Quantitative Estimation of the Effect of Nasal Mucociliary Function on in Vivo Absorption of Norfloxacin after Intranasal Administration to Rats.
Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.


The influence of feeding crimped kernel maize silage on broiler production, nutrient digestibility and meat quality.
Two experiments were carried out in parallel with male Ross 308 broilers over 37 d. An experiment with a total of 736 broilers was performed to study the effect of dietary inclusion of crimped kernel maize silage (CKMS) on broiler production and meat quality. Another study with 32 broilers was carried out from 21 to 25 d to investigate the inclusion of CKMS on nutrient digestibility. In both trials, 4 dietary treatments were used: wheat-based feed (WBF), maize-based feed (MBF), maize-based feed supplemented with 15% CKMS (CKMS-15) and maize-based feed supplemented with 30% CKMS (CKMS-30). Compared with MBF, the dry matter (DM) intakes of broilers receiving CKMS-15 and CKMS-30, respectively, were numerically 7.5 and 6.2% higher and feed conversion ratio 6 and 12% poorer (significant for 30% CKMS), although there were no significant differences in AME content between the three diets. At 37 d, the body weight of birds receiving 15% CKMS was similar to birds fed with MBF. However, the inclusion of 30% CKMS decreased broiler growth. Dietary supplementation with CKMS significantly reduced the apparent digestibility of phosphorus. The fat digestibility was significantly lower for CKMS-30 than for the other three diets. Broiler mortality decreased significantly when CKMS was added to the diet. The consumption of drinking water was significantly lower in all maize-based diets as compared to WBF and was lowest in broilers fed with CKMS-30. An improved litter quality in terms of DM content and a lower frequency of foot pad lesions was observed with broilers supplemented with both dietary levels of CKMS. The addition of CKMS to maize-based diets increased juiciness, tenderness and crumbliness of the meat. In conclusion, the dietary supplementation of 15% CKMS had no negative effect on broiler growth and positively influenced bird welfare in terms of mortality and foot pad health. Therefore, the addition of 15% CKMS to maize-based diets is considered an advantageous feeding strategy in broiler production.


The establishment of the Household Air Pollution Consortium (HAPCO).
Household air pollution (HAP) is of public health concern with ~3 billion people worldwide (including >15 million in the US) exposed. HAP from coal use is a human lung carcinogen, yet the epidemiological evidence on carcinogenicity of HAP from biomass use, primarily wood, is not conclusive. To robustly assess biomass's carcinogenic potential, prospective studies of individuals experiencing a variety of HAP exposures are needed. We have built a global consortium of 13 prospective cohorts (HAPCO: Household Air Pollution Consortium) that have site- and disease-specific mortality and solid fuel use data, for a combined sample size of 587,257 participants and 57,483 deaths. HAPCO provides a novel opportunity to assess the association of HAP with lung cancer death while controlling for important confounders such as tobacco and outdoor air pollution exposures. HAPCO is also uniquely positioned to determine the risks associated with cancers other than lung as well as non-malignant respiratory and cardiometabolic outcomes, for which prospective epidemiologic research is limited. HAPCO will facilitate research to address public health concerns associated with HAP-attributed exposures by enabling investigators to evaluate sex-specific and smoking status-specific effects under various exposure scenarios.


Behavioural and operational outcomes of a Master's programme on improvement knowledge and leadership.
The purpose of this paper is to evaluate behavioural changes and operational outcomes resulting from a Master's programme on improvement knowledge and leadership in the Swedish welfare sector. The welfare sector is the collective term for tax-funded services the state, county councils and municipalities are responsible to provide. A survey combined open-ended and closed questions using a five-point Likert scale. The questions were based on the learning objectives of the Master's programme. The survey was sent to 139 graduates and achieved a response rate of 41 per cent (57 respondents). Responses were entered into a survey programme to enable the descriptive presentation of data; open-ended responses were analysed using conventional content analysis. Respondents reported their increased knowledge and changed behaviours had impacted operational outcomes, e.g. processes efficiency, compliance with guidelines and quality. They said the programme was of value to themselves and society but requested more leadership knowledge. All respondents recommended the programme to others. By operationalizing the Kirkpatrick framework, the paper describes outcomes on levels three and four, and the use of numerous best practice techniques for adult learning. This is valuable knowledge for organisers of improvement knowledge educations.


The impact of extrafamilial victimization and poly-victimization on the psychological well-being of English young people.
Childhood victimization impacts on the well-being of children and young people, particularly those experiencing an extreme amount of different types of victimization (i.e., poly-victims). However, limited attention has been given to the impact of different categories of extrafamilial victimization (experienced outside of the family), particularly in the UK. The intricacies of the significant detrimental impact poly-victimization has on victims are also poorly understood. In this study, 730 young people, aged 13 to 16 years (mean 13.8 years), from one county in the UK, were surveyed about their lifetime and past year experiences of extrafamilial victimization, the locations in which these occurred, and current trauma symptoms. The results showed that interpersonal forms of extrafamilial victimization (e.g., sexual victimization) were significant predictors of trauma, whilst more indirect forms of extrafamilial victimization (e.g., witnessing the victimization of others) were not. When extrafamilial poly-victimization and number of extrafamilial victim locations were accounted for within regression models, however, this impact was reduced. Poly-victimization within the past year was the strongest predictor of trauma symptoms. Number of victim locations did not significantly predict trauma symptoms above and beyond the impact of poly-victimization, although it was a contributory predictor. These findings suggest that a holistic exploration of a young person's extrafamilial victim experiences is needed in any clinical assessment or research into its psychological impact. Specifically, attention should be given to the experiencing of extreme levels of victimization (e.g., poly-victimization). Further longitudinal research is needed to understand why poly-victimization has the greatest impact on psychological well-being.


Prostate cancer screening decisions: results from the National Survey of Medical Decisions (DECISIONS study).
Guidelines recommend informing patients about the risks and benefits of prostate cancer screening. We evaluated the medical decision-making process for prostate-specific antigen (PSA) testing. We conducted a telephone survey of a randomly selected national sample of 3010 English-speaking US adults 40 years and older. Included in the survey were 375 men who had either undergone or discussed (with health care providers [HCPs]) PSA testing in the previous 2 years. We asked subjects about sociodemographic characteristics, prostate cancer screening discussion features, prostate cancer knowledge, and the importance of various decision factors and sources of information. Overall, 69.9% of subjects discussed screening before making a testing decision, including 14.4% who were not tested. Health care providers most often (64.6%) raised the idea of screening, and 73.4% recommended PSA testing. Health care providers emphasized the pros of testing in 71.4% of discussions but infrequently addressed the cons (32.0%). Although 58.0% of subjects felt well-informed about PSA testing, 47.8% failed to correctly answer any of the 3 knowledge questions. Only 54.8% of subjects reported being asked for their screening preferences. An HCP recommendation (odds ratio, 2.67; 95% confidence interval, 1.08-6.58) was the only discussion characteristic associated with testing. Valuing HCP information was also associated with testing (odds ratio, 1.26; 95% confidence interval, 1.04-1.54). Recommendations and information from HCPs strongly influenced testing decisions. However, most prostate cancer screening decisions did not meet criteria for shared decision making because subjects did not receive balanced discussions of decision consequences, had limited knowledge, and were not routinely asked for their preferences.


Pediatric and Adolescent Extracranial Germ Cell Tumors: The Road to Collaboration.
During the past 35 years, survival rates for children with extracranial malignant germ cell tumors (GCTs) have increased significantly. Success has been achieved primarily through the application of platinum-based chemotherapy regimens; however, clinical challenges in GCTs remain. Excellent outcomes are not distributed uniformly across the heterogeneous distribution of age, histologic features, and primary tumor site. Despite good outcomes overall, the likelihood of a cure for certain sites and histologic conditions is less than 50%. In addition, there are considerable long-term treatment-related effects for survivors. Even modest cisplatin dosing can cause significant long-term morbidities. A particular challenge in designing new therapies for GCT is that a variety of specialists use different risk stratifications, staging systems, and treatment approaches for three distinct age groups (childhood, adolescence, and young adulthood). Traditionally, pediatric cancer patients younger than 15 years have been treated by pediatric oncologists in collaboration with their surgical specialty colleagues. Adolescents and young adults with GCTs often are treated by medical oncologists, urologists, or gynecologic oncologists. The therapeutic dilemma for all is how to best define disease risk so that therapy and toxicity can be appropriately reduced for some patients and intensified for others. Further clinical and biologic insights can only be achieved through collaborations that do not set limitations by age, sex, and primary tumor site. Therefore, international collaborations, spanning different cooperative groups and disciplines, have been developed to address these challenges.


