant capacity and susceptibility in lipid profile and lipoprotein content to atherogenicity.


Effects of pH, nitrite, and ascorbic acid on nonenzymatic nitric oxide generation and bacterial growth in urine.
Nitrite may be generated by bacteria in urine during urinary tract infections. Acidification of nitrite results in the formation of nitric oxide (NO) and other reactive nitrogen oxides, which are toxic to a variety of microorganisms. We have studied NO formation and bacterial growth in mildly acidified human urine containing nitrite and the reducing agent vitamin C. Urine collected from healthy subjects was incubated in closed syringes at different pH values with varying amounts of nitrite and/or ascorbic acid added. NO generation was measured in headspace gas using a chemiluminescence technique. A similar setup was also used to study the growth of three strains of bacteria in urine. Mildly acidified nitrite-containing urine generated large amounts of NO and this production was greatly potentiated by ascorbic acid. The growth of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus saprophyticus was markedly reduced by the addition of nitrite to acidified urine. This inhibition was enhanced by ascorbic acid. In conclusion, we show that the growth of three common urinary pathogens is markedly inhibited in mildly acidified urine when nitrite is present. The bacteriostatic effect of acidified nitrite is likely related to the release of NO and other toxic reactive nitrogen intermediates. These results may help to explain the well-known beneficial effects of urinary acidification with, e.g., vitamin C in treatment and prevention of urinary tract infection.


Anomalous coronary origin: the challenge in preventing exercise-related sudden cardiac death.
The sudden cardiac death (SCD) of a young athlete is a catastrophic event, particularly in the absence of prodromal warning symptoms. Anomalous coronary origin (ACO) is a well-described cause of cardiac symptoms and SCD, but the diagnosis is usually missed by conventional non-invasive investigations designed to identify myocardial ischaemia. SCD is preventable by correction of the anomaly. A tragic case of a promising young athlete who had underlying ACO and who presented with prodromal symptoms with multiple "negative" investigations is described to highlight the typical clinical features and outline the difficulties encountered in accurate premortem diagnosis.


Serious Gaming During Multidisciplinary Rehabilitation for Patients With Chronic Pain or Fatigue Symptoms: Mixed Methods Design of a Realist Process Evaluation.
Serious gaming could support patients in learning to cope with chronic pain or functional somatic syndromes and reduce symptom burdens. To realize this potential, insight is needed into how, why, for whom, and when it works in actual treatment circumstances. Following a realist approach, process evaluations were performed before, during, and after a two-armed, natural quasi-experiment (n=275). A group of patients with interfering chronic pain or fatigue symptoms received a short additional blended mindfulness-based serious gaming intervention during a multidisciplinary rehabilitation program. A control group only received the regular rehabilitation program. During two sessions before and one session after the experiment, expectations about serious gaming processes were discussed in focus groups with local care providers, implementers, and experts. Patients participated in a survey (n=114) and in semistructured interviews (n=10). The qualitative data were used to develop tentative expectations about aspects of serious gaming that, in certain patients and circumstances, trigger mechanisms of learning and health outcome change. Hypotheses about indicative quantitative data patterns for tentative expectations were formulated before inspecting, describing, and analyzing-with regression models-routinely collected clinical outcome data. An updated program theory was formulated after mixing the qualitative and quantitative results. Qualitative data showed that a subset of patients perceived improvement of their self-awareness in moments of daily social interactions. These results were explained by patients, who played the serious game LAKA, as a "confrontation with yourself," which reflected self-discrepancies. Important characteristics of serious gaming in the study's context included innovation factors of relative advantage with experiential learning opportunity, compatibility with the treatment approach, and the limited flexibility in regard to patient preferences. Perceived patient factors included age and style of coping with stress or pain. Learning perceptions could also depend on care provider role-taking and the planning and facilitating (ie, local organization) of serious gaming introduction and feedback sessions in small groups of patients. Quantitative data showed very small average differences between the study groups in self-reported depression, pain, and fatigue changes (-.07<beta<-.17, all 95% CI upper bounds <0), which were mediated by small group differences in mindfulness (beta=.26, 95% CI .02-.51). Mindfulness changes were positively associated with patient involvement in serious gaming (n=114, beta=.36, P=.001). Acceptance of serious gaming was lower in older patients. Average health outcome changes went up to a medium size in patients that reported lower active coping with stress and lower pain coping before serious gaming. Mindfulness changes and gaming acceptance perceptions covaried with group structure and immediate feedback sessions after serious gaming. This study developed transferable insight into how and why serious gaming can facilitate additional learning about coping in order to reduce burdens of chronic pain or fatigue symptoms in certain patients and in actual treatment circumstances. Future studies are needed to continue the development of this fallible theory. Such research will further support decisions about using, designing, allocating, and tailoring serious gaming to optimize important patient health benefits. Netherlands Trial Register NTR6020; https://www.trialregister.nl/trial/5754.


Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1.
Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been implicated in the susceptibility to a range of inflammatory diseases, including inflammatory bowel disease (IBD). Primary sclerosing cholangitis (PSC) is an immune-mediated chronic cholestatic liver disease associated with IBD. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts in late stage PSC and serum levels of soluble intercellular adhesion molecules are increased in PSC. The aim of this study was to analyse ICAM-1 gene polymorphisms in PSC patients. In this study, 104 patients with PSC and 213 healthy controls were recruited from Oxfordshire Caucasians. PCR with sequence-specific primers (PCR-SSP) was used to detect both ICAM-1 biallelic polymorphisms G241R and K469E. The results were controlled for the HLA haplotypes associated with PSC. The E/E frequency of K469E in PSC was 12% (12/104), significantly lower than that in controls (24%, 51/213;P = 0.009; Pc = 0.02; OR, 0.41). The occurrence of the haplotype G241-E469/G241-E469 in PSC was 4% (4/104), significantly lower than the control group (13%, 28/213; P = 0.01; Pc = 0.04; OR, 0.26). There was no difference between PSC and control groups in the frequencies of the genotype R241G or in allele frequencies of K469E. The E469E homozygote status for ICAM-1 is associated with protection against PSC.


Driving Pressure-Guided Individualized Positive End-Expiratory Pressure in Abdominal Surgery: A Randomized Controlled Trial.
The optimal positive end-expiratory pressure (PEEP) to prevent postoperative pulmonary complications (PPCs) remains unclear. Recent evidence showed that driving pressure was closely related to PPCs. In this study, we tested the hypothesis that an individualized PEEP guided by minimum driving pressure during abdominal surgery would reduce the incidence of PPCs. This single-centered, randomized controlled trial included a total of 148 patients scheduled for open upper abdominal surgery. Patients were randomly assigned to receive an individualized PEEP guided by minimum driving pressure or an empiric fixed PEEP of 6 cm H2O. The primary outcome was the incidence of clinically significant PPCs within the first 7 days after surgery, using a χ2 test. Secondary outcomes were the severity of PPCs, the area of atelectasis, and pleural effusion. Other outcomes, such as the incidence of different types of PPCs (including hypoxemia, atelectasis, pleural effusion, dyspnea, pneumonia, pneumothorax, and acute respiratory distress syndrome), intensive care unit (ICU) admission rate, length of hospital stay, and 30-day mortality were also explored. The median value of PEEP in the individualized group was 10 cm H2O. The incidence of clinically significant PPCs was significantly lower in the individualized PEEP group compared with that in the fixed PEEP group (26 of 67 [38.8%] vs 42 of 67 [62.7%], relative risk = 0.619, 95% confidence intervals, 0.435-0.881; P = .006). The overall severity of PPCs and the area of atelectasis were also significantly diminished in the individualized PEEP group. Higher respiratory compliance during surgery and improved intra- and postoperative oxygenation was observed in the individualized group. No significant differences were found in other outcomes between the 2 groups, such as ICU admission rate or 30-day mortality. The application of individualized PEEP based on minimum driving pressure may effectively decrease the severity of atelectasis, improve oxygenation, and reduce the incidence of clinically significant PPCs after open upper abdominal surgery.


