Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene.
Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inherited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to chromosome 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same village. Results provide evidence for a codominant major gene, with.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males a 50% penetrance is reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remains <.02 after 20 years of exposure. Linkage analysis performed in four candidate regions shows that this major locus maps to chromosome 6q22-q23 and that it is closely linked (multipoint LOD score 3.12) to the IFN-gammaR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-gamma. These results show that infection levels and advanced hepatic fibrosis in human schistosomiasis are controlled by distinct loci; they suggest that polymorphisms within the IFN-gammaR1 gene could determine severe hepatic disease due to S. mansoni infection and that the IFN-gammaR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.


Effect of emergency department crowding on outcomes of admitted patients.
Emergency department (ED) crowding is a prevalent health delivery problem and may adversely affect the outcomes of patients requiring admission. We assess the association of ED crowding with subsequent outcomes in a general population of hospitalized patients. We performed a retrospective cohort analysis of patients admitted in 2007 through the EDs of nonfederal, acute care hospitals in California. The primary outcome was inpatient mortality. Secondary outcomes included hospital length of stay and costs. ED crowding was established by the proxy measure of ambulance diversion hours on the day of admission. To control for hospital-level confounders of ambulance diversion, we defined periods of high ED crowding as those days within the top quartile of diversion hours for a specific facility. Hierarchic regression models controlled for demographics, time variables, patient comorbidities, primary diagnosis, and hospital fixed effects. We used bootstrap sampling to estimate excess outcomes attributable to ED crowding. We studied 995,379 ED visits resulting in admission to 187 hospitals. Patients who were admitted on days with high ED crowding experienced 5% greater odds of inpatient death (95% confidence interval [CI] 2% to 8%), 0.8% longer hospital length of stay (95% CI 0.5% to 1%), and 1% increased costs per admission (95% CI 0.7% to 2%). Excess outcomes attributable to periods of high ED crowding included 300 inpatient deaths (95% CI 200 to 500 inpatient deaths), 6,200 hospital days (95% CI 2,800 to 8,900 hospital days), and $17 million (95% CI $11 to $23 million) in costs. Periods of high ED crowding were associated with increased inpatient mortality and modest increases in length of stay and costs for admitted patients.


Interaction of 6-phosphofructokinase with cytosolic proteins of Saccharomyces cerevisiae.
Hetero-octameric 6-phosphofructokinase (Pfk-1) from Saccharomyces cerevisiae is composed of two types of subunits, alpha and beta, which are encoded by the unlinked genes PFK1 and PFK2. Pfk single deletion mutants expressing only one type of subunit exhibit Pfk-1 activity in vivo which, however, is completely lost immediately after cell disruption. In order to elucidate the preconditions of the in vivo activity of the mutant enzymes composed of either alpha- or beta-subunits, we have investigated their potential interaction with selected heat shock and cytoskeletal proteins, employing co-immunoprecipitation and immunofluorescence microscopy. Western blot analysis identified the mitochondrial chaperonin Hsp60, as well as the cytoskeleton proteins alpha-tubulin and actin, in complexes with Pfk-1 that were co-precipitated from a cell-free extract of a pfk2 single deletion mutant expressing only the alpha-subunit. The interaction of the corresponding mutant enzyme and Hsp60 was found to depend on the ATP concentration of the extract. Immunofluorescence microscopy displayed a conspicuously filamentous arrangement of the Pfk-1 mutant protein, exclusively in the pfk2 single deletion mutant. The analysis of structure and activity of Pfk-1 expressed in S. cerevisiae mutant strains defective in various heat shock proteins (TRiC/CCT, Hsp70, Hsp 104) and in the respective wild-type background did not reveal significant differences.


Salmonella paratyphi A in hamsters concurrently infected with Schistosoma mansoni.
The present work deals with the development of an improved animal model to study the association of salmonellosis and schistosomiasis. The animal chosen was the hamster, Mesocricetus auratus, which can be readily infected with Schistosoma mansoni. Normal hamsters and schistosome-infected hamsters (SIH) were given approximately 2.0 x 10(7) Salmonella paratyphi A intracardially. It was found that S. mansoni infections enhanced and prolonged the growth of S. paratyphi A in hamsters. Animals with dual infections had increased mortality in comparison with those infected with just bacteria or parasite during the 50 days post-bacterial challenge. Further studies showed that in SIH, S. paratyphi A persisted in various organs for up to 8 weeks post infection. In contrast, concurrent Leishmania donovani infections have no effect on S. paratyphi A infections. Significant numbers of bacteria were cultured from well-washed schistosome worms recovered from SIH 6--8 weeks post-bacterial challenge. These findings suggest that a direct physical relationship between the bacteria and worms facilitates the establishment and growth of S. paratyphi A in vivo, and that a deficit in host immune response is not a major factor involved in the enhanced growth of S. paratyphi A.


Operational storm surge forecasting in the Netherlands: developments in the last decade.
The accurate forecasting of storm surges is an important issue in the Netherlands. With the emergence of the first numerical hydrodynamic models for surge forecasting at the beginning of the 1980s, new demands and possibilities were raised. This article describes the main phases of the development and the present operational set-up of the Dutch continental shelf model, which is the main hydrodynamic model for storm surges in the Netherlands. It includes a brief discussion of applied data-assimilation techniques, such as Kalman filtering, the model calibration process and some thoughts on quality assurance in an operational environment. After further describing some select recent investigations, the paper concludes with some remarks on future developments in a European context.


Community-Driven Data Analysis Training for Biology.
The primary problem with the explosion of biomedical datasets is not the data, not computational resources, and not the required storage space, but the general lack of trained and skilled researchers to manipulate and analyze these data. Eliminating this problem requires development of comprehensive educational resources. Here we present a community-driven framework that enables modern, interactive teaching of data analytics in life sciences and facilitates the development of training materials. The key feature of our system is that it is not a static but a continuously improved collection of tutorials. By coupling tutorials with a web-based analysis framework, biomedical researchers can learn by performing computation themselves through a web browser without the need to install software or search for example datasets. Our ultimate goal is to expand the breadth of training materials to include fundamental statistical and data science topics and to precipitate a complete re-engineering of undergraduate and graduate curricula in life sciences. This project is accessible at https://training.galaxyproject.org.


Enhancement of oxidative response and damage caused by human neutrophils to Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon.
Invasive aspergillosis is a serious fungal infection caused by the proliferation and invasion of Aspergillus hyphae in tissue. Neutrophils (PMNs) are the most important line of defense against Aspergillus hyphae. To investigate the role of granulocyte colony-stimulating factor (G-CSF) and gamma interferon (IFN-gamma) against Aspergillus fumigatus, we studied the effects of the two cytokines on the oxidative burst and the capacity of normal human PMNs to damage hyphae of the organism. G-CSF enhanced PMN oxidative burst measured as superoxide anion (O2-) production in response to N-formylmethionyl leucyl phenylalanine, serum opsonized hyphae, and nonopsonized hyphae by 75, 37, and 24%, respectively, compared with control PMNs (P < 0.015). IFN-gamma also induced increases of 52, 71, and 96%, respectively, in response to the same stimuli (P < 0.006). In addition, the capacity of PMNs to damage hyphae as measured by the 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) colorimetric metabolic assay was significantly enhanced by G-CSF and IFN-gamma (P < 0.01 and < 0.05, respectively). The enhancement was achieved irrespective of serum opsonization of the hyphae, suggesting upregulatory actions of the two cytokines on signal pathways specific for opsonized and nonopsonized hyphae. The combination of the two cytokines exhibited an additive effect at the higher concentrations compared with the effects of the cytokines alone (P < 0.05). Pretreatment of PMNs with protein synthesis inhibitors showed that IFN-gamma activates PMN function through transcriptional regulation, whereas the effect of G-CSF does not require new proteins. These in vitro effects suggest modulatory roles for G-CSF and IFN-gamma in the host defense against Aspergillus hyphae irrespective of serum opsonization and a potential utility of the cytokines as adjuncts for the prevention and possible treatment of invasive aspergillosis.


Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device.
Coronary computed tomography angiography (CCTA) is a first-line modality in the investigation of suspected coronary artery disease (CAD). Mapping of perivascular fat attenuation index (FAI) on routine CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which integrates standardized FAI mapping together with clinical risk factors and plaque metrics to provide individualized cardiovascular risk prediction. The study included 3912 consecutive patients undergoing CCTA as part of clinical care in the USA (n = 2040) and Europe (n = 1872). These cohorts were used to generate age-specific nomograms and percentile curves as reference maps for the standardized interpretation of FAI. The first output of CaRi-Heart® is the FAI-Score of each coronary artery, which provides a measure of coronary inflammation adjusted for technical, biological, and anatomical characteristics. FAI-Score is then incorporated into a risk prediction algorithm together with clinical risk factors and CCTA-derived coronary plaque metrics to generate the CaRi-Heart® Risk that predicts the likelihood of a fatal cardiac event at 8 years. CaRi-Heart® Risk was trained in the US population and its performance was validated externally in the European population. It improved risk discrimination over a clinical risk factor-based model [Δ(C-statistic) of 0.085, P = 0.01 in the US Cohort and 0.149, P < 0.001 in the European cohort] and had a consistent net clinical benefit on decision curve analysis above a baseline traditional risk factor-based model across the spectrum of cardiac risk. Mapping of perivascular FAI on CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which allows standardized measurement of coronary inflammation by calculating the FAI-Score of each coronary artery. The CaRi-Heart® device provides a reliable prediction of the patient's absolute risk for a fatal cardiac event by incorporating traditional cardiovascular risk factors along with comprehensive CCTA coronary plaque and perivascular adipose tissue phenotyping. This integration advances the prognostic utility of CCTA for individual patients and paves the way for its use as a dual diagnostic and prognostic tool among patients referred for CCTA.