The Feasibility of the "Omega Kid" Study Protocol: A Double-Blind, Randomised, Placebo-Controlled Trial Investigating the Effect of Omega-3 Supplementation on Self-Regulation in Preschool-Aged Children.
Self-regulation, the regulation of behaviour in early childhood, impacts children's success at school and is a predictor of health, wealth, and criminal outcomes in adulthood. Self-regulation may be optimised by dietary supplementation of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs). The aim of the "Omega Kid" study is to investigate the feasibility of a protocol to investigate whether n-3 LCPUFA supplementation enhances self-regulation in preschool-aged children. The protocol assessed involved a double-blind, randomised, placebo-controlled trial of 12 weeks duration, with an intervention of 1.6 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day (0.3 g EPA and 1.3 g DHA) in a microencapsulated powder compared to placebo. Children (n = 78; 40 boys and 38 girls) aged 3-5 years old were recruited and randomly allocated to the treatment (n = 39) or placebo group (n = 39). The HS-Omega-3 Index® served as a manipulation check on the delivery of either active (n-3 LCPUFAs) or placebo powders. Fifty-eight children (76%) completed the intervention (28-30 per group). Compliance to the study protocol was high, with 92% of children providing a finger-prick blood sample at baseline and high reported-adherence to the study intervention (88%). Results indicate that the protocol is feasible and may be employed in an adequately powered clinical trial to test the hypothesis that n-3 LCPUFA supplementation will improve the self-regulation of preschool-aged children.


Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics.
The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility. We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences. In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.


The evolution of ageing and longevity.
Ageing is not adaptive since it reduces reproductive potential, and the argument that it evolved to provide offspring with living space is hard to sustain for most species. An alternative theory is based on the recognition that the force of natural selection declines with age, since in most environments individuals die from predation, disease or starvation. Ageing could therefore be the combined result of late-expressed deleterious genes which are beyond the reach of effective negative selection. However, this argument is circular, since the concept of 'late expression' itself implies the prior existence of adult age-related physiological processes. Organisms that do not age are essentially in a steady state in which chronologically young and old individuals are physiologically the same. In this situation the synthesis of macromolecules must be sufficiently accurate to prevent error feedback and the development of lethal 'error catastrophes'. This involves the expenditure of energy, which is required for both kinetic proof-reading and other accuracy promoting devices. It may be selectively advantageous for higher organisms to adopt an energy saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death. This 'disposable soma' theory of the evolution of ageing also proposes that a high level of accuracy is maintained in immortal germ line cells, or alternatively, that any defective germ cells are eliminated. The evolution of an increase in longevity in mammals may be due to a concomitant reduction in the rates of growth and reproduction and an increase in the accuracy of synthesis of macromolecules. The theory can be tested by measuring accuracy in germ line and somatic cells and also by comparing somatic cells from mammals with different longevities.


Measurement error causes scale-dependent threshold erosion of biological signals in animal movement data.
Recent advances in telemetry technology have created a wealth of tracking data available for many animal species moving over spatial scales from tens of meters to tens of thousands of kilometers. Increasingly, such data sets are being used for quantitative movement analyses aimed at extracting fundamental biological signals such as optimal searching behavior and scale-dependent foraging decisions. We show here that the location error inherent in various tracking technologies reduces the ability to detect patterns of behavior within movements. Our analyses endeavored to set out a series of initial ground rules for ecologists to help ensure that sampling noise is not misinterpreted as a real biological signal. We simulated animal movement tracks using specialized random walks known as Lévy flights at three spatial scales of investigation: 100-km, 10-km, and 1-km maximum daily step lengths. The locations generated in the simulations were then blurred using known error distributions associated with commonly applied tracking methods: the Global Positioning System (GPS), Argos polar-orbiting satellites, and light-level geolocation. Deviations from the idealized Lévy flight pattern were assessed for each track after incrementing levels of location error were applied at each spatial scale, with additional assessments of the effect of error on scale-dependent movement patterns measured using fractal mean dimension and first-passage time (FPT) analyses. The accuracy of parameter estimation (Lévy mu, fractal mean D, and variance in FPT) declined precipitously at threshold errors relative to each spatial scale. At 100-km maximum daily step lengths, error standard deviations of > or = 10 km seriously eroded the biological patterns evident in the simulated tracks, with analogous thresholds at the 10-km and 1-km scales (error SD > or = 1.3 km and 0.07 km, respectively). Temporal subsampling of the simulated tracks maintained some elements of the biological signals depending on error level and spatial scale. Failure to account for large errors relative to the scale of movement can produce substantial biases in the interpretation of movement patterns. This study provides researchers with a framework for understanding the limitations of their data and identifies how temporal subsampling can help to reduce the influence of spatial error on their conclusions.


A strategy for improving the supervision and performance of moonlighting residents.
In 1990 the Ambulatory Care Service of the Ralph H. Johnson Department of Veterans Affairs Medical Center, affiliated with the Medical University of South Carolina College of Medicine, developed written clinical protocols for the management of patients with certain high-risk medical conditions. Appropriateness of care was assessed by determining physician compliance to the protocols over a 24-month period (October 1990-September 1992). All physicians who did not comply received individualized feedback from the service chief. For the first 12 months, both staff physicians and moonlighting second- and third-year medical residents were assessed (a total of seven staff physicians and 20 residents participated in the study). For the second 12 months, only the residents were assessed. The moonlighting residents were notably less consistent than the staff physicians in protocol compliance (95-100% for the staff physicians; 78-100% for the moonlighters). Additional interventions were then implemented to improve the moonlighters' utilization of the protocols. Moonlighters' compliance over the subsequent 12 months was less variable (mean compliance of 92%, SD, 3%, the first year versus 95%, SD, 8%, the second year). The strategy seemed to improve the supervision and performance of the moonlighting residents and promoted consistent delivery of high-quality outpatient care.


Mitovirus and Mitochondrial Coding Sequences from Basal Fungus Entomophthora muscae.
Fungi constituting the Entomophthora muscae species complex (members of subphylum Entomophthoromycotina, phylum Zoopagamycota) commonly kill their insect hosts and manipulate host behaviors in the process. In this study, we made use of public transcriptome data to identify and characterize eight new species of mitoviruses associated with several different E. muscae isolates. Mitoviruses are simple RNA viruses that replicate in host mitochondria and are frequently found in more phylogenetically apical fungi (members of subphylum Glomeromyoctina, phylum Mucoromycota, phylum Basidiomycota and phylum Ascomycota) as well as in plants. E. muscae is the first fungus from phylum Zoopagomycota, and thereby the most phylogenetically basal fungus, found to harbor mitoviruses to date. Multiple UGA (Trp) codons are found not only in each of the new mitovirus sequences from E. muscae but also in mitochondrial core-gene coding sequences newly assembled from E. muscae transcriptome data, suggesting that UGA (Trp) is not a rarely used codon in the mitochondria of this fungus. The presence of mitoviruses in these basal fungi has possible implications for the evolution of these viruses.


Can Academic Medicine Lead the Way in the Refugee Crisis?
The world is currently in the midst of the largest refugee crisis since World War II, with the highest interval of mass displacement in recorded history according to the United Nations. The United States has pledged to maintain its position as one of the world's top resettlement countries in response to this crisis. These new immigrants will arrive with exceptional chronic and acute medical needs, including higher rates of behavioral health disorders. The author describes the health care challenges experienced by refugees seeking asylum in the United States and outlines the ways in which our health care system is currently deficient in helping refugee patients to overcome these challenges. He argues that the academic medical community can change this dynamic by standardizing and expanding instruction in cross-cultural competence and behavioral health screenings throughout the spectrum of medical education. Ensuring the long-term well-being of refugees in the United States, including meeting their mental health needs, will be the best inoculation against the risks of violent extremism which so many fear. With the absence of national leadership on this issue, academic medicine can and should lead the way.


Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.
To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.


