Corticotropin-releasing activity of monokines.
Hepatocyte-stimulating factor and interleukin-1 are proteins produced by monocytes in response to inflammatory challenge. Neither of these monokines had direct effects on steroid production by cultured adrenocortical cells. Both monokines stimulated pituitary cells (AtT-20) to release adrenocorticotropic hormone; interleukin-1 was equipotent with a combination of corticotropin-releasing factor and arginine vasopressin, and hepatocyte-stimulating factor was at least three times as effective. The synthetic glucocorticoid, dexamethasone, inhibited production of hepatocyte-stimulating factor by cultured monocytes. These results indicate an axis between monocytes and pituitary and adrenocortical cells which may play a role in regulating host defense.


CRISPR/cas loci of type II Propionibacterium acnes confer immunity against acquisition of mobile elements present in type I P. acnes.
Propionibacterium acnes is a skin commensal that occasionally acts as an opportunistic pathogen. The population structure of this species shows three main lineages (I-III). While type I strains are mainly associated with sebaceous follicles of human skin and inflammatory acne, types II and III strains are more often associated with deep tissue infections. We investigated the occurrence and distribution of the clustered regularly interspaced short palindromic repeats (CRISPR) in P. acnes, assessed their immunological memory, and addressed the question if such a system could account for type-specific properties of the species. A collection of 108 clinical isolates covering all known phylotypes of P. acnes was screened for the existence of CRISPR/cas loci. We found that CRISPR loci are restricted to type II P. acnes strains. Sequence analyses of the CRISPR spacers revealed that the system confers immunity to P. acnes-specific phages and to two mobile genetic elements. These elements are found almost exclusively in type I P. acnes strains. Genome sequencing of a type I P. acnes isolate revealed that one element, 54 kb in size, encodes a putative secretion/tight adherence (TAD) system. Thus, CRISPR/cas loci in P. acnes recorded the exposure of type II strains to mobile genetic elements of type I strains. The CRISPR/cas locus is deleted in type I strains, which conceivably accounts for their ability to horizontally acquire fitness or virulence traits and might indicate that type I strains constitute a younger subpopulation of P. acnes.


Partial Least Squares with Structured Output for Modelling the Metabolomics Data Obtained from Complex Experimental Designs: A Study into the Y-Block Coding.
Partial least squares (PLS) is one of the most commonly used supervised modelling approaches for analysing multivariate metabolomics data. PLS is typically employed as either a regression model (PLS-R) or a classification model (PLS-DA). However, in metabolomics studies it is common to investigate multiple, potentially interacting, factors simultaneously following a specific experimental design. Such data often cannot be considered as a "pure" regression or a classification problem. Nevertheless, these data have often still been treated as a regression or classification problem and this could lead to ambiguous results. In this study, we investigated the feasibility of designing a hybrid target matrix Y that better reflects the experimental design than simple regression or binary class membership coding commonly used in PLS modelling. The new design of Y coding was based on the same principle used by structural modelling in machine learning techniques. Two real metabolomics datasets were used as examples to illustrate how the new Y coding can improve the interpretability of the PLS model compared to classic regression/classification coding.