Perceptions of anger and aggression in rural adolescent Australian males.
Problematic anger is often the outward manifestation and expression of deeper mental health issues in young men with strong links to depression, aggression, and suicide. Few studies have explored adolescent anger and aggression from the perspective of adolescent males and even fewer studies focus specifically on a rural context. This research aimed to understand the role of anger and aggression from the perspective of Australian rural adolescent males. Mental health nurses can build upon this knowledge to promote more adaptive ways of coping with anger therefore identifying specific interventions for the prevention of violence and promotion of mental health in this cohort. One hundred and eighty-seven rural adolescent males participated in focus groups that were conducted during their participation in the Rock and Water Program (RWP). Participants identified a number of factors they felt contributed to the aggression they both witnessed and experienced with eight themes emerging in response to the research questions. Four themes related to personological factors, that is racism, homophobia, family influences, and media influence. A further four themes related to situational factors, that is alcohol, territorialism, school context, and peer pressure. The study identified that racist and homophobic attitudes and beliefs were evident and clearly contributed to aggressive scripts as did family and media messages that normalized aggressive behaviour by way of endorsing stereotypical images of an aggressive masculinity. Situational factors such as alcohol use, territorialism, school context, and peer pressure were directly linked by participants to aggressive incidents embedded within their notions of masculinity.


Tailored communication methods as key to implementation of evidence-based solutions in primary child health care.
Evidence-based policies should underpin successful implementation of innovations within child health care. The EU-funded Models of Child Health Appraised project enabled research into effective methods to communicate research evidence. The objective of this study was to identify and categorize methods to communicate evidence-based research recommendations and means to tailor this to stakeholder audiences. We conducted an online survey among national stakeholders in child health. Analysis of the most effective strategies to communicate research evidence and reach the target audience was carried out in order to ensure implementation of optimal child health care models at a national level. Representatives of stakeholders from 21 of the then 30 EU MS and EEA countries responded to the questionnaire. Three main approaches in defining the strategies for effective communication of research recommendations were observed, namely: dissemination of information, involvement of stakeholders and active attitude towards change expressed in actions. The target audience for communicating recommendations was divided into two layers: proximal, which includes those who are remaining in close contact with the child, and distal, which contains those who are institutionally responsible for high quality of child health services. They should be recipients of evidence-based results communicated by different formats, such as scientific, administrative, popular and personal. Influential stakeholders impact the process of effective research dissemination and guide necessary actions to strengthen the process of effective communication of recommendations. Communication of evidence-based results should be targeted to each audience's profile, both professional and non-professionals, by adjusting appropriate communication formats.


Effects of volume-based overload plyometric training on maximal-intensity exercise adaptations in young basketball players.
The aim of the present study was to compare maximal-intensity exercise adaptations in young basketball players (who were strong individuals at baseline) participating in regular basketball training versus regular plus a volume-based plyometric training program in the pre-season period. Young basketball players were recruited and assigned either to a plyometric with regular basketball training group (experimental group [EG]; N.=8), or a basketball training only group (control group [CG]; N.=8). The athletes in EG performed periodized (i.e., from 117 to 183 jumps per session) plyometric training for eight weeks. Before and after the intervention, players were assessed in vertical and broad jump, change of direction, maximal strength and a 60-meter sprint test. No significant improvements were found in the CG, while the EG improved vertical jump (effect size [ES] 2.8), broad jump (ES=2.4), agility T test (ES=2.2), Illinois agility test (ES=1.4), maximal strength (ES=1.8), and 60-m sprint (ES=1.6) (P<0.05) after intervention, and the improvements were greater compared to the CG (P<0.05). Plyometric training in addition to regular basketball practice can lead to meaningful improvements in maximal-intensity exercise adaptations among young basketball players during the pre-season.


Stuttering: Clinical and research update.
To provide an update on the epidemiology, genetics, pathophysiology, diagnosis, and treatment of developmental stuttering. The MEDLINE and Cochrane databases were searched for past and recent studies on the epidemiology, genetics, pathophysiology, diagnosis, and treatment of developmental stuttering. Most recommendations are based on small studies, limited-quality evidence, or consensus. Stuttering is a speech disorder, common in persons of all ages, that affects normal fluency and time patterning of speech. Stuttering has been associated with differences in brain anatomy, functioning, and dopamine regulation thought to be due to genetic causes. Attention to making a correct diagnosis or referral in children is important because there is growing consensus that early intervention with speech therapy for children who stutter is critical. For adults, stuttering can be associated with substantial psychosocial morbidity including social anxiety and low quality of life. Pharmacologic treatment has received attention in recent years, but clinical evidence is limited. The mainstay of treatment for children and adults remains speech therapy. A growing body of research has attempted to uncover the pathophysiology of stuttering. Referral for speech therapy remains the best option for children and adults.


Modulation of dendritic cell differentiation and function by YopJ of Yersinia pestis.
Yersinia pestis evades immune responses in part by injecting into host immune cells several effector proteins called Yersinia outer proteins (Yops) that impair cellular function. This has been best characterized in the innate effector cells, but much less so for cells involved in adaptive immune responses. Dendritic cells (DC) sit at the crossroads between innate and adaptive immunity, and can function to initiate or inhibit adaptive immune responses. Although Y. pestis can target and inactivate DC, the mechanism responsible for this remains unclear. We have found that injection of Y. pestis YopJ into DC progenitors disrupts key signal transduction pathways and interferes with DC differentiation and subsequent function. YopJ injection prevents up-regulation of the NF-kappaB transcription factor Rel B and inhibits MAPK/ERK activation--both having key roles in DC differentiation. Furthermore, YopJ injection prevents costimulatory ligand up-regulation, LPS-induced cytokine expression, and yields differentiated DC with diminished capability to induce T cell proliferation and IFN-gamma induction. By modulating DC function through YopJ-mediated disruption of signaling pathways during progenitor to DC differentiation, Yersinia may interfere with the adaptive responses necessary to clear the infection as well as establish a tolerant immune environment that leads to chronic infection/carrier state in the surviving host.


Chronic central serous chorioretinopathy: long-term follow-up and vision-related quality of life.
To describe the clinical findings and long-term outcome of patients with chronic central serous chorioretinopathy (cCSC). This was a retrospective case series in 52 eyes of 36 patients with a follow-up period of at least 1 year. Extensive ophthalmic examination and a validated questionnaire concerning vision-related quality of life (National Eye Institute Visual Function Questionnaire [NEI-VFQ]-39) were analyzed. Mean visual acuity showed a significant decline over time of 0.16 logarithm of minimum angle of resolution ([logMAR] range: -0.22 to 1.3; P=0.009) after a mean follow-up period of 10.6 years. Also, patients reported lower vision-related quality of life based on the NEI-VFQ-39 for almost all categories compared to healthy controls. Macular atrophy was diagnosed more often on optical coherence tomography compared to other diagnostic entities. Retinal pigment epithelium detachments in the macula were documented on optical coherence tomography in 56% of the patients. A significant thinning of foveal thickness was measured over time compared to unaffected fellow eyes (P=0.002). On long-term follow-up, 13 eyes (37%) showed an increase in number of hot spots on fluorescein angiography. This study indicates that cCSC is a progressive disease in many patients, causing a progressive decline in visual acuity, accompanied by lower reported vision-related quality of life. In deciding whether or not to treat, the progressive nature of cCSC should be taken into account in this relatively young and often still professionally active patient group.


Drug-eluting versus bare-metal stent for treatment of saphenous vein grafts: a meta-analysis.
Saphenous vein grafts develop an aggressive atherosclerotic process and the efficacy of drug eluting stents (DES) in treating saphenous vein graft (SVG) lesions has not been convincingly demonstrated. The aim of this study was to review and analyze the current literature for controlled studies comparing DES versus bare metal stents (BMS) for treatment of SVG stenoses. We searched several scientific databases and conference proceedings up to March 15, 2010 for controlled studies comparing target vessel revascularization (TVR) between DES and BMS. Summary odds ratios (OR) for the primary endpoint TVR and secondary endpoints infarction, stent thrombosis and death were calculated using random-effect models. A total of 29 studies (3 randomized controlled trials RCT) involving 7549 (202 in RCT) patients were included. The need for target vessel revascularization in the DES group tended to be lower compared to BMS for the 3 RCT (OR 0.50 [0.24-1.00]; p = 0.051) and for observational studies (0.62 [0.49-0.79]; p<0.001). There was no significant difference in the risk for myocardial infarction in the RCT (OR 1.25 [0.22-6.99]; p = 0.250) but a lower risk for DES based on the observational studies 0.68 [0.49-0.95]; p = 0.023. The risk for stent thrombosis was found to be non-different in the RCT (OR 0.78 [0.03-21.73], p = 0.885) while it was in favor of DES in the observational studies (0.58 [0.38 - 0.84]; p<0.001). The mortality was not significantly different between DES and BMS in the RCT's (OR 2.22 [0.17 - 29.50]; p = 0.546) while the observation studies showed a decreased mortality in the DES group (0.69 [0.55-0.85]; p<0.001). DES may decrease TVR rate in treatment of SVG stenoses. No differences in reinfarction rate, stent thrombosis or mortality was found between the DES and BMS groups in the RCT's while the observational data showed lower risk for myocardial infarction, stent thrombosis and death in the DES group. This may be a result of patient selection bias in the observational studies or represent a true finding that was not the detected in the RCT analysis due to limited statistical power.