The Effect of Midline Corset Platysmaplasty on Degree of Face-lift Flap Elevation During Concomitant Deep-Plane Face-lift: A Cadaveric Study.
The evaluation of the effects of midline platysmaplasty concomitant with rhytidectomy. To determine whether midline platysmaplasty limits the degree of lift during deep-plane face-lift. Deep-plane rhytidectomy was performed on 10 cadaveric hemifaces. The redundant skin for excision after performing the face-lift was measured with and without midline platymaplasty. Deep-plane rhytidectomy. The redundant skin was measured preauricularly in the vertical and horizontal dimension, and postauricularly after deep-plane face-lift and after adding a midline platysmaplasty. Concomitant midline platysmaplasty significantly reduced the amount of lift during concomitant deep-plane rhytidectomy preauricularly in the vertical dimension by 40.5% (from 37.0 mm excess skin redraped to 22.0 mm) and postauricularly by 23.9% (from 40.6 mm excess skin redraped to 30.9 mm) (P < .001 and P < .001, respectively). The 19.7% reduction in the horizontal skin redraping after midline platysmaplasty (from 14.7 mm excess skin redraped to 11.8 mm) did not reach statistical significance (P = .15). Concomitant midline corset platysmaplasty significantly limits the ability to lift the neck as well as the jawline and midface during rhytidectomy. NA.


Multilayer white light-emitting organic electroluminescent device.
Organic electroluminescent devices are light-emitting diodes in which the active materials consist entirely of organic materials. Here, the fabrication of a white light-emitting organic electroluminescent device made from vacuum-deposited organic thin films is reported. In this device, three emitter layers with different carrier transport properties, each emitting blue, green, or red light, are used to generate white light. Bright white light, over 2000 candelas per square meter, nearly as bright as a fluorescent lamp, was successfully obtained at low drive voltages such as 15 to 16 volts. The applications of such a device include paper-thin light sources, which are particularly useful for places that require lightweight illumination devices, such as in aircraft and space shuttles. Other uses are a backlight for liquid crystal display as well as full color displays, achieved by combining the emitters with micropatterned color filters.


Psychological resilience and the gene regulatory impact of posttraumatic stress in Nepali child soldiers.
Adverse social conditions in early life have been linked to increased expression of proinflammatory genes and reduced expression of antiviral genes in circulating immune cells-the conserved transcriptional response to adversity (CTRA). However, it remains unclear whether such effects are specific to the Western, educated, industrialized, rich, and democratic (WEIRD) cultural environments in which previous research has been conducted. To assess the roles of early adversity and individual psychological resilience in immune system gene regulation within a non-WEIRD population, we evaluated CTRA gene-expression profiles in 254 former child soldiers and matched noncombatant civilians 5 y after the People's War in Nepal. CTRA gene expression was up-regulated in former child soldiers. These effects were linked to the degree of experienced trauma and associated distress-that is, posttraumatic stress disorder (PTSD) severity-more than to child soldier status per se. Self-perceived psychological resilience was associated with marked buffering of CTRA activation such that PTSD-affected former child soldiers with high levels of personal resilience showed molecular profiles comparable to those of PTSD-free civilians. These results suggest that CTRA responses to early life adversity are not restricted to WEIRD cultural contexts and they underscore the key role of resilience in determining the molecular impact of adverse environments.


Short- and long-term effects of calcium and exercise on bone mineral density in ovariectomized rats.
At the level of prevention of bone mineral loss produced by ovariectomy, the aim of the present study was to determine the effect produced by supplementation of Ca in the diet and a moderate exercise programme (treadmill), simultaneously or separately, in ovariectomized rats, an experimental model of postmenopausal bone loss. Female Wistar rats (n 110, 15 weeks old) were divided into five groups: (1) OVX, rats ovariectomized at 15 weeks of age, fed a standard diet; (2) SHAM, rats sham operated at 15 weeks of age, fed a standard diet; (3) OVX-EX, ovariectomized rats, fed a standard diet and performing the established exercise programme; (4) OVX-Ca, ovariectomized rats fed a diet supplemented with Ca; (5) OVX-EXCa, ovariectomized rats with the exercise programme and diet supplemented with Ca. The different treatments were initiated 1 week after ovariectomy and were continued for 13 weeks for subgroup 1 and 28 weeks for subgroup 2, to look at the interaction of age and time passed from ovariectomy on the treatments. Bone mineral density (BMD) was determined, at the end of the study, in the lumbar spine (L2, L3 and L4) and in the left femur using a densitometer. Bone turnover was also estimated at the end of the study, measuring the serum formation marker total alkaline phosphatase (AP) and the resorption marker serum tartrate-resistant acid phosphatase (TRAP). As expected, OVX rats showed a significant decrease (P<0.05) in BMD, more pronounced in subgroup 2, and a significant increase in AP and TRAP with regard to their respective SHAM group. The simultaneous treatment with Ca and exercise produced the best effects on lumbar and femoral BMD of ovariectomized rats, partially avoiding bone loss produced by ovariectomy, although it was not able to fully maintain BMD levels of intact animals. This combined treatment produced a significant increase in AP, both in subgroups 1 and 2, and a decrease in TRAP in subgroup 1, with regard to OVX group. The exercise treatment alone was able to produce an increase in BMD with regard to OVX group only in subgroup 1 of rats (younger animals and less time from ovariectomy), but not in subgroup 2. In agreement with this, there was an increase of AP in both subgroups, lower than that observed in animals submitted to exercise plus Ca supplement, and a decrease of TRAP in subgroup 1, without significant changes in this marker in the older rats. Ca treatment did not produce any significant effect on BMD in OVX rats in both subgroups of animals, showing a decrease of AP and TRAP levels in the younger animals with no significant variations in markers of bone remodelling in the older female rats compared with their respective OVX group.


Protein-loaded bioresorbable fibers and expandable stents: Mechanical properties and protein release.
There is an increasing interest in bioresorbable polymeric stents for coronary, urethral and tracheal applications. These stents can support body conduits during their healing process and release biologically active agents from an internal reservoir to the surrounding tissue. A removal operation is not needed. Bioresorbable poly(L-lactic acid) fibers were prepared through melt spinning accompanied by a postpreparation drawing process. Novel expandable bioresorbable stents were developed from these fibers. Bioresorbable microspheres containing albumin were prepared and attached to the stents, to serve as a protein reservoir coating. The controlled release of albumin from the microsphere-loaded stent was studied. The fibers combine high strength and modulus, together with good ductility and flexibility. An increase in draw ratio increases the tensile strength and modulus and decreases the ultimate strain. The stents demonstrated excellent initial radial compression strength and good in vitro degradation resistivity, which makes them applicable for supporting blood vessels for at least 20 weeks. Microspheres bound to these stents enable effective protein loading, without reducing the stent's mechanical properties. The protein release from the microsphere-loaded stent occurs by diffusion, is determined mainly by the initial molecular weight of the bioresorbable polymer and its erosion rate, and is strongly affected by the microsphere structure.


Identifying high-risk areas for sporadic measles outbreaks: lessons from South Africa.
To develop a model for identifying areas at high risk for sporadic measles outbreaks based on an analysis of factors associated with a national outbreak in South Africa between 2009 and 2011. Data on cases occurring before and during the national outbreak were obtained from the South African measles surveillance programme, and data on measles immunization and population size, from the District Health Information System. A Bayesian hierarchical Poisson model was used to investigate the association between the risk of measles in infants in a district and first-dose vaccination coverage, population density, background prevalence of human immunodeficiency virus (HIV) infection and expected failure of seroconversion. Model projections were used to identify emerging high-risk areas in 2012. A clear spatial pattern of high-risk areas was noted, with many interconnected (i.e. neighbouring) areas. An increased risk of measles outbreak was significantly associated with both the preceding build-up of a susceptible population and population density. The risk was also elevated when more than 20% of infants in a populous area had missed a first vaccine dose. The model was able to identify areas at high risk of experiencing a measles outbreak in 2012 and where additional preventive measures could be undertaken. The South African measles outbreak was associated with the build-up of a susceptible population (owing to poor vaccine coverage), high prevalence of HIV infection and high population density. The predictive model developed could be applied to other settings susceptible to sporadic outbreaks of measles and other vaccine-preventable diseases.


Mortality after hospital discharge for people with schizophrenia or bipolar disorder: retrospective study of linked English hospital episode statistics, 1999-2006.
To investigate whether the mortality gap has reduced in recent years between people with schizophrenia or bipolar disorder and the general population. Record linkage study. English hospital episode statistics and death registration data for patients discharged 1999-2006. People discharged from inpatient care with a diagnosis of schizophrenia or bipolar disorder, followed for a year after discharge. Age standardised mortality ratios at each time, comparing the mortality in people with schizophrenia or bipolar disorder with mortality in the general population. Poisson test of trend was used to investigate trend in ratios over time. By 2006 standardised mortality ratios in the psychiatric cohorts were about double the population average. The mortality gap widened over time. For people discharged with schizophrenia, the ratio was 1.6 (95% confidence interval 1.5 to 1.8) in 1999 and 2.2 (2.0 to 2.4) in 2006 (P < 0.001 for trend). For bipolar disorder, the ratios were 1.3 (1.1 to 1.6) in 1999 and 1.9 (1.6 to 2.2) in 2006 (P = 0.06 for trend). Ratios were higher for unnatural than for natural causes. About three quarters of all deaths, however, were certified as natural, and increases in ratios for natural causes, especially circulatory disease and respiratory diseases, were the main components of the increase in all cause mortality. The total burden of premature deaths from natural causes in people with schizophrenia or bipolar disorder is substantial. There is a need for better understanding of the reasons for the persistent and increasing gap in mortality between discharged psychiatric patients and the general population, and for continued action to target risk factors for both natural and unnatural causes of death in people with serious mental illness.