An interactional network of genes involved in chitin synthesis in Saccharomyces cerevisiae.
In S. cerevisiae the beta-1,4-linked N-acetylglucosamine polymer, chitin, is synthesized by a family of 3 specialized but interacting chitin synthases encoded by CHS1, CHS2 and CHS3. Chs2p makes chitin in the primary septum, while Chs3p makes chitin in the lateral cell wall and in the bud neck, and can partially compensate for the lack of Chs2p. Chs3p requires a pathway of Bni4p, Chs4p, Chs5p, Chs6p and Chs7p for its localization and activity. Chs1p is thought to have a septum repair function after cell separation. To further explore interactions in the chitin synthase family and to find processes buffering chitin synthesis, we compiled a genetic interaction network of genes showing synthetic interactions with CHS1, CHS3 and genes involved in Chs3p localization and function and made a phenotypic analysis of their mutants. Using deletion mutants in CHS1, CHS3, CHS4, CHS5, CHS6, CHS7 and BNI4 in a synthetic genetic array analysis we assembled a network of 316 interactions among 163 genes. The interaction network with CHS3, CHS4, CHS5, CHS6, CHS7 or BNI4 forms a dense neighborhood, with many genes functioning in cell wall assembly or polarized secretion. Chitin levels were altered in 54 of the mutants in individually deleted genes, indicating a functional relationship between them and chitin synthesis. 32 of these mutants triggered the chitin stress response, with elevated chitin levels and a dependence on CHS3. A large fraction of the CHS1-interaction set was distinct from that of the CHS3 network, indicating broad roles for Chs1p in buffering both Chs2p function and more global cell wall robustness. Based on their interaction patterns and chitin levels we group interacting mutants into functional categories. Genes interacting with CHS3 are involved in the amelioration of cell wall defects and in septum or bud neck chitin synthesis, and we newly assign a number of genes to these functions. Our genetic analysis of genes not interacting with CHS3 indicate expanded roles for Chs4p, Chs5p and Chs6p in secretory protein trafficking and of Bni4p in bud neck organization.


Skin Barrier Function Is Not Impaired and Kallikrein 7 Gene Polymorphism Is Frequently Observed in Korean X-linked Ichthyosis Patients Diagnosed by Fluorescence in Situ Hybridization and Array Comparative Genomic Hybridization.
X-linked ichthyosis (XLI) is a recessively inherited ichthyosis. Skin barrier function of XLI patients reported in Western countries presented minimally abnormal or normal. Here, we evaluated the skin barrier properties and a skin barrier-related gene mutation in 16 Korean XLI patients who were diagnosed by fluorescence in situ hybridization and array comparative genomic hybridization analysis. Skin barrier properties were measured, cytokine expression levels in the stratum corneum (SC) were evaluated with the tape stripped specimen from skin surface, and a genetic test was done on blood. XLI patients showed significantly lower SC hydration, but normal basal trans-epidermal water loss and skin surface pH as compared to a healthy control group. Histopathology of ichthyosis epidermis showed no acanthosis, and levels of the pro-inflammatory cytokines in the corneal layer did not differ between control and lesional/non-lesional skin of XLI patients. Among the mutations in filaggrin (FLG), kallikrein 7 (KLK7), and SPINK5 genes, the prevalence of KLK7 gene mutations was significantly higher in XLI patients (50%) than in controls (0%), whereas FLG and SPINK5 prevalence was comparable. Korean XLI patients exhibited unimpaired skin barrier function and frequent association with the KLK7 gene polymorphism, which may differentiate them from Western XLI patients.


Tobacco harm reduction: an alternative cessation strategy for inveterate smokers.
According to the Centers for Disease Control and Prevention, about 45 million Americans continue to smoke, even after one of the most intense public health campaigns in history, now over 40 years old. Each year some 438,000 smokers die from smoking-related diseases, including lung and other cancers, cardiovascular disorders and pulmonary diseases. Many smokers are unable--or at least unwilling--to achieve cessation through complete nicotine and tobacco abstinence; they continue smoking despite the very real and obvious adverse health consequences. Conventional smoking cessation policies and programs generally present smokers with two unpleasant alternatives: quit, or die. A third approach to smoking cessation, tobacco harm reduction, involves the use of alternative sources of nicotine, including modern smokeless tobacco products. A substantial body of research, much of it produced over the past decade, establishes the scientific and medical foundation for tobacco harm reduction using smokeless tobacco products. This report provides a description of traditional and modern smokeless tobacco products, and of the prevalence of their use in the United States and Sweden. It reviews the epidemiologic evidence for low health risks associated with smokeless use, both in absolute terms and in comparison to the much higher risks of smoking. The report also describes evidence that smokeless tobacco has served as an effective substitute for cigarettes among Swedish men, who consequently have among the lowest smoking-related mortality rates in the developed world. The report documents the fact that extensive misinformation about ST products is widely available from ostensibly reputable sources, including governmental health agencies and major health organizations. The American Council on Science and Health believes that strong support of tobacco harm reduction is fully consistent with its mission to promote sound science in regulation and in public policy, and to assist consumers in distinguishing real health threats from spurious health claims. As this report documents, there is a strong scientific and medical foundation for tobacco harm reduction, and it shows great potential as a public health strategy to help millions of smokers.