Prevalence of potentially inappropriate medications and risk of adverse clinical outcome in a cohort of hospitalized elderly patients: results from the REPOSI Study.
Inappropriate prescribing is highly prevalent for older people and has become a global healthcare concern because of its association with negative health outcomes including ADEs, hospitalization and resource utilization. Beers' criteria are widely utilized for evaluating the appropriateness of medications, and an up-to-date version has recently been published. To assess the prevalence of patients exposed to PIMs at hospital discharge according to the 2003 and 2012 versions of Beers' criteria and to evaluate the risk of adverse clinical events, re-hospitalization and all-cause mortality at 3-month follow-up. This cross-sectional study was held in 66 Italian internal medicine and geriatric wards. The sample included 1380 inpatients aged 65 years or older. Prescriptions of PIM were analysed at hospital discharge. We considered all patients with complete 3-month follow-up. The prevalence of patients receiving at least one PIM was 20·1% and 23·5% according to the 2003 and 2012 versions of the Beers' criteria, respectively. The 2012 Beers' criteria identified more patients with at least one PIM than the 2003 version, although a high percentage of those patients (72·2%) were also identified by the criteria updated in 2003. The main difference in the prevalence of patients receiving a PIM according to the two versions of Beers' criteria involved prescriptions of benzodiazepines for insomnia or agitation, chronic use of non-benzodiazepine hypnotics, prescription of antipsychotics in people with dementia and oral iron at dosage higher than 325 mg/day. Prescription of PIMs was not associated with a higher risk of adverse clinical events, re-hospitalization and all-cause mortality at 3-month follow-up in both univariate and multivariate analysis, after adjusting for age, sex and CIRS comorbidity index. This study found no significant effect of inappropriate drug use according to Beers' criteria on health outcomes among older adults 3 month after discharge. Even though these criteria have been suggested as helpful in promoting appropriate prescribing, reducing drug-related adverse events and associated healthcare costs, to date there is no clear evidence that their application can achieve objective and quantifiable improvements in clinical outcomes. A possible explanation is that both versions of the Beers' criteria have several recognized limitations, one of the main ones being the restricted availability of some drugs in Europe or their limited prescription in everyday clinical practice.


Neural correlates of outcome processing post dishonest choice: an fMRI and ERP study.
A dishonest person often utilizes another person's obliviousness to appropriate the property that belongs to the other person. Previous researchers have studied the making of a dishonest choice and the manipulation of truthful information. Here, we have investigated the neural correlates of processing the outcomes of dishonest decisions. Participants in this study were asked to interact with counterparts in an economic game. They could accept the counterparts' proposals on how to divide the profits (honest choice) or choose the alternative plan that was advantageous to themselves (dishonest choice), playing to the ignorance of their counterparts who had a 50% chance of detecting the situation. Successful dishonest choices (not being detected) would bring large rewards, whereas honest choices would lead to less of a reward, and failed dishonest choices (being caught) would result in no reward. Participants' neural responses during the outcome presentations were recorded by functional magnetic resonance imaging (fMRI) and event-related potential (ERP) methods in different sessions. We found that the outcomes of successful dishonest (vs. honest) choices elicited stronger activations in the ventral striatum and posterior cingulate cortex and a smaller ERP component called feedback-related negativity (FRN), which suggests that positive outcome evaluation and attention processing were aroused by successful dishonest choices. Moreover, the outcomes of failed dishonest (relative to honest) choices were associated with different neural response patterns in the medial orbitofrontal cortex and P3b ERP component between human and computer counterparts, suggesting that processing the output of social decision making (playing human) is different from that of risk taking (playing computer). The findings advanced our understanding about the neural processing of outcome presentation after a dishonest choice has been made.


Potential physiological importance of pyrroloquinoline quinone.
Pyrroloquinoline quinone (PQQ) is a novel biofactor for which a proposition can be made for physiological importance. PQQ was first recognized as an enzyme cofactor in bacteria. It has recently been tentatively identified as a component of interstellar dust. Thus, PQQ may have been present throughout early biological conception and evolution. PQQ is also a potent plant growth factor. Consequently, for animals and humans, there has been constant exposure to PQQ. In animals, PQQ is reported to participate in a range of biological functions with apparent survival benefits (e.g., improved neonatal growth and reproductive performance). There are also benefits from PQQ supplementation related to cognitive, immune, and antioxidant functions, as well as protection from cardiac and neurological ischemic events. Although PQQ is not currently viewed as a vitamin, its involvement in cell signaling pathways, particularly those important to mitochondriogenesis in experimental animal models, may eventually provide a rationale for defining PQQ as vital to life. For humans, such evidence suggests there may be similar parallels or benefits from improving PQQ status.


Evolutionary plasticity in the innate immune function of Akirin.
Eukaryotic gene expression requires the coordinated action of transcription factors, chromatin remodelling complexes and RNA polymerase. The conserved nuclear protein Akirin plays a central role in immune gene expression in insects and mammals, linking the SWI/SNF chromatin-remodelling complex with the transcription factor NFκB. Although nematodes lack NFκB, Akirin is also indispensable for the expression of defence genes in the epidermis of Caenorhabditis elegans following natural fungal infection. Through a combination of reverse genetics and biochemistry, we discovered that in C. elegans Akirin has conserved its role of bridging chromatin-remodellers and transcription factors, but that the identity of its functional partners is different since it forms a physical complex with NuRD proteins and the POU-class transcription factor CEH-18. In addition to providing a substantial step forward in our understanding of innate immune gene regulation in C. elegans, our results give insight into the molecular evolution of lineage-specific signalling pathways.