Adsorption of nicotine in aqueous solution by a defective graphene oxide.
Extensive concerns have been focused on the emerging contaminants including nicotine in the aquatic system recently. Graphene oxide (GO) and modified graphene oxides (GO-COOH and defective GO-COOH) are used as effective adsorbents to remove nicotine from aqueous solution. The adsorption isotherms and kinetics of the adsorbents all fit well with Langmuir model and pseudo-second-order model, respectively. The thermodynamic studies show that the adsorption is an exothermic and spontaneous process. The influence of pH and ionic solution strength on the adsorbents is also investigated. The maximum adsorption capacity can be observed at pH value of ca. 8. The adsorption capacities of nicotine are decreased upon the increase of sodium ion concentration. Among all the adsorbents, the defective GO-COOH adsorbents possess the maximum adsorption capacity of nicotine of 196.5 mg g-1 obtained from Langmuir isotherm. In regeneration experiments, the defective GO-COOH adsorbents can maintain 95.1% of adsorption capacity after five times of cyclic adsorption-desorption processes. The adsorbents are identified by Fourier transform infrared, 13C solid-state magic-angle spinning nuclear magnetic resonance, X-ray photoelectron and Raman spectroscopies to determine the adsorption mechanisms and structure on the adsorbents. It can be deduced that the surpassing performance of defective GO-COOH may be ascribed to the unique adsorption mechanism of defects, the enhanced π-π interaction and cation-π bonding. The highly-efficient and stable features enable the defective GO-COOH a promising adsorbent to eliminate nicotine from water.


Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals.
An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS. MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183).


Suicide risk and suicide method in patients with personality disorders.
The influence of psychopathology on suicide method has revealed different distributions among different psychiatric disorders. However, evidence is still scarce. We hypothesized that having a diagnosis of personality disorder (PD) affect the suicide method, and that different PD clusters would influence the suicide method in different ways. In addition, we hypothesized that the presence of psychiatric and somatic co-morbidity also affects the suicide method. We examined 25,217 individuals aged 15-64 who had been hospitalized in Sweden with a main diagnosis of PD the years 1987-2013 (N = 25,217). The patients were followed from the date of first discharge until death or until the end of the follow-up period, i.e. December 31, 2013, for a total of 323,508.8 person-years, with a mean follow up time of 11.7 years. The SMR, i.e. the ratio between the observed number of suicides and the expected number of suicides, was used as a measure of risk. Overall PD, different PD-clusters, and comorbidity influenced the suicide method. Hanging evidenced highest SMR in female PD patients (SMR 34.2 (95% CI: 29.3-39.8)), as compared to non-PD patients and jumping among male PD patients (SMR 24.8 (95% CI: 18.3-33.6)), as compared to non PD-patients. Furthermore, the elevated suicide risk was related to both psychiatric and somatic comorbidity. The increased suicide risk was unevenly distributed with respect to suicide method and type of PD. However, these differences were only moderate and greatly overshadowed by the overall excess suicide risk in having PD. Any attempt from society to decrease the suicide rate in persons with PD must take these characteristics into account.


Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF).
The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.


Rapid inference of antibiotic resistance and susceptibility by genomic neighbour typing.
Surveillance of drug-resistant bacteria is essential for healthcare providers to deliver effective empirical antibiotic therapy. However, traditional molecular epidemiology does not typically occur on a timescale that could affect patient treatment and outcomes. Here, we present a method called 'genomic neighbour typing' for inferring the phenotype of a bacterial sample by identifying its closest relatives in a database of genomes with metadata. We show that this technique can infer antibiotic susceptibility and resistance for both Streptococcus pneumoniae and Neisseria gonorrhoeae. We implemented this with rapid k-mer matching, which, when used on Oxford Nanopore MinION data, can run in real time. This resulted in the determination of resistance within 10 min (91% sensitivity and 100% specificity for S. pneumoniae and 81% sensitivity and 100% specificity for N. gonorrhoeae from isolates with a representative database) of starting sequencing, and within 4 h of sample collection (75% sensitivity and 100% specificity for S. pneumoniae) for clinical metagenomic sputum samples. This flexible approach has wide application for pathogen surveillance and may be used to greatly accelerate appropriate empirical antibiotic treatment.


Cfh genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice.
Age-related macular degeneration (AMD) is a leading cause of visual impairment worldwide. Genetics and diet contribute to the relative risk for developing AMD, but their interactions are poorly understood. Genetic variations in Complement Factor H (CFH), and dietary glycemic index (GI) are major risk factors for AMD. We explored the effects of GI on development of early AMD-like features and changes to central nervous system (CNS) inflammation in Cfh-null mice. Aged 11-week-old wild type (WT) C57Bl/6J or Cfh-null mice were group pair-fed high or low GI diets for 33 weeks. At 10 months of age, mice were evaluated for early AMD-like features in the neural retina and RPE by light and electron microscopy. Brains were analyzed for Iba1 macrophage/microglia immunostaining, an indicator of inflammation. The 10-month-old WT mice showed no retinal abnormalities on either diet. The Cfh-null mice, however, showed distinct early AMD-like features in the RPE when fed a low GI diet, including vacuolation, disruption of basal infoldings, and increased basal laminar deposits. The Cfh-null mice also showed thinning of the RPE, hypopigmentation, and increased numbers of Iba1-expressing macrophages in the brain, irrespective of diet. The presence of early AMD-like features by 10 months of age in Cfh-null mice fed a low GI diet is surprising, given the apparent protection from the development of such features in aged WT mice or humans consuming lower GI diets. Our findings highlight the need to consider gene-diet interactions when developing animal models and therapeutic approaches to treat AMD.


Are Three-Dimensional-Printed Foot Orthoses Able to Cover the Podiatric Physician's Needs?
Current management of foot pain requires foot orthoses (FOs) with various design features (eg, wedging, height) and specific mechanical properties (eg, hardness, volume). Development of additive manufacturing (three-dimensional [3-D] printing) raises the question of applying its technology to FO manufacturing. Recent studies have demonstrated the physical benefits of FO parts with specific mechanical properties, but none have investigated the relationship between honeycomb architecture (HcA) infilling density and Shore A hardness of thermoplastic polyurethane (TPU) used to make FOs, which is the aim of this study. Sixteen different FO samples were made with a 3-D printer using TPU (97 Shore A), with HcA infilling density ranging from 10 to 40. The mean of two Shore A hardness measurements was used in regression analysis. Interdurometer reproducibility was excellent (intraclass correlation coefficient, 0.91; 95% confidence interval [CI], 0.64-0.98; P < .001) and interprinter reproducibility was excellent/good (intraclass correlation coefficient, 0.84; 95% CI, 0.43-0.96; P < .001). Linear regression showed a positive significant relationship between Shore A hardness and HcA infilling density (R2 = 0.955; P < .001). Concordance between evaluator and durometer was 86.7%. This study revealed a strong relationship between Shore A hardness and HcA infilling density of TPU parts produced by 3-D printing and highlighted excellent concordance. These results are clinically relevant because 3-D printing can cover Shore A hardness values ranging from 40 to 70, representing most FO production needs. These results could provide important data for 3-D manufacturing of FOs to match the population needs.


Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review.
Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. We undertook a systematic review of the literature to identify, describe and critique the clinical and pre-clinical evidence for the use of oxaliplatin in patients with "cisplatin-resistant" cancer. We identified 25 pre-clinical cell models of platinum resistance and 24 clinical trials reporting oxaliplatin based salvage therapy for cisplatin-resistant cancer. The pre-clinical data suggests that there is cross-resistance between cisplatin and oxaliplatin in low-level resistance models. In models with high level resistance (>10-fold) there is less cross-resistance between cisplatin and oxaliplatin, which may be a reason why oxaliplatin is thought to be active in cisplatin-resistant cancer. In clinical trials where oxaliplatin has been used as part of salvage therapy for patients who have failed cisplatin or carboplatin combination chemotherapy, there was a much lower response rate in patients with platinum-refractory or resistant cancers compared to platinum-sensitive cancers. This suggests that there may be cross-resistance between cisplatin and oxaliplatin in the clinic. Oxaliplatin as a single agent had a poor response rate in cisplatin refractory and resistant cancer. Oxaliplatin performed better in combination with other agents for the treatment of platinum-resistant/refractory cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer.