Investigation of the disparity between New York City and national prevalence of nonspecific psychological distress among Hispanics.
In New York City, the age-adjusted prevalence of nonspecific psychological distress (NPD) among Hispanics is twice that of non-Hispanic whites; nationally, there is little Hispanic-white disparity. We aimed to explain the pattern of disparity in New York City. Data came from the 2006 National Health Interview Survey and 2006 Community Health Survey in New York City. Respondents with scores higher than 12 on the K6, a brief scale used to screen for mental health disorders, were defined as having NPD. Multivariate analyses controlled for Hispanic ancestry, socioeconomic status (education, employment, and income), nativity, language of interview, and health characteristics. In New York City, the disparity between Hispanics and whites was fully explained after accounting for the disproportionate concentration of low socioeconomic status among Hispanics (odds ratio for NPD, 0.81; 95% confidence interval, 0.60-1.11). These factors also partially accounted for differences between Hispanics in New York City and the United States, but the prevalence of NPD overall in New York City remained elevated relative to the United States. Elevated NPD prevalence among New York City Hispanics was primarily attributable to large disparities in socioeconomic status; differences between New York City and the United States remained but were not specific to Hispanics. Interventions in New York City aimed at addressing racial/ethnic disparities in health may overlap with those addressing socioeconomic inequalities. Further study into the higher overall prevalence of NPD in New York City will be necessary to inform the design and targeting of interventions.


Melittin adsorption and lipid monolayer disruption at liquid-liquid interfaces.
Melittin, a membrane-active peptide with antimicrobial activity, was investigated at the interface formed between two immiscible electrolyte solutions (ITIES) supported on a metallic electrode. Ion-transfer voltammetry showed well-defined semi-reversible transfer peaks along with adsorptive peaks. The reversible adsorption of melittin at the liquid-liquid interface is qualitatively discussed from voltammetric data and experimentally confirmed by real-time image analysis of video snapshots. It is also demonstrated that polarization of the water/1,2-DCE interface results in drastic drop shape variations caused by large variations of the interfacial tension. The experimental data also confirmed that maximum adsorption occurs near the ion transfer potential. Finally, the interaction of melittin with a monolayer of L-α-dipalmitoyl phosphatidylcholine (DPPC) was also investigated showing that melittin destabilizes the lipidic monolayer facilitating its desorption. The non-covalent complex formation between melittin and DPPC was confirmed by mass spectrometry.


Reproducibility of fetal lung volume measurements with 3-dimensional ultrasonography.
To build a nomogram of normal fetal lung volumes and to assess the reproducibility of measurements using 3-dimensional ultrasonography. Inclusion criteria were healthy women, singleton normal pregnancies, reliable dating, and 20 to 30 weeks' gestation. Exclusion criteria were discordance between clinical and ultrasonographic dating, patients lost to follow-up, and birth weight disorders. Patients were scanned at intervals longer than 2 weeks. Three volumes were acquired for each patient; only data from the volume with the best image quality was used for analysis. Volumes were rated and measured by the manual tracing method. We recorded whether the clavicle was visualized. Only good-quality volumes were included in analysis. The best volume was chosen, and each lung was measured. A total of 75 patients were studied over a 9-month period, from which 182 volumes were analyzed. Of the 182 volumes, 15 (8.2%) were excluded for poor quality. The remaining 167 volumes were included in the final analysis. In 83 volumes (50%), the clavicle was not visualized. The best fit for total lung volume was a second-degree polynomial regression curve. Lung volume was 10.28 mL at 20 weeks and 51.49 mL at 30 weeks. Assessment of agreement was studied by selection of 40 volumes. Intraobserver variability was 5.48 mL (10.6%) and 3.07 mL (5.96%). Interobserver variability was 7 mL. Our findings suggest that 3-dimensional ultrasonographically derived measurements are reliable and reproducible up to 30 weeks if a standard measurement technique is used.


Presentation of endogenous peptide/MHC class I complexes is profoundly influenced by specific C-terminal flanking residues.
Processing of intracellular proteins yields 8-11 residue peptides that are displayed on the APC surface as peptide/MHC class I complexes. The remarkably precise excision of antigenic peptides from their precursor polypeptides raises the question of whether specific flanking residues influence presentation efficiency. Here we addressed this question by analyzing the generation of OVA/Kb or influenza nucleoprotein/Db complexes in APC expressing precursors with varying N- or C-terminal flanking residues. We find that T cell responses were not significantly affected by varying the N-terminal flanking residue in the precursors. In contrast, presentation of peptide/MHC complexes was inhibited with the addition of a single C-terminal flanking residue. The most dramatic inhibition was observed with isoleucine, leucine, cysteine, and proline as the C-terminal flanking residues. These residue-specific variations in presentation activity could not be accounted for by differences in the stimulatory activity of corresponding synthetic peptides but were proportional to the relative amounts of naturally processed peptides recovered in the cell extracts. These findings suggest differences in the susceptibility of N- vs C-terminal flanking residues to proteolytic cleavage during Ag processing. The strong influence of specific C-terminal flanking residue(s) could be an important factor affecting the choice of peptides presented to T cells on the APC surface.


Chirality-driven folding of short β-lactam pseudopeptides.
Novel enantiopure pseudopeptide models containing a central -(β-lactam)-(Aa)- scaffold characterized by the combined presence of an α-alkyl-α-amino-β-lactam (i+1) residue and a α-substituted (i + 2) amino acid have been readily synthesized from α-alkyl serines. The conformational analysis of such β-lactam pseudopeptides conducted in CDCl(3) and DMSO-d(6) solutions using 1D- and 2D-NMR techniques revealed an equilibrium between β-II turn and γ-turn conformers, which was ultimately modulated by the relative configuration of the -(β-lactam)-(Aa)- residues. Long-range chiral effects on the α-lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(β-lactam)-(Aib)- segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a β-II turn conformer, whereas homochiral corner residues stabilized an overlapped β-II/ β-I double turn motif. No β-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, β-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(β-lactam)-(i + 2)- segment was proposed to account for the observed chiral effects.


What you saw is what you will hear: Two new illusions with audiovisual postdictive effects.
Neuroscience investigations are most often focused on the prediction of future perception or decisions based on prior brain states or stimulus presentations. However, the brain can also process information retroactively, such that later stimuli impact conscious percepts of the stimuli that have already occurred (called "postdiction"). Postdictive effects have thus far been mostly unimodal (such as apparent motion), and the models for postdiction have accordingly been limited to early sensory regions of one modality. We have discovered two related multimodal illusions in which audition instigates postdictive changes in visual perception. In the first illusion (called the "Illusory Audiovisual Rabbit"), the location of an illusory flash is influenced by an auditory beep-flash pair that follows the perceived illusory flash. In the second illusion (called the "Invisible Audiovisual Rabbit"), a beep-flash pair following a real flash suppresses the perception of the earlier flash. Thus, we showed experimentally that these two effects are influenced significantly by postdiction. The audiovisual rabbit illusions indicate that postdiction can bridge the senses, uncovering a relatively-neglected yet critical type of neural processing underlying perceptual awareness. Furthermore, these two new illusions broaden the Double Flash Illusion, in which a single real flash is doubled by two sounds. Whereas the double flash indicated that audition can create an illusory flash, these rabbit illusions expand audition's influence on vision to the suppression of a real flash and the relocation of an illusory flash. These new additions to auditory-visual interactions indicate a spatio-temporally fine-tuned coupling of the senses to generate perception.


Surface modifications for antimicrobial effects in the healthcare setting: a critical overview.
The spread of infections in healthcare environments is a persistent and growing problem in most countries, aggravated by the development of microbial resistance to antibiotics and disinfectants. In addition to indwelling medical devices (e.g. implants, catheters), such infections may also result from adhesion of microbes either to external solid-water interfaces such as shower caps, taps, drains, etc., or to external solid-gas interfaces such as door handles, clothes, curtains, computer keyboards, etc. The latter are the main focus of the present work, where an overview of antimicrobial coatings for such applications is presented. This review addresses well-established and novel methodologies, including chemical and physical functional modification of surfaces to reduce microbial contamination, as well as the potential risks associated with the implementation of such anticontamination measures. Different chemistry-based approaches are discussed, for instance anti-adhesive surfaces (e.g. superhydrophobic, zwitterions), contact-killing surfaces (e.g. polymer brushes, phages), and biocide-releasing surfaces (e.g. triggered release, quorum sensing-based systems). The review also assesses the impact of topographical modifications at distinct dimensions (micrometre and nanometre orders of magnitude) and the importance of applying safe-by-design criteria (e.g. toxicity, contribution for unwanted acquisition of antimicrobial resistance, long-term stability) when developing and implementing antimicrobial surfaces.


microRNA-494 Favors HO-1 Expression in Neuroblastoma Cells Exposed to Oxidative Stress in a Bach1-Independent Way.
Heme oxygenase 1 (HO-1) is crucially involved in cell adaptation to oxidative stress and has been demonstrated to play an important role in cancer progression and resistance to therapies. We recently highlighted that undifferentiated neuroblastoma (NB) cells are prone to counteract oxidative stress through the induction of HO-1. Conversely, differentiated NB cells were more sensitive to oxidative stress since HO-1 was scarcely upregulated. In this work, we investigated the role played by miR-494, which has been proved to be involved in cancer biology and in the modulation of oxidative stress, in the upregulation of HO-1. We showed that NB differentiation downregulates miR-494 level. In addition, endogenous miR-494 inhibition in undifferentiated cells impairs HO-1 induction in response to exposure to 500 µM H2O2, reducing the number of viable cells. The analysis of Bach1 expression did not reveal any significant modifications in any experimental conditions tested, proving that the impairment of HO-1 induction observed in cells treated with miR-494 inhibitor and exposed to H2O2 is independent from Bach1. Our results underline the role played by miR-494 in favoring HO-1 induction and cell adaptation to oxidative stress and contribute to the discovery of new potential pharmacological targets to improve anticancer therapies.