Temperature and Size Effects on Structural and Dynamical Properties of Water Confined in 1 - 10 nm-scale Pores Using Proton NMR Spectroscopy.
We were able to fill 1 - 10 nm-scale silica pores with water by vapor condensation, and examined the freezing phenomena, structures, and molecular motions of the confined water in the temperature range from 293 to 188 K by 1H-NMR spectroscopy. The results showed that almost all water molecules confined in 10 nm-scale pores were frozen and that approximately half of the water confined in 1 nm-scale pores existed in the liquid state even below the freezing point. The water adsorbed on the pore surfaces was estimated as a monolayer in 2.58 nm pores and bi- and tri-layers in 6.48 nm and larger pores, respectively. Furthermore, it was clarified from the proton relaxation rate (1H-1/T1) measurements that the molecular motions of adsorbed water itself were restricted by nanoconfinement and were extremely dependent on the conditions of proton exchange and hydrogen bond rearrangements of the adsorbed water.


Profiling glucose-induced selective inhibition of disaccharide catabolism in Bacillus megaterium QM B1551 by stable isotope labelling.
We investigated the co-catabolism of carbohydrate mixtures in Bacillus megaterium QM B1551 using a 13C-assisted metabolomics profiling approach. Specifically, we monitored the ability of B. megaterium to achieve the simultaneous catabolism of glucose and a common disaccharide - cellobiose, maltose, or sucrose. Growth experiments indicated that each disaccharide alone can serve as a sole carbon source for B. megaterium, in accordance with the genetic analysis of this bacterium, which predicted diverse metabolic capabilities. However, following growth on 13C-labelled glucose and each unlabelled disaccharide, the labelling patterns of the intracellular metabolites in glycolysis and the pentose phosphate pathway revealed a hierarchy in disaccharide catabolism: (i) complete inhibition of cellobiose catabolism, (ii) minimal catabolism of maltose and (iii) unbiased catabolism of sucrose. The labelling of amino acids confirmed this selective assimilation of each substrate in biomass precursors. This study highlights the fact that B. megaterium exhibits a mixed-carbohydrate utilization that is different from that of B. subtilis, the most studied model Bacillus species.


[Diagnosis and medical care of raptors in a compilation of cases from 1985-1994].
This article summarises the clinical findings in 554 birds of prey, that were admitted to the zoo animal and exotic pet clinic of the veterinary faculty in Zurich between 1 January 1985 and 31 December 1994. Details on the diagnosis, therapy and prognosis are intended to give the practitioner information on the possibilities for the management of diseased raptors. However, it has to be emphasized that the ultimate goal of treatment has to be the rehabilitation of an animal that will be able to survive to a suitable environment. The data presented shows that 31% of the birds of prey were successfully released. The most frequent reason for admission was trauma and 47% of the patients had one or more fractures. But only one out of three fractures was considered suitable for treatment. The management of birds that are starving is a challenge because they require a special dietary regimen. Successful work in the field of the treatment and rehabilitation of raptors requires detailed knowledge of their biology and medicine.


Patterns of gynaecological check-up and their association with body mass index within the CONSTANCES cohort.
To investigate the relationship between patterns of gynaecological check-up and body mass index while accounting for various determinants of health care use. Sequence analysis and clustering were used to highlight patterns of gynaecological check-up, which included the regularity of breast and cervical cancer screening and visits to the gynaecologist over four years, among 6182 women aged 54-65 included in the CONSTANCES cohort between 2013 and 2015 in France. Multinomial logistic regressions were used to study the association between these patterns and women's body mass index. We identified four patterns of gynaecological check-up, from (A) no or inappropriate check-up (20%) to (D) almost one visit to the gynaecologist every year, overscreening for cervical cancer and frequent use of opportunistic breast cancer screening (12%). From patterns A to D, the proportion of obese women decreased and that of women with normal body mass index increased. Obese and overweight women underwent more breast than cervical cancer screening and were less often overscreened than normal weight women. These differences were only partly explained by the lower socioeconomic situation of overweight and obese women. Beyond the financial barrier, the screening modality and the type of exam may play a role. Among women who were screened for cervical cancer, obese and overweight women were less often screened by a gynaecologist. Further efforts should be made to enhance the take-up of screening among obese women who are deterred by the healthcare system.