Self-consistency test reveals systematic bias in programs for prediction change of stability upon mutation.
Computational prediction of the effect of mutations on protein stability is used by researchers in many fields. The utility of the prediction methods is affected by their accuracy and bias. Bias, a systematic shift of the predicted change of stability, has been noted as an issue for several methods, but has not been investigated systematically. Presence of the bias may lead to misleading results especially when exploring the effects of combination of different mutations. Here we use a protocol to measure the bias as a function of the number of introduced mutations. It is based on a self-consistency test of the reciprocity the effect of a mutation. An advantage of the used approach is that it relies solely on crystal structures without experimentally measured stability values. We applied the protocol to four popular algorithms predicting change of protein stability upon mutation, FoldX, Eris, Rosetta and I-Mutant, and found an inherent bias. For one program, FoldX, we manage to substantially reduce the bias using additional relaxation by Modeller. Authors using algorithms for predicting effects of mutations should be aware of the bias described here. All calculations were implemented by in-house PERL scripts. Supplementary data are available at Bioinformatics online. The article 10.1093/bioinformatics/bty348, published alongside this paper, also addresses the problem of biases in protein stability change predictions.


Establishing benchmarks for the hospitalized care of children with asthma, bronchiolitis, and pneumonia.
Asthma, pneumonia, and bronchiolitis are the leading causes of admission for pediatric patients; however, the lack of accepted benchmarks is a barrier to quality improvement efforts. Using data from children hospitalized with asthma, bronchiolitis, or pneumonia, the goals of this study were to: (1) measure the 2012 performance of freestanding children's hospitals using clinical quality indicators; and (2) construct achievable benchmarks of care (ABCs) for the clinical quality indicators. This study was a cross-sectional trial using the Pediatric Health Information System database. Patient inclusions varied according to diagnosis: asthma (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 493.0-493.92) from 2 to 18 years of age; bronchiolitis (ICD-9-CM codes 466.11 and 466.19) from 2 months to 2 years of age; and pneumonia (ICD-9-CM codes 480-486, 487.0) from 2 months to 18 years of age. ABC methods use the best-performing hospitals that comprise at least 10% of the total population to compute the benchmark. Encounters from 42 hospitals included: asthma, 22186; bronchiolitis, 14882; and pneumonia, 12983. Asthma ABCs include: chest radiograph utilization, 24.5%; antibiotic administration, 6.6%; and ipratropium bromide use >2 days, 0%. Bronchiolitis ABCs include: chest radiograph utilization, 32.4%; viral testing, 0.6%; antibiotic administration, 18.5%; bronchodilator use >2 days, 11.4%; and steroid use, 6.4%. Pneumonia ABCs include: complete blood cell count utilization, 28.8%; viral testing, 1.5%; initial narrow-spectrum antibiotic use, 60.7%; erythrocyte sedimentation rate, 3.5%; and C-reactive protein, 0.1%. We report achievable benchmarks for inpatient care for asthma, bronchiolitis, and pneumonia. The establishment of national benchmarks will drive improvement at individual hospitals.


Temperament, family environment and anxiety in preschool children.
This research examines the relationship between behavioural inhibition (BI), family environment (overinvolved and negative parenting, parental anxiety and parent-child attachment) and anxiety in a sample of 202 preschool children. Participants were aged between 3 years 2 months and 4 years 5 months, 101 were male. A thorough methodology was used that incorporated data from multiple observations of behaviour, diagnostic interviews and questionnaire measures. The results showed that children categorised as behaviourally inhibited were significantly more likely to meet criteria for a range of anxiety diagnoses. Furthermore, a wide range of family environment factors, including maternal anxiety, parenting and attachment were significantly associated with BI, with inhibited children more likely to experience adverse family environment factors. No interactions between temperament and family environment were found for child anxiety. However, a significant relationship between current maternal anxiety and child anxiety was found consistently even after controlling for BI. Additionally, there was some evidence of a relationship between maternal negativity and child anxiety, after controlling for BI. The results may suggest that temperament and family environment operate as additive, rather than interactive risk factors for child anxiety. This is discussed in the context of theoretical models of child anxiety and directions for future research.


Reinvestigation of aminoacyl-tRNA synthetase core complex by affinity purification-mass spectrometry reveals TARSL2 as a potential member of the complex.
Twenty different aminoacyl-tRNA synthetases (ARSs) link each amino acid to their cognate tRNAs. Individual ARSs are also associated with various non-canonical activities involved in neuronal diseases, cancer and autoimmune diseases. Among them, eight ARSs (D, EP, I, K, L, M, Q and RARS), together with three ARS-interacting multifunctional proteins (AIMPs), are currently known to assemble the multi-synthetase complex (MSC). However, the cellular function and global topology of MSC remain unclear. In order to understand the complex interaction within MSC, we conducted affinity purification-mass spectrometry (AP-MS) using each of AIMP1, AIMP2 and KARS as a bait protein. Mass spectrometric data were funneled into SAINT software to distinguish true interactions from background contaminants. A total of 40, 134, 101 proteins in each bait scored over 0.9 of SAINT probability in HEK 293T cells. Complex-forming ARSs, such as DARS, EPRS, IARS, Kars, LARS, MARS, QARS and RARS, were constantly found to interact with each bait. Variants such as, AIMP2-DX2 and AIMP1 isoform 2 were found with specific peptides in KARS precipitates. Relative enrichment analysis of the mass spectrometric data demonstrated that TARSL2 (threonyl-tRNA synthetase like-2) was highly enriched with the ARS-core complex. The interaction was further confirmed by coimmunoprecipitation of TARSL2 with other ARS core-complex components. We suggest TARSL2 as a new component of ARS core-complex.


Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters.
Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID. 1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters. Nine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence). We found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings.


[Measuring change in rehabilitative cardiology: reliability of a short questionnaire to assess an outcome].
The present Italian health planning demands the use of tools, care and treatments useful for the National Health Service, but with empirical effectiveness scientifically sustained. Aim of the present paper is to verify the validity, the reliability and the responsiveness of the factor "Perception of positive change" (named Schedule C) in cardiovascular rehabilitation. The reliability of the Schedule C of the CBA VE has been examined comparing the mean scores obtained from each item at the entry and just before the discharge through the t-Student for paired sample. To assess the concurrent validity we used the AD Short Scale to measure anxiety and depression. 100 patients who underwent cardiac surgery were enrolled during hospitalization for a Cardiac Rehabilitation Programme. Cronbach's alpha was used to assess internal consistency of each item. Each item of the Schedule C demonstrated good internal consistency (Cronbach Alpha > .88) and elevated correlations item-total for each item. The strong correlation of anxiety and depression scores with the Schedule C points out appropriate concurrent validation. We believe that the Schedule C of the CBA VE is endowed with suitable metric validity and then useful as outcome evaluation in cardiovascular rehabilitation settings.


Searching for a relationship between manganese and welding and Parkinson's disease.
Research into the causes of Parkinson disease (PD) has accelerated recently with the discovery of novel gene mutations. The majority of PD cases, however, remain idiopathic and in those cases environmental causes should be considered. Several recent reports have focused on welding and manganese toxicity as potential risk factors for parkinsonism and some have even proposed that welding is a risk factor for PD. The controversy has stimulated this review, the primary aim of which is to critically and objectively examine the evidence or lack of evidence for a relationship among welding, manganese, parkinsonism, and PD.


Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water.
A number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs.