Streptococcal M1 protein constructs a pathological host fibrinogen network.
M1 protein, a major virulence factor of the leading invasive strain of group A Streptococcus, is sufficient to induce toxic-shock-like vascular leakage and tissue injury. These events are triggered by the formation of a complex between M1 and fibrinogen that, unlike M1 or fibrinogen alone, leads to neutrophil activation. Here we provide a structural explanation for the pathological properties of the complex formed between streptococcal M1 and human fibrinogen. A conformationally dynamic coiled-coil dimer of M1 was found to organize four fibrinogen molecules into a specific cross-like pattern. This pattern supported the construction of a supramolecular network that was required for neutrophil activation but was distinct from a fibrin clot. Disruption of this network into other supramolecular assemblies was not tolerated. These results have bearing on the pathophysiology of streptococcal toxic shock.


Rational design of 5'-thiourea-substituted alpha-thymidine analogues as thymidine monophosphate kinase inhibitors capable of inhibiting mycobacterial growth.
Recently, thymidine monophosphate kinase (TMPK) emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. The elucidation of the X-ray structure of TMPK of M. tuberculosis (TMPKmt), as well as the structure of an earlier serendipitously discovered dimeric thymidine inhibitor, laid the foundation for the design of potent and selective TMPKmt inhibitors reported here. Several hits identified within a series of 3'-C-branched thiourea-substituted beta-thymidine derivatives inspired us to construct a set of 5'-thiourea-substituted alpha-thymidine derivatives characterized by a similar relative orientation of the thymine and arylthiourea moieties. alpha-Thymidine derivative 15, featuring a (3-trifluoromethyl-4-chlorophenyl)thiourea moiety, has a Ki of 0.6 microM and a selectivity index of 600 versus human TMPK. Moreover, it represents the first TMPK inhibitor showing good inhibitory activity on growing M. bovis (MIC99 = 20 microg/mL) and M. tuberculosis (MIC50 = 6.25 microg/mL) strains.


Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity.
Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging. In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (Ki = 0.84 ± 0.03 nM). A fluorine atom introduced in the para-position of phenylalanine enhanced the binding affinity as much as 10-fold. Furthermore, we improved the proteolytic stability by substituting the N-terminal arginine by norarginine. The resulting inhibitor combines high inhibitory affinity and selectivity with a good stability in plasma (Ki = 1.63 ± 0.18 nM, >27 000-fold selectivity, t1/2(plasma) =16 ± 4 h). The inhibitor efficiently blocked activation of the intrinsic coagulation pathway in human blood ex vivo.


Synthesis of 2-aminoBODIPYs by palladium catalysed amination.
Palladium catalysed coupling of the 2-iodoBODIPY 3 with a range of anilines and a primary alkylamine succeeds in generating the corresponding 2-aminoBODIPYs. These 2-aminoBODIPY derivatives are non-emissive and quantum chemical calculations and electrochemistry are consistent with charge transfer from the amine substituent. Attenuation of this charge transfer pathway by conversion of the 1,2-phenylenediamine derivative 9 into the corresponding benzimidazolone 10 restores the fluorescence and has been used as the basis for a fluorescence sensor for phosgene.


High-throughput peptide identification from protein digests using data-dependent multiplexed tandem FTICR mass spectrometry coupled with capillary liquid chromatography.
Tandem mass spectrometry (MS/MS) plays an important role in the unambiguous identification and structural elucidation of biomolecules. In contrast to conventional MS/MS approaches for protein identification where an individual polypeptide is sequentially selected and dissociated, a multiplexed-MS/MS approach increases throughput by selecting several peptides for simultaneous dissociation using either infrared multiphoton dissociation (IRMPD) or multiple frequency sustained off-resonance irradiation (SORI) collisionally induced dissociation (CID). The high mass measurement accuracy and resolution of FTICR combined with knowledge of peptide dissociation pathways allows the fragments arising from several different parent ions to be assigned. Herein we report the application of multiplexed-MS/MS coupled with on-line separations for the identification of peptides present in complex mixtures (i.e., whole cell lysate digests). Software was developed to enable "on-the-fly" data-dependent peak selection of a subset of polypeptides from each FTICR MS acquisition. In the subsequent MS/MS acquisitions, several coeluting peptides were fragmented simultaneously using either IRMPD or SORI-CID techniques. The utility of this approach has been demonstrated using a bovine serum albumin tryptic digest separated by capillary LC where multiple peptides were readily identified in single MS/MS acquisitions. We also present initial results from multiplexed-MS/MS analysis of a D. radiodurans whole cell digest to illustrate the utility of this approach for high-throughput analysis of a bacterial proteome.


Peptide-Dendron Hybrids that Adopt Sequence-Encoded β-Sheet Conformations.
Rational design rules for programming hierarchical organization and function through mutations of monomers in sequence-defined polymers can accelerate the development of novel polymeric and supramolecular materials. Our strategy for designing peptide-dendron hybrids that adopt predictable secondary and quaternary structures in bulk is based on patterning the sites at which dendrons are conjugated to short peptides. To validate this approach, we have designed and characterized a series of β-sheet-forming peptide-dendron hybrids. Spectroscopic studies of the hybrids in films reveal that the peptide portion of the hybrids adopts the intended secondary structure.


Storage and access procedures in schizophrenia: evidence for a two phase model of lexical impairment.
Evidence has accumulated to show that schizophrenia is characterized by lexical-semantic difficulties; however, questions remain about whether schizophrenics have problems in accessing intact representations or a loss of the representations themselves. Both access and storage types of disorder have been reported and it has been speculated that this may reflect a transition from the former to latter with increasing length of illness. This study investigated whether illness duration, age or estimated premorbid IQ predict the size and accessibility of the lexical store. Fifty-six schizophrenic patients (chosen to represent a wide range of illness duration from 3-40 years) and 24 matched healthy controls were asked to name 120 pictures on two occasions. Estimates of store size and retrieval probability were derived from a two parameter stochastic Markov chain model. This revealed that even early in the course of illness, schizophrenics appear to have suffered a reduction in lexical store size and that those with longer length of illness show deficits in both their store size and their ability to retrieve names from that store.


Jumping nanodroplets.
Flat gold nanostructures on inert substrates like glass or graphite were illuminated by single intensive laser pulses with fluences above the gold melting threshold. The liquid structures produced in this way are far from their equilibrium shape, and a dewetting process sets in. On a time scale of a few nanoseconds, the liquid contracted toward a sphere. During this contraction, the center of mass moved upward, which could lead to detachment of droplets from the surface due to inertia. The resulting velocities were on the order of 10 meters per second for droplets with radii in the range of 100 nanometers.


Emergency Department visits due to intoxications in a Dutch university hospital: Occurrence, characteristics and health care costs.
Intoxications with alcohol and drugs are common in the Emergency Department. This study aimed to describe the occurrence and characteristics of intoxications (alcohol, Drugs of Abuse (DOA), pharmaceutical and chemical) presented to the Emergency Department and the health care costs of these intoxications. This was a retrospective medical record study of all patients (≥ 16 years) who presented to the Emergency Department of an inner-city academic hospital in the Netherlands due to single or multiple intoxication(s) as the primary or secondary reason in the year 2016. An intoxication was reported as present if the attending physician described the intoxication in the patient's medical record. A total of 783 patients were included, accounting for 3.2% of the adult Emergency Department population (age ≥ 16 year). In 30% more than one substance was used. Intoxications with alcohol, Drugs of Abuse and pharmaceuticals was reported in respectively 62%, 29% and 21% of the intoxicated patients. The mean costs per patient presenting with an intoxication to the Emergency Department was € 1,490. The mean costs per patient were highest for pharmaceutical intoxications (€ 2,980), followed by Drugs of Abuse (€ 1,140) and alcohol (€ 1,070). Intoxications among patients aged 16 years and older are frequently seen at the Emergency Department and are frequently caused by multiple substances. Alcohol is the most common intoxication. Substantial healthcare costs are involved. Therefore, this study suggests that further research into hazardous alcohol consumption and DOA abuse is warranted.


Confirmatory factor analysis of the motor unified Parkinson's disease rating scale.
The motor examination section of the unified Parkinson's disease rating scale (UPDRS) is widely used in research but few studies have examined whether subscales exist that tap relatively distinct motor abnormalities. We analyzed data from 193 persons enrolled in a population-based study in Central California. Patients were examined after overnight PD medication washout ("OFF" state) and approximately one hour after taking medication ("ON" state). We performed confirmatory factor analysis of the UPDRS for OFF and ON state examinations; correlations, reliability, and relative validity of resulting subscales were evaluated. A model with five factors (gait/posture, tremor, rigidity, bradykinesia affecting the left extremities, bradykinesia affecting the right extremities) fit the data well, with similar results for OFF and ON states. Internal consistency reliability coefficients were 0.90 or higher for all subscales. The gait/posture subscale most strongly discriminated across levels of patient reported PD symptom severity and of how PD affects them on a daily basis. Compared to the right sided bradykinesia subscale, the left sided bradykinesia subscale had higher discrimination across levels of self-reported PD symptom severity and functional impairment. This supports motor UPDRS containing multiple subscales that can be analyzed separately and provide information distinct from the total score that may be useful in clinical studies.