Oligodendroglioma occurring after radiation therapy for pituitary adenoma.
A 38 year old male dentist developed an oligodendroglioma of the left medial temporal lobe and parasellar region 12 years after radiotherapy with 6600 rads of acromegaly. The 30 cases of radiation-induced gliomas reported in the English literature are reviewed and analysed. The criteria for defining radiation-induced tumours of the central nervous system are proposed as follows: the tumour has a long quiescent "latency period", a location in the previously irradiated field, a verified histological difference from a primary condition, and does not arise from a primary condition associated with a genetic syndrome such as neurofibromatosis or tuberous sclerosis. The reported case fulfilled these criteria but appears to be the only reported radiation-induced oligodendroglioma.


An enzyme free electrochemical biosensor for sensitive detection of miRNA with a high discrimination factor by coupling the strand displacement reaction and catalytic hairpin assembly recycling.
An isothermal, enzyme free, ultra-specific and ultra-sensitive protocol for electrochemical detection of miRNAs is proposed based on the toehold-mediated strand displacement reaction (SDR) and non-enzymatic catalytic hairpin reaction (CHA) recycling. The SDR was first triggered only in the presence of target miRNA and this process also affects other miRNA interferences having similar target sequences, thus guaranteeing a high discrimination factor and could be used in rare content miRNA detection with various amounts of interferences having similar target sequences. The output protector strand then triggered enzyme free CHA amplification and generates plenty of hairpin self-assembly products. This process in turn influences SDR equilibrium to move to the right and generates large amounts of protector output to ensure analysis sensitivity. Compared with traditional CHA, our proposed method greatly improved the signal to noise ratio and shows excellent performance in rare miRNA detection with miRNA analogue interference. Under the optimal experimental conditions and using square wave voltammetry, the established biosensor could detect target miRNA-21 down to 30 fM (S/N = 3) with a dynamic range from 100 fM to 2 nM, and discriminate rare target miRNA-21 from mismatched miRNA with high selectivity. This method holds great promise in miRNA detection from human cancer cell lines and would be a versatile and powerful tool for clinical molecular diagnostics.


A Video Analysis of Intra- and Interprofessional Leadership Behaviors Within "The Burns Suite": Identifying Key Leadership Models.
Leadership is particularly important in complex highly interprofessional health care contexts involving a number of staff, some from the same specialty (intraprofessional), and others from different specialties (interprofessional). The authors recently published the concept of "The Burns Suite" (TBS) as a novel simulation tool to deliver interprofessional and teamwork training. It is unclear which leadership behaviors are the most important in an interprofessional burns resuscitation scenario, and whether they can be modeled on to current leadership theory. The purpose of this study was to perform a comprehensive video analysis of leadership behaviors within TBS. A total of 3 burns resuscitation simulations within TBS were recorded. The video analysis was grounded-theory inspired. Using predefined criteria, actions/interactions deemed as leadership behaviors were identified. Using an inductive iterative process, 8 main leadership behaviors were identified. Cohen's κ coefficient was used to measure inter-rater agreement and calculated as κ = 0.7 (substantial agreement). Each video was watched 4 times, focusing on 1 of the 4 team members per viewing (senior surgeon, senior nurse, trainee surgeon, and trainee nurse). The frequency and types of leadership behavior of each of the 4 team members were recorded. Statistical significance to assess any differences was assessed using analysis of variance, whereby a p < 0.05 was taken to be significant. Leadership behaviors were triangulated with verbal cues and actions from the videos. All 3 scenarios were successfully completed. The mean scenario length was 22 minutes. A total of 362 leadership behaviors were recorded from the 12 participants. The most evident leadership behaviors of all team members were adhering to guidelines (which effectively equates to following Advanced Trauma and Life Support/Emergency Management of Severe Burns resuscitation guidelines and hence "maintaining standards"), followed by making decisions. Although in terms of total frequency the senior surgeon engaged in more leadership behaviors compared with the entire team, statistically there was no significant difference between all 4 members within the 8 leadership categories. This analysis highlights that "distributed leadership" was predominant, whereby leadership was "distributed" or "shared" among team members. The leadership behaviors within TBS also seemed to fall in line with the "direction, alignment, and commitment" ontology. Effective leadership is essential for successful functioning of work teams and accomplishment of task goals. As the resuscitation of a patient with major burns is a dynamic event, team leaders require flexibility in their leadership behaviors to effectively adapt to changing situations. Understanding leadership behaviors of different team members within an authentic simulation can identify important behaviors required to optimize nontechnical skills in a major resuscitation. Furthermore, attempting to map these behaviors on to leadership models can help further our understanding of leadership theory. Collectively this can aid the development of refined simulation scenarios for team members, and can be extrapolated into other areas of simulation-based team training and interprofessional education.