Hemoglobin-derived peptides as novel type of bioactive signaling molecules.
Most bioactive peptides are generated by proteolytic cleavage of large precursor proteins followed by storage in secretory vesicles from where they are released upon cell stimulation. Examples of such bioactive peptides include peptide neurotransmitters, classical neuropeptides, and peptide hormones. In the last decade, it has become apparent that the breakdown of cytosolic proteins can generate peptides that have biological activity. A case in point and the focus of this review are hemoglobin-derived peptides. In vertebrates, hemoglobin (Hb) consists of a tetramer of two α- and two β-globin chains each containing a prosthetic heme group, and is primarily involved in oxygen delivery to tissues and in redox reactions (Schechter Blood 112:3927-3938, 2008). The presence of α- and/or β-globin chain in tissues besides red blood cells including rodent and human brain and peripheral tissues (Liu et al. Proc Natl Acad Sci USA 96:6643-6647, 1999; Newton et al. J Biol Chem 281:5668-5676, 2006; Wride et al. Mol Vis 9:360-396, 2003; Setton-Avruj Exp Neurol 203:568-578, 2007; Ohyagi et al. Brain Res 635:323-327, 1994; Schelshorn et al. J Cereb Blood Flow Metab 29:585-595, 2009; Richter et al. J Comp Neurol 515:538-547, 2009) suggests that globins and/or derived peptidic fragments might play additional physiological functions in different tissues. In support of this hypothesis, a number of Hb-derived peptides have been identified and shown to have diverse functions (Ivanov et al. Biopoly 43:171-188, 1997; Karelin et al. Neurochem Res 24:1117-1124, 1999). Modern mass spectrometric analyses have helped in the identification of additional Hb peptides (Newton et al. J Biol Chem 281:5668-5676, 2006; Setton-Avruj Exp Neurol 203:568-578, 2007; Gomes et al. FASEB J 23:3020-3029, 2009); the molecular targets for these are only recently beginning to be revealed. Here, we review the status of the Hb peptide field and highlight recent reports on the identification of a molecular target for a novel set of Hb peptides, hemopressins, and the implication of these peptides to normal cell function and disease. The potential therapeutic applications for these Hb-derived hemopressin peptides will also be discussed.


Outcomes of chronic hepatitis C therapy in patients treated in community versus academic centres in Canada: final results of APPROACH (a prospective study of peginterferon alfa-2a and ribavirin at academic and community centres in Canada).
In patients chronically infected with the hepatitis C virus (HCV), it is not established whether viral outcomes or health-related quality of life (HRQoL) differ between individuals treated at academic or community centres. In the present observational study, adults with chronic HCV were treated with peginterferon alfa-2a 180 ìg⁄week plus ribavirin at 45 Canadian centres (16 academic, 29 community). The primary efficacy end point was sustained virological response (SVR). Other outcome measures included HRQoL (assessed using the 36-item Short-Form Health Survey), heath resource use, and workplace productivity and absences within a 60-day interval. In treatment-naive patients infected with HCV genotype 1, significantly higher SVR rates were achieved in those treated at academic (n=54) compared with community (n=125) centres (52% versus 32% [P=0.01]), although rates of dosage reduction and treatment discontinuation were similar across settings. SVR rates among patients infected with genotype 2⁄3 were similar between academic (n=59) and community (n=100) centres (64% versus 67% [P=0.73]). Following antiviral therapy, patients with genotype 1 who achieved an SVR (n=67) had significantly higher mean scores on the physical (P=0.005) and mental components of the 36-item Short-Form Health Survey (P=0.043) compared with those without an SVR (n=111). In contrast, HRQoL scores were similar in HCV genotype 2⁄3 patients with and without an SVR. There were no differences in workplace productivity or absences between patients with and without an SVR. The most frequently used health care resources by all patients were visits and phone calls to hepatitis nurses, and general practice or walk-in clinics. Patients infected with HCV genotype 1 achieved higher SVR rates when treated at academic rather than community centres in Canada. The reasons for this difference require additional investigation.


Discrimination of influenza infection (A/2009 H1N1) from prior exposure by antibody protein microarray analysis.
Reliable discrimination of recent influenza A infection from previous exposure using hemagglutination inhibition (HI) or virus neutralization tests is currently not feasible. This is due to low sensitivity of the tests and the interference of antibody responses generated by previous infections. Here we investigate the diagnostic characteristics of a newly developed antibody (HA1) protein microarray using data from cross-sectional serological studies carried out before and after the pandemic of 2009. The data are analysed by mixture models, providing a probabilistic classification of sera (susceptible, prior-exposed, recently infected). Estimated sensitivity and specificity for identifying A/2009 infections are low using HI (66% and 51%), and high when using A/2009 microarray data alone or together with A/1918 microarray data (96% and 95%). As a heuristic, a high A/2009 to A/1918 antibody ratio (>1.05) is indicative of recent infection, while a low ratio is indicative of a pre-existing response, even if the A/2009 titer is high. We conclude that highly sensitive and specific classification of individual sera is possible using the protein microarray, thereby enabling precise estimation of age-specific infection attack rates in the population even if sample sizes are small.


[Cancer pain assessment].
Adequate assessment is a necessary precondition for effective pain management. The objectives of cancer pain assessment include: (1) the accurate characterization of the pain, including the pain syndrome and inferred pathophysiology; and (2) the evaluation of the impact of the pain and the role it plays in the overall suffering of the patient. Because patient's self-report is the primary source of information for the measurement of pain, assessment is predicated on the establishment of a trusting relationship with the patient in which the clinician emphasizes the relief of pain and suffering, and encourages open communication about symptoms. Physical examination, including neurological evaluation, is necessary to identify the underlying aetiology of the pain problem, and clarify the extent of the underlying disease. Assessment is an ongoing and dynamic process that includes evaluation of presenting problems, elucidation of pain syndromes and pathophysiology, and formulation of a comprehensive plan for continuing care.


Surface plasmon interferometer in silicon-on-insulator: novel concept for an integrated biosensor.
We propose a novel configuration for a highly integrated and highly sensitive optical biosensor. The basic element of the sensor is a surface plasmon interferometer consisting of a thin layer of gold embedded in a silicon membrane. We investigate the performance of the sensor by simulation using eigenmode expansion. We calculate that refractive index changes in the order of 10(-6) RIU should be easily detectable for a component of length 10 microm. Moreover, we illustrate that the operation wavelength of the sensor can be easily tuned to a desired wavelength for a wide range of environmental refractive indices, making our device suitable for chemo- and biosensing.


Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates.
About 45% of the human genome is comprised of mobile transposable elements or "junk DNA". The exaptation or co-option of these elements to provide important cellular functions is hypothesized to have played a powerful force in evolution; however, proven examples are rare. An ancient primate-specific Alu short interspersed element (SINE) put the human CAMP gene under the regulation of the vitamin D pathway by providing a perfect vitamin D receptor binding element (VDRE) in its promoter. Subsequent studies demonstrated that the vitamin D-cathelicidin pathway may be a key component of a novel innate immune response of human to infection. The lack of evolutionary conservation in non-primate mammals suggested that this is a primate-specific adaptation. Evidence for evolutionary conservation of this regulation in additional primate lineages would provide strong evidence that the TLR2/1-vitamin D-cathelicidin pathway evolved as a biologically important immune response mechanism protecting human and non-human primates against infection. PCR-based amplification of the Alu SINE from human and non-human primate genomic DNA and subsequent sequence analysis, revealed perfect structural conservation of the VDRE in all primates examined. Reporter gene studies and induction of the endogenous CAMP gene in Rhesus macaque peripheral blood mononuclear cells demonstrated that the VDREs were conserved functionally. In addition, New World monkeys (NWMs) have maintained additional, functional steroid-hormone receptor binding sites in the AluSx SINE that confer retinoic acid responsiveness and provide potential thyroid hormone receptor binding sites. These sites were less well-conserved during human, ape and Old World monkey (OWM) evolution and the human CAMP gene does not respond to either retinoic acid or thyroid hormone. We demonstrated that the VDRE in the CAMP gene originated from the exaptation of an AluSx SINE in the lineage leading to humans, apes, OWMs and NWMs and remained under purifying selection for the last 55-60 million years. We present convincing evidence of an evolutionarily fixed, Alu-mediated divergence in steroid hormone nuclear receptor gene regulation between humans/primates and other mammals. Evolutionary selection to place the primate CAMP gene under regulation of the vitamin D pathway potentiates the innate immune response and may counter the anti-inflammatory properties of vitamin D.


Isotopic variance among plant lipid homologues correlates with biodiversity patterns of their source communities.
Plant diversity is important to human welfare worldwide, and this importance is exemplified in subtropical and tropical [(sub)tropical] African savannahs where regional biodiversity enhances the sustaining provision of basic ecosystem services available to millions of residents. Yet, there is a critical lack of knowledge about how savannahs respond to climate change. Here, we report the relationships between savannah vegetation structure, species richness, and bioclimatic variables as recorded by plant biochemical fossils, called biomarkers. Our analyses reveal that the stable carbon isotope composition (δ13C) of discrete sedimentary plant biomarkers reflects vegetation structure, but the isotopic range among plant biomarkers-which we call LEaf Wax Isotopic Spread (LEWIS)-reflects species richness. Analyses of individual biomarker δ13C values and LEWIS for downcore sediments recovered from southeast Africa reveal that the region's species richness mirrored trends in atmospheric carbon dioxide concentration (pCO2) throughout the last 25,000 years. This suggests that increasing pCO2 levels during post-industrialization may prompt future declines in regional biodiversity (1-10 species per unit CO2 p.p.m.v.) through imminent habitat loss or extinction.