Study protocol of the YOU CALL--WE CALL TRIAL: impact of a multimodal support intervention after a "mild" stroke.
More than 60% of new strokes each year are "mild" in severity and this proportion is expected to rise in the years to come. Within our current health care system those with "mild" stroke are typically discharged home within days, without further referral to health or rehabilitation services other than advice to see their family physician. Those with mild stroke often have limited access to support from health professionals with stroke-specific knowledge who would typically provide critical information on topics such as secondary stroke prevention, community reintegration, medication counselling and problem solving with regard to specific concerns that arise. Isolation and lack of knowledge may lead to a worsening of health problems including stroke recurrence and unnecessary and costly health care utilization.The purpose of this study is to assess the effectiveness, for individuals who experience a first "mild" stroke, of a sustainable, low cost, multimodal support intervention (comprising information, education and telephone support)--"WE CALL" compared to a passive intervention (providing the name and phone number of a resource person available if they feel the need to)--"YOU CALL", on two primary outcomes: unplanned-use of health services for negative events and quality of life. We will recruit 384 adults who meet inclusion criteria for a first mild stroke across six Canadian sites. Baseline measures will be taken within the first month after stroke onset. Participants will be stratified according to comorbidity level and randomised to one of two groups: YOU CALL or WE CALL. Both interventions will be offered over a six months period. Primary outcomes include unplanned use of heath services for negative event (frequency calendar) and quality of life (EQ-5D and Quality of Life Index). Secondary outcomes include participation level (LIFE-H), depression (Beck Depression Inventory II) and use of health services for health promotion or prevention (frequency calendar). Blind assessors will gather data at mid-intervention, end of intervention and one year follow up. If effective, this multimodal intervention could be delivered in both urban and rural environments. For example, existing infrastructure such as regional stroke centers and existing secondary stroke prevention clinics, make this intervention, if effective, deliverable and sustainable. ISRCTN95662526.


A Latent Class Approach for Classifying the Problem and Disordered Gamers in a Group of Adolescence.
Gaming disorder is not yet recognized as a formal psychiatric disorder, and consensus is still lacking in the field concerning the definition of gaming disorder and what methods should be used to measure it. In order to deal with methodological challenges related to previously suggested approaches, the aim of the present study was to develop an alternative assessment procedure for gaming disorder using a latent class cluster approach, and to compare the criterion validity of this procedure with existing assessment procedures. A representative sample of 3,000 adolescents (n = 1,500 female) aged 17.5 years was drawn from the National Registry, and 2,055 participants responded (yielding a response rate of 70.3%). The Gaming Addiction Scale for Adolescents was used to measure gaming disorder and measures of loneliness, anxiety, depression, and aggression were used to test criterion validity. A model with five Latent Class Clusters represented the best fit [BIC(LL) = 21,253,7; L2 = 3,881,204; df = 1,978; Class. Err. = 0.1239]. The five different groups were labeled never symptoms (46.2%), rarely symptoms (22.3%), occasionally symptoms (23.5%), problem gamers (6.9%), and disordered gamers (1.2%). The groups displayed different probabilities of responses (never/rarely/sometimes/often/very often) to the seven Gaming Addiction Scale items. Regarding criterion validity, MANOVA revealed a significant overall main effect of latent classes [F (20, 6359) = 13.50, p < 0.001; Wilks Lambda = 0.871]. All dependent variables (loneliness, depression, anxiety, verbal, and physical aggression) reached statistical significance when results from the dependent variables were considered separately. Comparing the present approach with previous suggested classifications of gaming addiction offered by Lemmens et al. and Charlton and Danforth, the present approach showed greater specificity in terms of number of classes identified. We conclude that the Latent Class approach identifying five different groups of gamers offers a more refined view on addiction compared to previous assessment procedures.


Deep inspiration and the emergence of ventilation defects during bronchoconstriction: a computational study.
Deep inspirations (DIs) have a dilatory effect on airway smooth muscle (ASM) that helps to prevent or reduce more severe bronchoconstriction in healthy individuals. However, this bronchodilation appears to fail in some asthmatic patients or under certain conditions, and the reason is unclear. Additionally, quantitative effects of the frequency and magnitude of DIs on bronchodilation are not well understood. In the present study, we used a computational model of bronchoconstriction to study the effects of DI volumes, time intervals between intermittent DIs, relative speed of ASM constriction, and ASM activation on bronchoconstriction and the emergence of ventilation defects (VDefs). Our results showed a synergistic effect between the volume of DIs and the time intervals between them on bronchoconstriction and VDefs. There was a domain of conditions with sufficiently large volumes of DIs and short time intervals between them to prevent VDefs. Among conditions without VDefs, larger volumes of DIs resulted in greater airway dilation. Similarly, the time interval between DIs, during which the activated ASM re-constricts, affected the amplitude of periodic changes in airway radii. Both the relative speed of ASM constriction and ASM activation affected what volume of DIs and what time interval between them could prevent the emergence of VDefs. In conclusion, quantitative characteristics of DIs, such as their volume and time interval between them, affect bronchoconstriction and may contribute to difficulties in asthma. Better understanding of the quantitative aspects of DIs may result in novel or improved therapeutic approaches.


Unintentional injury in England: an analysis of the emergency care data set pilot in Oxfordshire from 2012 to 2014.
A pilot injury data collection exercise at the emergency departments (EDs) of Oxford University Hospitals National Health Service (NHS) Foundation Trust (OUH) ran from 2012 to 2014 to inform the current development of the new NHS England emergency care data set. Data collected at the EDs of OUH 1 January 2012 to 30 March 2014 analysed for Oxford City and Cherwell District Council areas. Data completeness and quality checked against Hospital Episode Statistic (HES) returns. Of the 63 877 injury attendances recorded at the 2 sites, 26 536 were unintentional with a home postcode within Oxford City or Cherwell District Council areas. The most frequent location, mechanism, activity and diagnosis were home (39.1% of all unintentional injuries (UIs)), low-level falls (47.1%), leisure (31.1%) and 'injuries to unspecified part of trunk, limb or body region' (20.5%), respectively. The most deprived quintile of the population (Index of Multiple Deprivation (IMD) 1) had the highest European Age Standardised Rate (EASR) for all UIs and IMD 5 had the lowest, 54.4 (95% CI 52.3 to 56.5) and 32.2 (31.4 to 33.0) per 1000 person-years, respectively. There was a significant association between increasing levels of deprivation and an increasing incidence rate ratio (IRR) for all UIs, for those in the home, for low-level fall UIs and for non-sport leisure UIs with a particularly sharp increase in the IRR for IMD 1 compared with IMD 5. Sport-related injuries were inversely related to deprivation apart from football. This pilot has demonstrated both the feasibility and importance of prioritising the collection of a national injury data set.


The micro-optical ring electrode. 3: Transient photocurrent studies of photophysical-electrochemical and photophysical-chemical-electrochemical systems.
The micro-optical ring electrode (MORE) is a photoelectrochemical device based on a ring microelectrode that uses the insulating material interior to the ring electrode as a light guide. In this paper, we describe the preparation and characterization of very thin ring MOREs with (ring inner radius)/(ring outer radius) > 0.99. Theoretically, we derive asymptotic analytical expressions for the time dependence of the diffusion-limited transient light-on photocurrent generated by two general types of photoelectrochemical systems: (a) the PE (photophysical-electrochemical) system, wherein the photoexcited species itself is directly detected on the ring; (b) the PCE (photophysical-chemical-electrochemical) system, wherein the photoexcited species undergoes a homogeneous electron transfer reaction prior to electrochemical detection. Experimentally, we establish that it is possible to use such MOREs to study the wavelength dependence of photocurrents derived from photoelectrochemically active systems, such as the Ru(bipy)3 2+/Fe3+ PCE system, demonstrating the potential utility of the MORE as a selective electroanalytical probe. We also use our expressions for the time dependence of photocurrents at the MORE to derive values for the photoelectrochemical kinetic parameters of this system, including the rate coefficient for the back reaction of photogenerated Ru(bipy)3 3+ (0.115 s(-1)) and the quantum efficiency for the primary redox products, Ru(bipy)3 3+ and Fe2+, escaping cage recombination, phi(CE) = 0.099.


Survival at nine neonatal intensive care units in São Paulo, Brazil. Paulista Collaborative Group on Neonatal Care.
A collaborative effort to assess factors affecting newborn survival at neonatal intensive care units (NICUs) was made by studying 1948 newborns admitted to nine NICUs in the city of São Paulo between 1 June and 30 November 1991. Data on the study subjects were obtained using a standardized form. This was the first activity undertaken by a network of neonatologists (the Paulista Collaborative Group on Neonatal Care) dedicated to jointly evaluating and improving neonatal care in that city. The study results showed an overall mortality of 59 deaths per 1,000 neonates, with survival improving as gestational age and birthweight rose. Other variables significantly affecting survival were a poor maternal obstetric history (a previous stillbirth or neonatal death, or two or more spontaneous abortions); birth asphyxia (Apgar at 5 minutes < 7); respiratory distress syndrome; severe infections; and major malformations. However, multiple logistic regression analysis showed that the rates of neonatal survival in the nine NICUs differed even when these factors were considered. Potential sources of this variability included undetermined population differences in neonatal disease severity and medical care. These results suggest a need for greater efforts to identify and reduce risk factors associated with neonatal mortality, and to adequately evaluate the medical care provided in NICUs. Within this context, the collaborative network of neonatologists established in São Paulo provides a sound organizational structure for evaluating and improving the effectiveness of neonatal care.