A prospective study of clinical outcomes related to third molar removal or retention.
We investigated outcomes of third molar removal or retention in adolescents and young adults. We recruited patients aged 16 to 22 years from a dental practice-based research network in the Pacific Northwest from May 2009 through September 2010 who had at least 1 third molar present and had never undergone third molar removal. Data were acquired via questionnaire and clinical examination at baseline, periodic online questionnaires, and clinical examination at 24 months. A total of 801 patients participated. Among patients undergoing third molar removal, rates of paresthesia and jaw joint symptoms lasting more than 1 month were 6.3 and 34.3 per 100 person-years, respectively. Among patients not undergoing removal, corresponding rates were 0.7 and 8.8. Periodontal attachment loss at distal sites of second molars did not significantly differ by third molar removal status. Incident caries at the distal surfaces of second molars occurred in fewer than 1% of all sites. Rates of paresthesia and temporomandibular joint disorder were higher after third molar removal. Periodontal attachment loss and incident caries at the distal sites of second molars were not affected by extraction status.


[Evaluation of selected parameters of circulatory system function in various occupational groups exposed to high frequency electromagnetic fields. II. Electrocardiographic changes].
The effect of electromagnetic fields (EMF) on the circulatory and nervous systems has been the subject of great interest for many years, since electric impulses generated in these systems by outer electric and magnetic fields can theoretically disturb their functions. The only data on chronic effect of weak EMFs on the human body come from the studies carried out in the Soviet Union between the fifties and the seventies. In view of a growing number of persons exposed to EMF, there is an urgent need for verifying those data by means of modern diagnostic methods. That is the reason why our study of the EMF effect on the circulatory system has been initiated. It covered 71 workers at four AM broadcast stations, 40 workers at ten radio link stations and 42 workers at three radioservices. Workers' exposure to EMF was evaluated (see part I). Subjective and objective medical examinations were performed in all workers in order to assess their state of health, then resting electrocardiogram, Holter measurements, and high intensity ECG were taken, and variation in cardiac rhythm was analysed by a long-term recording of blood pressure. The results of the analysis of the questionnaire survey as well as the Holter and resting ECG examinations are presented. The study indicated that exposure to EMF in parameters found in AM broadcast station increased risk for electrographic disturbances (detected by means of resting ECG and a 24-hour Holter recording) by six times in comparison with that in radio link station workers not exposed to medium wave EMF. In radioservice workers this risk was twice as high as that in link station workers. It seems that in AM broadcast station workers, resting ECG should be complemented by a 24-hour Holter measurements, particularly, if workers complain of the circulatory system disturbances.


Perioperative use of transthoracic echocardiography in a patient with congenitally corrected transposition of great arteries, atrial septal defect and severe pulmonary stenosis for lower segment cesarean section.
A 25-year-old female with congenitally corrected transposition of great arteries (CCTGAs), atrial septal defect, and severe pulmonary stenosis underwent lower segment cesarean section at 34 weeks of gestation using combined spinal epidural anesthesia (CSEA). We used transthoracic echocardiography (TTE) for intraoperative monitoring of the cardiovascular system because these patients are reported to have a high prevalence of myocardial perfusion defects, regional wall motion abnormalities, and impaired ventricular contractility. Scanning was done at four different time intervals; preoperatively, after initiation of CSEA, after delivery of child and postoperatively (6 and 24 h postdelivery) to detect regional wall motion and valvular abnormalities, calculate ejection fractions and optimize fluid administration. In this case report, we thus discuss the anatomical defects of CCTGA, physiologic concerns and emphasize on the use of TTE for perioperative management of such cases.


Mu suppression - A good measure of the human mirror neuron system?
Mu suppression has been proposed as a signature of the activity of the human mirror neuron system (MNS). However the mu frequency band (8-13 Hz) overlaps with the alpha frequency band, which is sensitive to attentional fluctuation, and thus mu suppression could potentially be confounded by changes in attentional engagement. The specific baseline against which mu suppression is assessed may be crucial, yet there is little consistency in how this is defined. We examined mu suppression in 61 typical adults, the largest mu suppression study so far conducted. We compared different methods of baselining, and examined activity at central and occipital electrodes, to both biological (hands) and non-biological (kaleidoscope) moving stimuli, to investigate the involvement of attention and alpha activity in mu suppression. We also examined changes in beta power, another candidate index of MNS engagement. We observed strong mu suppression restricted to central electrodes when participants performed hand movements, demonstrating that mu is indeed responsive to the activity of the motor cortex. However, when we looked for a similar signature of mu suppression to passively observed stimuli, the baselining method proved to be crucial. Selective suppression for biological versus non-biological stimuli was seen at central electrodes only when we used a within-trial baseline based on a static stimulus: this method greatly reduced trial-by-trial variation in the suppression measure compared with baselines based on blank trials presented in separate blocks. Even in this optimal condition, 16-21% of participants showed no mu suppression. Changes in beta power also did not match our predicted pattern for MNS engagement, and did not seem to offer a better measure than mu. Our conclusions are in contrast to those of a recent meta-analysis, which concluded that mu suppression is a valid means to examine mirror neuron activity. We argue that mu suppression can be used to index the human MNS, but the effect is weak and unreliable and easily confounded with alpha suppression.


Perioperative course and recovery after heparin-coated cardiopulmonary bypass: low-dose versus high-dose heparin management.
To compare two heparin managements for a cardiopulmonary bypass (CPB) procedure with heparin-coated equipment. The hypothesis was that a lower heparin dose may reduce blood loss and homologous transfusion requirements and influence the speed of postoperative recovery. Prospective, randomized, and open study. Operating room and intensive care unit in a university hospital. Twenty-four patients undergoing first-time elective coronary artery surgery. Heparin-coated CPB equipment (Duraflo II; Baxter-Bentley) was used in all patients. The study group (n = 12) received low-dose (100 IU/kg i.v. and 0 to 1,000 IU/L priming; target level of activated coagulation time [ACT] over 180 seconds during CPB; suction in a red cell washing device); and the control group (n = 12) received high-dose (300 IU/kg i.v. and 5,000 IU/L priming; ACT over 480 seconds; standard cardiotomy suction) heparin management. ACT remained above 200 seconds after the initial heparin dose in the study group for the CPB duration up to 99 minutes. In 11 of 12 patients in the control group, additional heparin was required during CPB. Total doses of heparin and protamine (mean 8,017 v 50,508 IU and 83 v 325 mg, respectively; p < 0.0001), volume of homologous blood transfusion (median 600 v 1450 mL; p < 0.025), and blood products exposure (median 0.5 v 5.0 units/patients; p < 0.05) were significantly lower in the study group. Postoperative chest drainage showed a trend to lower volume loss (median 705 v 930 mL; p < 0.08) in patients managed with low-dose heparin. Oxygenator resistance during CPB, perioperative laboratory analyses (oxygen and metabolic data, hematocrit, platelet count, prothrombin, thrombin, activated partial thromboplastin time, fibrinogen, D-dimers, creatine kinase, and myocardial band of creatine kinase concentration), fluid balance, and the time periods required for extubation, stay in the intensive care unit, and hospital discharge were not different between the groups. There were no evidences of myocardial infarction in any of 24 patients, and all recovered after the procedure. Low-dose heparin management enabled uneventful procedures with heparin-coated CPB equipment, significantly decreased protamine and homologous blood requirements, but did not reduce chest drainage or influence the postoperative course and recovery in patients after coronary artery surgery.


Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults.
Protective immunity to the liver stage of the malaria parasite can be conferred by vaccine-induced T cells, but no subunit vaccination approach based on cellular immunity has shown efficacy in field studies. We randomly allocated 121 healthy adult male volunteers in Kilifi, Kenya, to vaccination with the recombinant viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia Ankara (MVA), both encoding the malaria peptide sequence ME-TRAP (the multiple epitope string and thrombospondin-related adhesion protein), or to vaccination with rabies vaccine as a control. We gave antimalarials to clear parasitemia and conducted PCR (polymerase chain reaction) analysis on blood samples three times a week to identify infection with the malaria parasite Plasmodium falciparum. On Cox regression, vaccination reduced the risk of infection by 67% [95% confidence interval (CI), 33 to 83%; P = 0.002] during 8 weeks of monitoring. T cell responses to TRAP peptides 21 to 30 were significantly associated with protection (hazard ratio, 0.24; 95% CI, 0.08 to 0.75; P = 0.016).