Prognostic value of systemic inflammatory response syndrome and serum concentrations of acute phase proteins, cholesterol, and total thyroxine in cats with panleukopenia.
Feline parvovirus (FPV) is a common and potentially lethal infectious agent in cats. To assess the prognostic value of age, neuter status, serum concentrations of serum amyloid A (SAA), haptoglobin, cholesterol and total thyroxine (tT4), and the presence of systemic inflammatory response syndrome (SIRS) in cats with panleukopenia. Client-owned cats with FPV infection diagnosed by a positive fecal ELISA test, positive PCR on feces or blood or both. Retrospective cohort study. The electronic medical database was searched for cats with FPV infection presented between January 2010 and January 2018. Cats were divided into survivors and nonsurvivors according to their survival status 28 days after hospital admission. The prognostic importance of each variable was investigated univariately and by multivariable Cox's proportional-hazards regression. Finally, receiver operator characteristic (ROC) curve analysis was used to identify the best cutoff value for discriminating survivors from nonsurvivors for the statistically significant prognostic predictors identified by multivariable analysis. Seventy cats were enrolled in the study. Multivariable analysis determined that only serum tT4 concentration at hospital admission was significantly (P = .01) associated with survival. A cutoff value of 0.82 μg/dL was identified by ROC curve analysis for serum tT4 concentration in discriminating survivors from nonsurvivors. Sensitivity at this cutoff was 73.9% and specificity was 82.9% (area under the curve, 0.783; 95% confidence interval, 0.668-0.873; P < .0001). Serum tT4 concentration at hospital admission has prognostic value in cats with FPV infection.


Impact of processing on the bioavailability and vascular effects of blueberry (poly)phenols.
Blueberries are a rich source of flavonoids and phenolic acids. Currently, little information is available regarding the impact of processing on the bioavailability and the bioactivity of blueberry (poly)phenols. In a randomized, controlled crossover trial, ten healthy volunteers consumed (a) blueberry-containing baked products, (b) an unprocessed blueberry drink containing the same amount of freeze-dried blueberry powder as used in the baked products, and (c) matched control baked products. Endothelial function was measured as flow-mediated dilation (FMD) and plasma samples taken at baseline and at 1, 2, 4, and 6 h postconsumption. Although processing did not significantly change the total (poly)phenolic amount, the processed products contained significantly less anthocyanins (-42%), more chlorogenic acid (23%), no flavanol nonamers or decamers, and significantly more flavanol dimers and trimers (36% and 28%, respectively). FMD increased after 1, 2, and 6 h consumption of the baked products to a similar degree as the unprocessed blueberries, despite significant differences in the levels of individual plasma metabolites. No changes were observed after the consumption of the control product. Careful processing can preserve important biological activities of blueberries despite changing the blueberry (poly)phenol composition and plasma metabolite profile.


Phosphocreatine interacts with phospholipids, affects membrane properties and exerts membrane-protective effects.
A broad spectrum of beneficial effects has been ascribed to creatine (Cr), phosphocreatine (PCr) and their cyclic analogues cyclo-(cCr) and phospho-cyclocreatine (PcCr). Cr is widely used as nutritional supplement in sports and increasingly also as adjuvant treatment for pathologies such as myopathies and a plethora of neurodegenerative diseases. Additionally, Cr and its cyclic analogues have been proposed for anti-cancer treatment. The mechanisms involved in these pleiotropic effects are still controversial and far from being understood. The reversible conversion of Cr and ATP into PCr and ADP by creatine kinase, generating highly diffusible PCr energy reserves, is certainly an important element. However, some protective effects of Cr and analogues cannot be satisfactorily explained solely by effects on the cellular energy state. Here we used mainly liposome model systems to provide evidence for interaction of PCr and PcCr with different zwitterionic phospholipids by applying four independent, complementary biochemical and biophysical assays: (i) chemical binding assay, (ii) surface plasmon resonance spectroscopy (SPR), (iii) solid-state (31)P-NMR, and (iv) differential scanning calorimetry (DSC). SPR revealed low affinity PCr/phospholipid interaction that additionally induced changes in liposome shape as indicated by NMR and SPR. Additionally, DSC revealed evidence for membrane packing effects by PCr, as seen by altered lipid phase transition. Finally, PCr efficiently protected against membrane permeabilization in two different model systems: liposome-permeabilization by the membrane-active peptide melittin, and erythrocyte hemolysis by the oxidative drug doxorubicin, hypoosmotic stress or the mild detergent saponin. These findings suggest a new molecular basis for non-energy related functions of PCr and its cyclic analogue. PCr/phospholipid interaction and alteration of membrane structure may not only protect cellular membranes against various insults, but could have more general implications for many physiological membrane-related functions that are relevant for health and disease.


Pupil dilation reveals top-down attentional load during spatial monitoring.
It has long been known that the diameter of human pupil enlarges with increasing effort during the execution of a task. This has been observed not only for purely mechanical effort but also for mental effort, as for example the computation of arithmetic problems with different levels of difficulty. Here we show that pupil dilation reflects changes in visuospatial awareness induced by attentional load during multi-tasking. In the single-task condition, participants had to report the position of lateralized, briefly presented, masked visual targets ("right", "left", or "both" sides). In the multitasking conditions, participants also performed additional tasks, either visual or auditory, to increase the attentional load. Sensory stimulation was kept constant across all conditions to rule out the influence of low-level factors. Results show that event-related pupil dilation strikingly increased with task demands, mirroring a concurrent decrease in visuospatial awareness. Importantly, pupil dilation significantly differed between two dual-task conditions that required to process the same number of stimuli but yielded differed levels of accuracy (difficulty). In contrast, pupil dilation did not differ between two conditions which were equally challenging but differed both in the modality of the dual task (auditory vs. visual) and in the number of stimuli to be attended. We conclude that pupil dilation genuinely reflects the top-down allocation of supramodal attentional resources.


Mononucleotide repeats are an abundant source of length variants in mouse genomic DNA.
Microsatellite sequences, such as dinucleotide repeats, show a high degree of polymorphism in eukaryotic DNA. These sequences are convenient as genetic markers and can be analyzed by the polymerase chain reaction (PCR). We have assessed the frequency of length variants in 18 mononucleotide repeats in mouse DNA and find that the variability is similar to that reported for dinucleotide repeats. Nine of the 18 repeat sequences (50%) have three or more alleles in the strains tested. Ten of these repeat sequences have been mapped using strain distribution patterns (SDPs) in recombinant inbred (RI) strains.


Digital image analysis of rhodanine-stained liver biopsy specimens for calculation of hepatic copper concentrations in dogs.
To evaluate the accuracy of digitally scanned rhodanine-stained liver biopsy specimens for determination of hepatic copper concentration and compare results with qualitatively assigned histologic copper scores in dogs. 353 liver biopsy specimens from dogs. Specimens (n = 139) with quantified copper concentration ranging from 93 to 6,900 μg/g were allocated to group 1 (< 400 μg/g [37]), group 2 (401 to 1,000 μg/g [27]), group 3 (1,001 to 2,000 μg/g [34]), and group 4 (> 2,001 μg/g [41]); stained with rhodanine; and digitally scanned and analyzed with a proprietary positive pixel algorithm. Measured versus calculated copper concentrations were compared, and limits of agreement determined. Influence of nodular remodeling, fibrosis, or parenchymal loss on copper concentration was determined by digitally analyzing selected regions in 17 specimens. After method validation, 214 additional liver specimens underwent digital scanning for copper concentration determination. All sections (n = 353) were then independently scored by 2 naive evaluators with a qualitative scoring schema. Agreement between assigned scores and between assigned scores and tissue copper concentrations was determined. Linear regression was used to develop a formula for calculating hepatic copper concentration ≥ 400 μg/g from scanned sections. Copper concentrations in unremodeled specimens were significantly higher than in remodeled specimens. Qualitative scores widely overlapped among quantitative copper concentration groups. Calculated copper concentrations determined by means of digital scanning of rhodanine-stained liver sections were highly correlated with measured values and more accurate than qualitative copper scores, which should improve diagnostic usefulness of hepatic copper concentrations and assessments in sequential biopsy specimens.


Self and parent-reported sleep problems of adolescents with childhood conduct problems and comorbid psychological problems.
Childhood conduct problems (CP) are characterized by maladaptive externalizing behaviors and are linked with poor sleep. CP are highly comorbid with other psychological problems, including attention deficit/hyperactivity disorder and depression, which are also associated with disturbed sleep. The present study examined if childhood CP and comorbid depressive and/or attentional-hyperactivity problems were prospectively associated with parent and self-reported sleep difficulties in adolescence. Participants (N = 744; 53% boys) from an ongoing longitudinal study in Québec, Canada were assessed for CP and comorbidities when they were between 6 and 9 years old. Participants were classified as without CP, CP only, CP and depressive symptoms, CP and attention-hyperactivity problems, or CP, depressive symptoms, and attention-hyperactivity problems. Regressions were conducted to examine the associations between comorbidity groups, parent, and self-reported sleep problems 7 years later (Median age = 15.33 years), controlling for sex, age, family income, primary caregiver education and medication. Adolescents in all CP groups had higher self and parent-reported sleep problems compared to adolescents without histories of CP. Adolescents with histories of CP, depressive symptoms and attention-hyperactivity problems had more sleep problems than all other groups according to self-reports, but not parent-reports. Childhood CP was prospectively linked to sleep problems in adolescence, and comorbid conditions exacerbated these problems, according to youth but not parents.


Increased Incidence of Thrombotic Microangiopathy After ABO-Incompatible Living Donor Liver Transplantation.
BACKGROUND Thrombotic microangiopathy (TMA) is a severe life-threatening complication associated with solid organ transplantation. We retrospectively investigated the incidence, risk factors, and appropriate treatment of TMA following adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The subjects were 129 adult patients who underwent LDLT in our department from 1997 to 2014. Patients with TMA were identified retrospectively based on diagnostic criteria. We calculated the incidence of TMA and performed a risk factor analysis for TMA occurrence. We also assessed our past treatments for TMA and sought to identify the most appropriate form of treatment. RESULTS Thirteen patients were identified as having TMA. The incidence of TMA in the study cohort was 10.1% but was especially high (37.9%) among ABO-incompatible cases. A univariate analysis revealed that ABO incompatibility, usage of tacrolimus, usage of rituximab, and cold ischemic time ≥50 minutes are risk factors for occurrence of TMA (p<0.10). Multivariate analysis demonstrated that ABO incompatibility was the only independent risk factor for TMA (p=0.009). Initiation of treatment on the day of TMA diagnosis was associated with better survival. CONCLUSIONS ABO incompatibility is an independent risk factor for TMA following adult LDLT. Our results suggest that early initiation of treatment is crucial for improving the outcomes.


SO2 dispersion and monthly evaluation of the industrial source complex short-term (ISCST32) model at Mina Al-Fahal refinery, Sultanate of Oman.
Modeling of air pollutant dispersion has been undertaken for emissions of sulfur dioxide (SO(2)) at the Mina Al-Fahal refinery in the Sultanate of Oman. The study was conducted during the period of November 1999 to October 2000. The Industrial Source Complex Short-Term (ISCST32) air pollution model was adopted to predict the ground level concentration of SO(2) in and around the refinery. The modeling results were validated against measured data during the study period. The comparison, based on the monthly average measurements, showed that the model underestimates the observed SO(2) concentrations. However, the predicted ground level concentrations of SO(2) during the months of September, October, November, and June were in better agreement with the observations. The predicted SO(2) values are presented in the form of concentration contours to determine the spatial distribution of SO(2) and to assess the impact on air quality over the survey area. Predicted SO(2) concentrations were found lower than the World Health Organisation (WHO) guideline value of 365 microg/m(3), with the maximum ground level concentrations being found to occur relatively close to the sources of emission. Moreover, concentration contour patterns for the modeled area vary with changes in meteorological conditions. On the basis of this study, the refinery is not likely to cause any significant deterioration in air quality, and predicted concentrations of SO(2) are well below those likely to influence health.


Increasing heterogeneity in the organization of synaptic inputs of mature olfactory bulb neurons generated in newborn rats.
New neurons are added into the mammalian olfactory bulb throughout life, but it remains unknown whether the properties of new neurons generated in newborn animals differ from those added during adulthood. We compared the densities of glutamatergic synapses of granule cells (GCs) generated in newborn and adult rats over extended periods of time. We observed that, whereas adult-born GCs maintained stable cell-to-cell variability of synaptic densities soon after they integrated into the circuit, cell-to-cell variability of synaptic densities of neonatal-born GCs increased months after their integration. We also investigated whether the synaptic reorganization induced by sensory deprivation occurred differently in mature neonatal- and adult-born GCs. Sensory deprivation after new GCs had differentiated induced more pronounced changes in the synaptic densities of neonatal-born GCs than in adult-born GCs. These observations suggest that the synapses of mature neonatal-born GCs retain a higher degree of malleability in response to changes in neuronal activity than adult-born GCs.


Factors affecting mortality in children with dilated cardiomyopathy.
Sabaz MN, Akın A, Bilici M, Demir F, Türe M, Balık H. Factors affecting mortality in children with dilated cardiomyopathy. Turk J Pediatr 2019; 61: 485-492. Dilated cardiomyopathy (DCMP) is a heart disease with high mortality rates that is often seen in children. Genetic and infectious reasons are primary in the etiology. The aim of this study was to investigate the etiology of DCMP and the parameters predicting mortality. A retrospective examination was made of 37 patients diagnosed with DCMP between January 2012 and October 2016. Data were recorded from the patient files of age, gender, complaints on presentation, findings of the physical examination, laboratory test results, echocardiography and electrocardiography findings at the time of diagnosis. These parameters were then compared between the surviving and nonsurviving patients. The patients comprised 21 males with a mean age of 27.50±50 months. Diagnosis was made at the age of < 12 months in 67.6% patients. Within mean 8 months of diagnosis, 16.2% of the patients were lost to mortality and 83.8% of the patients survived. In 83.3% of the non-surviving patients and in 29% of the surviving patients, sinus tachycardia was present at the time of diagnosis (p=0.023). Corrected QT (QTc) at the time of diagnosis was longer in the non-surviving patients (p=0.007). On ECG, the rate of ST-T wave change was higher in the non-surviving patients (80% vs. 17.8%, p=0.012). In conclusion, a significant proportion of the patients were diagnosed below the age of one year. In the non-surviving patients, as sinus tachycardia and ischaemic changes on ECG were seen more often and the QTc was longer, these findings could be considered to be predictors of mortality.


Engineering a clinically-useful matrix for cell therapy.
The design criteria for matrices for encapsulation of cells for cell therapy include chemical, biological, engineering, marketing, regulatory, and financial constraints. What is required is a biocompatible material for culture of cells in three-dimensions (3-D) that offers ease of use, experimental flexibility to alter composition and compliance, and a composition that would permit a seamless transition from in vitro to in vivo use. The challenge is to replicate the complexity of the native extracellular matrix (ECM) environment with the minimum number of components necessary to allow cells to rebuild a given tissue. Our approach is to deconstruct the ECM to a few modular components that can be reassembled into biomimetic materials that meet these criteria. These semi-synthetic ECMs (sECMs) employ thiol-modified derivatives of hyaluronic acid (HA) that can form covalently crosslinked, biodegradable hydrogels. These sECMs are "living" biopolymers, meaning that they can be crosslinked in the presence of cells or tissues to enable cell therapy and tissue engineering. Moreover, the sECMs allow inclusion of the appropriate biological cues needed to simulate the complexity of the ECM of a given tissue. Taken together, the sECM technology offers a manufacturable, highly reproducible, flexible, FDA-approvable, and affordable vehicle for cell expansion and differentiation in 3-D.


Low Dose Rate Irradiation Facility: initial study on chronic exposures to medaka.
Uncertainties associated with the effects from chronic low-level exposures to radiation prompted us to construct a Low Dose Rate Irradiation Facility (LoDIF). The facility was designed specifically to test the appropriateness of the 10 mGy d(-1) guideline often espoused as acceptable for protection of aquatic biota from ionizing radiation. Scientists at the 0.4 ha facility use 40 outdoor mesocosms and 137Cs irradiators of three different source strengths to research the effects of chronic low-level irradiation at different levels of biological organization. A description of the facility is included along with results from a pilot study in which Japanese medaka (a small fish native to Asia) were chronically irradiated at the highest dose rate possible within the facility (350+/-150 mGy d(-1)). Irradiated fish produced fewer eggs per day (p=0.03); had a lower percentage of viable eggs (p=0.04), and produced a lower percentage of hatchlings (p=0.05). Although these data are not surprising based on the relatively high dose rates, they are important to future work at the LoDIF because they confirm the utility of our chosen model organism for detecting population-level responses, and they illustrate the statistical power achieved from using replicated mesocosms, in that statistical significance was achieved with few replicates per treatment. Future directions for the LoDIF are presented, as well as an invitation for interested researchers to participate in our studies.


Course and predictors of pain and physical functioning in patients with hip osteoarthritis: Systematic review and meta-analysis.
To systematically summarize the literature on: (i) the course of pain and physical functioning; and (ii) predictors of deterioration of pain and physical functioning in patients with osteoarthritis of the hip. A literature search was conducted in PubMed, CINAHL, Embase, PsychINFO and SPORTDiscus up to July 2015. Meta-analyses and qualitative data syntheses were performed. Eleven of the 15 included studies were of high quality. With regard to the course of pain and physical functioning, high heterogeneity was found across studies (I² > 71%) and within study populations (reflected by large standard deviations (SDs) of change scores). Therefore, the course of pain and physical functioning was interpreted to be indistinct. Clinical characteristics (higher comorbidity count and presence of knee osteoarthritis), health behaviour factors (no supervised exercise and physical inactivity) and socio-demographics (lower education) were found to predict deterioration of pain (weak evidence). Higher comorbidity count and lower vitality were found to predict deterioration of physical functioning (strong evidence). For several other predictive factors weak evidence was found (e.g. bilateral hip pain, increase in hip pain (change), bilateral knee pain, presence of knee osteoarthritis). Because of high heterogeneity across studies and within study populations, no conclusions can be drawn with regard to the course of pain and physical functioning. Several clinical characteristics, health behaviours and psychosocial factors prognosticate deterioration of pain and physical functioning. These findings may guide future research aimed at the identification of subgroups of patients with hip osteoarthritis.


Residential Aged Care Pharmacist: An Australian Pilot Trial Exploring the Impact on Quality Use of Medicines Indicators.
This pilot study aimed to assess whether an on-site pharmacist could influence indicators of quality use of medicines in residential aged care. Methods: A pharmacist was embedded in a residential aged care home for six months. A similar control site received usual care. Polypharmacy, drug burden index, antipsychotic and benzodiazepine use, hospital admission rates and length of stay, and emergency department presentation rates were outcomes used to indicate medication use quality. Data were extracted from participating resident health records. Results: Fifty-eight residents at the study site and 39 residents at the control site were included in the analysis. There was a reduction in the proportion of residents at the study site who had at least one hospital admission at follow-up (28% to 12%, p < 0.01), but no significant difference in other outcomes. Conclusions: This pilot study suggests that a residential care pharmacist may positively influence indicators of medication use quality in aged care; however, further research is needed to expand on these findings.


Energy transfer and the photon lifetime within an aerosol particle.
The theory of enhanced energy transfer within an aerosol particle based on donor coupling to morphological dependent resonances is tested for the first time to our knowledge. The correspondence between theory and experiment is good and allows one to obtain the photon lifetime within the longest-lived resonances. A comparison between this lifetime and the lifetime as obtained by Mie theory is discussed.