Low-power switching of phase-change materials with carbon nanotube electrodes.
Phase-change materials (PCMs) are promising candidates for nonvolatile data storage and reconfigurable electronics, but high programming currents have presented a challenge to realize low-power operation. We controlled PCM bits with single-wall and small-diameter multi-wall carbon nanotubes. This configuration achieves programming currents of 0.5 microampere (set) and 5 microamperes (reset), two orders of magnitude lower than present state-of-the-art devices. Pulsed measurements enable memory switching with very low energy consumption. Analysis of over 100 devices finds that the programming voltage and energy are highly scalable and could be below 1 volt and single femtojoules per bit, respectively.


Stress alters the discriminative stimulus and response rate effects of cocaine differentially in lewis and Fischer inbred rats.
Stress enhances the behavioral effects of cocaine, perhaps via hypothalamic-pituitary-adrenal (HPA) axis activity. Yet, compared to Fischer 344 (F344) rats, Lewis rats have hyporesponsive HPA axis function and more readily acquire cocaine self-administration. We hypothesized that stress would differentially affect cocaine behaviors in these strains. The effects of three stressors on the discriminative stimulus and response rate effects of cocaine were investigated. Rats of both strains were trained to discriminate cocaine (10 mg/kg) from saline using a two-lever, food-reinforced (FR10) procedure. Immediately prior to cumulative dose (1, 3, 10 mg/kg cocaine) test sessions, rats were restrained for 15-min, had 15-min of footshock in a distinct context, or were placed in the shock-paired context. Another set of F344 and Lewis rats were tested similarly except they received vehicle injections to test if stress substituted for cocaine. Most vehicle-tested rats failed to respond after stressor exposures. Among cocaine-tested rats, restraint stress enhanced cocaine's discriminative stimulus effects in F344 rats. Shock and shock-context increased response rates in Lewis rats. Stress-induced increases in corticosterone levels showed strain differences but did not correlate with behavior. These data suggest that the behavioral effects of cocaine can be differentially affected by stress in a strain-selective manner.


Legal advocacy as a tool to advance Roma Health.
Roma in central Europe face many violations of their rights, including those that impede their access to high-quality health care. Legal frameworks have the potential to address these violations, whereas legal advocacy services offer a means for enforcement of rights. We undertook key informant interviews with Roma civil society organisations and selected knowledgeable individuals in Macedonia, Romania and Serbia to identify lessons from the development of these services. Achievements were reported in four areas. Legal empowerment, with employment of Roma paralegals was especially effective, increasing awareness of the ability to challenge violations. Documentation of human rights violations is an important basis for advocacy, but does not guarantee redress, and may work best in combination with legal empowerment or international pressure. Strategic litigation can play a key role in removing bureaucratic obstacles that prevent Roma from exercising their right to access to health care. Progress in changing the narrative on Roma in the mainstream media has been limited but examples of good practice exist. Although much remains to be done, Roma groups report that legal advocacy has strengthened their ability to challenge rights violations, thereby enhancing their ability to access effective and responsive care.


The relationship between reproductive work and sociodemographic and psychosocial factors in regard to psychological distress in men and women in Spain.
Studies have shown that some sociodemographic factors, such as marital status, employment status or social class, can affect mental health in different ways for each gender. However, up until now, few research projects have tried to ascertain if the role that reproductive work or psychosocial factors play in mental health is different for men and women. The aim of this study is to assess the differences between men and women in terms of how reproductive work, sociodemographic and psychosocial factors are linked to psychological distress in Spain. A cross-sectional study of 29,478 male and female adults using data gathered for the Spanish National Health Survey 2006 was carried out. Psychological distress was measured using the GHQ-12. The independent variables analyzed were: sociodemographic, psychosocial (family functionality and functional social support) and those related to reproductive work (living with or being in charge of different types of people needing care and number of hours devoted to caregiver tasks). Different independent logistic regression models were developed for men and women. In general, with the exception of men who were more prone to psychological distress if they were signed off work for 3 months or more, no major differences were observed regarding the effect of sociodemographic and psychosocial characteristics on psychological distress. With regard to reproductive work, the likelihood of psychological distress doubles in both sexes when the person lives with someone who needs care. In women, a greater number of hours devoted to caring for another person is associated with an increase in distress. Men play a less frequent role in caregiving, but the impact on psychological distress is similar to that in women. Women experienced more psychological distress when they had to live with or be in charge of a disabled person or different types of persons needing care, while men were not affected by this. Major differences have been identified in terms of psychological distress in women and men in several aspects of reproductive work to date unexplored.


Global sensitivity analysis of bandpass and antireflection coating manufacturing by numerical space filling designs.
We present the effectiveness of global sensitivity analyses of optical coatings manufacturing to assess the robustness of filters by computer experiments. The most critical interactions of layers are determined for a 29 quarter-wave layer bandpass filter and for an antireflection coating with eight non-quarter-wave layers. Two monitoring techniques with the associated production performances are considered, and their influence on the interactions classification is discussed. Global sensitivity analyses by numerical space filling designs give clues to improve filter manufacturing against error effects and to assess the potential robustness of the coatings.


Quantum mechanics/molecular mechanics studies of the mechanism of cysteine protease inhibition by peptidyl-2,3-epoxyketones.
Cysteine proteases are the most abundant proteases in parasitic protozoa and they are essential enzymes to the life cycle of several of them, thus becoming attractive therapeutic targets for the development of new inhibitors. In this paper, a computational study of the inhibition mechanism of cysteine protease by dipeptidyl-2,3-epoxyketone Cbz-Phe-Hph-(S), a recently proposed inhibitor, has been carried out by means of molecular dynamics (MD) simulations with hybrid QM/MM potentials. The computed free energy surfaces of the inhibition mechanism of cysteine proteases by peptidyl epoxyketones showing how the activation of the epoxide ring and the attack of Cys25 on either C2 or C3 atoms take place in a concerted manner. According to our results, the acid species responsible for the protonation of the oxygen atom of the ring would be able to conserve His159, in contrast to previous studies that proposed a water molecule as the activating species. The low activation free energies for the reaction where Cys25 attacks the C2 atom of the epoxide ring (12.1 kcal mol-1) or to the C3 atom (15.4 kcal mol-1), together with the high negative reaction energies suggest that the derivatives of peptidyl-2,3-epoxyketones can be used to develop new potent inhibitors for the treatment of Chagas disease.


The effects of self-assessed health: Dealing with and understanding misclassification bias.
Self-assessed health (SAH) is often used in health econometric models as the key explanatory variable or as a control variable. However, there is evidence questioning its test-retest reliability, with up to 30% of individuals changing their response. Building on recent advances in the econometrics of misclassification, we develop a way to consistently estimate and account for misclassification in reported SAH by using data from a large representative longitudinal survey where SAH was elicited twice. From this we gain new insights into the nature of SAH misclassification and its potential for biasing health econometric estimates. The results from applying our approach to nonlinear models of long-term mortality and chronic morbidities reveal that there is substantial heterogeneity in misclassification patterns. We find that adjusting for misclassification is important for estimating the impact of SAH. For other explanatory variables of interest, we find significant but generally small changes to their estimates when SAH misclassification is ignored.


Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitro growth of Plasmodium falciparum.
The development of novel chemotherapeutic agents has become an urgent task due to the development and rapid spread of drug resistance in Plasmodium falciparum, the protozoan parasite responsible for cerebral malaria. Cyclin-dependent kinases (CDKs) are essential for the regulation of the eukaryotic cell cycle, and several enzymes of this family have been identified in P. falciparum. In recent years, a number of purine-derived kinase inhibitors have been synthesised, some of which display selective activity against CDKs. This report describes a study in which various purine derivatives were screened for in vitro antimalarial activity. The erythrocytic asexual stages of the chloroquine-resistant P. falciparum strain (FCR-3) were cultivated in vitro in the presence of the various purines, and their effect on parasite proliferation was determined by the [3H]hypoxanthine incorporation assay. Our results show considerable variation in the sensitivity of P. falciparum to the different purines, as well as a general independence from their effect on purified starfish CDK1/cyclin B activity, which has been the standard assay used to identify CDK-specific inhibitors. Two subfamilies of purines with moderate to poor activity against CDK1/cyclin B activity showed submicromolar activity against P. falciparum. Structure-activity analysis indicates that certain structural features are associated with increased activity against P. falciparum. These features can be exploited to synthesise compounds with higher activity and specificity towards P. falciparum.