The structure, frequency, and forensic application of the STR locus D16S543 in the Japanese population.
D16S543 is a complex STR locus consisting of five types of repeat units. The frequency distribution and genetic characteristics of this locus in Japanese were investigated using blood samples from 124 unrelated Japanese and 15 families. Alleles were detected using denatured polyacrylamide gels followed by automated analysis on an ABI 373 sequencer using Genescan software 672. Twenty-one alleles were identified, ranging in size from 281 to 489 bp. An allelic ladder containing the 21 alleles was constructed and used as a typing standard. The repeat unit arrays allowed the 21 alleles to be classified into three distinct groups, including alleles 1 to 7 in group I, alleles 8 to 14 in group II, and alleles 15 to 22 in group III. The alleles in group II were characterized by the insertion of one repeat unit of CAGG, one of AAAG, and three of AAGG, while the group III alleles differed from those of groups I and II by the insertion of a total of 32 repeat units ranging in 5 types. Within each group, the alleles differed from each other only in one 5' side tetranucleotide AAGG. The power of discrimination (Pd) and the estimated heterozygosity were calculated to be 0.989 and 0.934, respectively. Typing of this locus was successfully applied in four old forensic materials. The study presented herein demonstrates that D16S543 is a highly polymorphic and applicable locus in Japanese.


Relating Chronic Pelvic Pain and Endometriosis to Signs of Sensitization and Myofascial Pain and Dysfunction.
Chronic pelvic pain is a frustrating symptom for patients with endometriosis and is frequently refractory to hormonal and surgical management. While these therapies target ectopic endometrial lesions, they do not directly address pain due to central sensitization of the nervous system and myofascial dysfunction, which can continue to generate pain from myofascial trigger points even after traditional treatments are optimized. This article provides a background for understanding how endometriosis facilitates remodeling of neural networks, contributing to sensitization and generation of myofascial trigger points. A framework for evaluating such sensitization and myofascial trigger points in a clinical setting is presented. Treatments that specifically address myofascial pain secondary to spontaneously painful myofascial trigger points and their putative mechanisms of action are also reviewed, including physical therapy, dry needling, anesthetic injections, and botulinum toxin injections.


Plasma catecholamines do not invariably reflect sympathetically induced changes in blood pressure in man.
Plasma concentrations of noradrenaline and adrenaline were measured radioenzymatically in nine subjects during 4 min pressor and depressor responses (intra-arterial measurements) induced by increasing and reducing sympathetic vasoconstrictor tone via carotid baroreceptor deactivation and stimulation (neck chamber technique). During the pressor response (15 +/- 3 mmHg, mean +/- SE) plasma noradrenaline and adrenaline showed various changes in the different subjects and on average were not significantly increased above control. During the depressor response (-9 +/- 2 mmHg) plasma noradrenaline and adrenaline also showed various changes in the subjects and were on average not significantly reduced below control. In contrast the same subjects all showed an increase in noradrenaline and adrenaline (average 76 and 117%) at the fourth minute of a tilting manoeuvre with a return to pretilting values no more than 4 min after resumption of the supine position. These results suggest that the moderate and/or restricted alterations in sympathetic tone produced by manipulating a single baroreflex, though capable of affecting blood pressure, are not reflected by alterations in plasma catecholamines. To modify these humoral indices significantly, the more drastic or more diffuse alterations in sympathetic activity that may be produced by manipulating low as well as high pressure reflexogenic areas are needed.


Contrasting above- and belowground sensitivity of three Great Plains grasslands to altered rainfall regimes.
Intensification of the global hydrological cycle with atmospheric warming is expected to increase interannual variation in precipitation amount and the frequency of extreme precipitation events. Although studies in grasslands have shown sensitivity of aboveground net primary productivity (ANPP) to both precipitation amount and event size, we lack equivalent knowledge for responses of belowground net primary productivity (BNPP) and NPP. We conducted a 2-year experiment in three US Great Plains grasslands--the C4-dominated shortgrass prairie (SGP; low ANPP) and tallgrass prairie (TGP; high ANPP), and the C3-dominated northern mixed grass prairie (NMP; intermediate ANPP)--to test three predictions: (i) both ANPP and BNPP responses to increased precipitation amount would vary inversely with mean annual precipitation (MAP) and site productivity; (ii) increased numbers of extreme rainfall events during high-rainfall years would affect high and low MAP sites differently; and (iii) responses belowground would mirror those aboveground. We increased growing season precipitation by as much as 50% by augmenting natural rainfall via (i) many (11-13) small or (ii) fewer (3-5) large watering events, with the latter coinciding with naturally occurring large storms. Both ANPP and BNPP increased with water addition in the two C4 grasslands, with greater ANPP sensitivity in TGP, but greater BNPP and NPP sensitivity in SGP. ANPP and BNPP did not respond to any rainfall manipulations in the C3 -dominated NMP. Consistent with previous studies, fewer larger (extreme) rainfall events increased ANPP relative to many small events in SGP, but event size had no effect in TGP. Neither system responded consistently above- and belowground to event size; consequently, total NPP was insensitive to event size. The diversity of responses observed in these three grassland types underscores the challenge of predicting responses relevant to C cycling to forecast changes in precipitation regimes even within relatively homogeneous biomes such as grasslands.


Optimising Interventions for Catheter-Associated Urinary Tract Infections (CAUTI) in Primary, Secondary and Care Home Settings.
Catheter-associated urinary tract infections (CAUTI) are common yet preventable. Healthcare professional behaviours, such as reducing unnecessary catheter use, are key for preventing CAUTI. Previous research has focused on identifying gaps in the national response to CAUTI in multiple settings in England. This study aimed to identify how national interventions could be optimised. We conducted a multi-method study comprising: a rapid review of research on interventions to reduce CAUTI; a behavioural analysis of effective research interventions compared to national interventions; and a stakeholder focus group and survey to identify the most promising options for optimising interventions. We identified 37 effective research interventions, mostly conducted in United States secondary care. A behavioural analysis of these interventions identified 39 intervention components as possible ways to optimise national interventions. Seven intervention components were prioritised by stakeholders. These included: checklists for discharge/admission to wards; information for patients and relatives about the pros/cons of catheters; setting and profession specific guidelines; standardised nationwide computer-based documentation; promotion of alternatives to catheter use; CAUTI champions; and bladder scanners. By combining research evidence, behavioural analysis and stakeholder feedback, we identified how national interventions to reduce CAUTI could be improved. The seven prioritised components should be considered for future implementation.


Blood eosinophils from atopic donors express messenger RNA for the alpha, beta, and gamma subunits of the high-affinity IgE receptor (Fc epsilon RI) and intracellular, but not cell surface, alpha subunit protein.
Blood eosinophils from hypereosinophilic donors were previously reported to possess the functional high-affinity IgE receptor (Fc epsilon RI), so providing a potential mechanism to account for eosinophil degranulation in atopic allergic disease. Furthermore, tissue eosinophils from allergic tissue reactions were shown to be mRNA(+) for the alpha, beta, and gamma subunits of Fc epsilon RI and gave positive immunostaining with an anti-Fc epsilon RI-alpha antibody. Recent studies, however, revealed negative surface staining on peripheral blood eosinophils, but intracellular Fc epsilon RI-alpha protein was identified by Western blot analysis. Our purpose was to examine on peripheral blood eosinophils from atopic subjects (1) surface expression and mRNA for Fc epsilon RI-alpha, (2) up-regulation of Fc epsilon RI-alpha by allergy-associated tissue factors, and (3) Fc epsilon RI-alpha-dependent release of eosinophil peroxidase (EPO). We measured (1) Fc epsilon RI mRNA expression by in situ hybridization, (2) Fc epsilon RI-alpha by flow cytometry and immunocytochemistry (with use of nonpermeabilized and permeabilized cells), and (3) Fc epsilon RI-alpha-dependent release of EPO. Eosinophils from atopic donors had negligible surface expression of Fc epsilon RI-alpha, which was not enhanced by culture with IgE, IL-3, IL-4, IL-5, GM-CSF, or fibronectin or coculture with fibroblasts. Permeabilization, however, revealed appreciable intracellular staining for Fc epsilon RI-alpha. The majority of eosinophils were mRNA(+) for the alpha, beta, and gamma subunits of Fc epsilon RI. Small but significant (P =.03) increases in alpha chain mRNA expression were observed after coculture of eosinophils with fibroblasts but not with IgE, IL-4, or fibronectin. Cross-linking of Fc epsilon RI on the surface of eosinophils from atopic donors did not lead to detectable EPO release. Human blood eosinophils express negligible, nonfunctional membrane Fc epsilon RI-alpha but have intracellular Fc epsilon RI-alpha protein and mRNA expression for the alpha, beta, and gamma subunits.


EULAR revised recommendations for the management of fibromyalgia.
The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'. A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations. 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability). These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.


The Swedish Knee Arthroplasty Register 1975-1997: an update with special emphasis on 41,223 knees operated on in 1988-1997.
From 1975, when the Swedish Knee Arthroplasty Register (SKAR) started, until the end of 1997, 57,533 primary arthroplasties and revisions have been registered. Recently, the register underwent a comprehensive validation and update regarding revisions. We now report on general demographic and epidemiological data for the whole period and on the survivorship of arthroplasties performed in Sweden during 1988-1997. During this 10-year period, 41,223 primary knee arthroplasties were performed on 34,877 patients. We found, as in our earlier reports, that survivorship was affected by patient-, time-, implant- and method-related factors but, apart from an overall higher cumulative revision rate, general conclusions reported from the register in recent years appeared to be unaffected.