Effects of a universal classroom management teacher training program on elementary children with aggressive behaviors.
The purpose of this study was to examine the treatment effects of the Incredible Years Teacher Classroom Management (IY TCM), a universal classroom management intervention, on the outcomes of children with aggressive behavior in elementary school. Classroom management has been demonstrated as a factor in either escalating children's aggressive behavior or decreasing those problematic behaviors. Participants included 1,817 students (Grade K to 3) and 105 teachers from nine elementary schools in a large urban Midwestern school district. Teachers were randomly assigned to receive IY TCM or to a wait-list comparison group. The hypotheses were that baseline levels of aggression would moderate the relationship between intervention status and outcomes. Findings indicated the hypothesized moderation effect on several outcome variables; specifically, children with baseline aggression problems who were in IY TCM classrooms had significantly improved math achievement, emotional regulation, prosocial behaviors, and observed aggression in comparison to similar peers in the control classrooms. Implications for practice and future research based on the findings are discussed. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma.
To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. We infer that ecDNA was unevenly inherited by offspring cells, a characteristic that affects the oncogenic potential of cells with more or fewer ecDNAs. Longitudinal patient tumor profiling found that oncogenic ecDNAs are frequently retained throughout the course of disease. Our analysis shows that extrachromosomal elements allow rapid increase of genomic heterogeneity during GBM evolution, independently of chromosomal DNA alterations.


Effects of competitive and non-competitive N-methyl-D-aspartate (NMDA) antagonists in squirrel monkeys trained to discriminate D-CPPene (SDZ EAA 494) from vehicle.
Drug discrimination studies have proven useful for comparing and contrasting the behavioral effects of site-selective N-methyl-D-aspartate (NMDA) antagonists. This study examined the effects of competitive and non-competitive NMDA antagonists in squirrel monkeys trained to discriminate 1 mg/kg D-CPPene [D-3-(2-carboxypiperazine-4-yl)-1- propenyl-1-phosphonic acid; SDZ EAA 494] from vehicle in a two-lever drug discrimination procedure. Results show that D-CPPene and several other competitive NMDA antagonists (NPC 17742, CGS 19755, and CGP 37849) completely substituted for D-CPPene in a dose-dependent manner. In contrast, phencyclidine (PCP) and ketamine produced only partial substitution at doses that severely suppressed response rates. These results are consistent with results of earlier studies with rats and monkeys showing differences in the discriminative stimulus effects of competitive and PCP-like non-competitive NMDA antagonists. The data support the predictions (1) that D-CPPene and the other competitive NMDA antagonists tested would have similar subjective effects in humans and (2) that some differences would be found in the subjective effects of competitive NMDA antagonists and PCP-like non-competitive antagonists.


Macroeconomic environment during infancy as a possible risk factor for adolescent behavioral problems.
CONTEXT Economic difficulties at the individual level can lead to a number of behavioral problems, including substance abuse and delinquent behaviors. OBJECTIVE To examine the influence of a nationwide adverse economic environment during infancy, specifically, the high unemployment rates during and after the 1980 and 1981-1982 recessions, on rates of subsequent adolescent substance use and delinquent behaviors. DESIGN We used data from the National Longitudinal Survey of Youth 1997 and estimated logit regressions to examine the effect of changes in unemployment rates during infancy on the incidence of adolescent behavioral problems, controlling for known youth, family, and environmental risk factors. SETTING Adolescents living in the United States in 1997. PARTICIPANTS Nationally representative sample of 8984 adolescents born from January 1, 1980, through December 31, 1984. MAIN OUTCOME MEASURES Probability of engaging in substance use (marijuana, smoking, alcohol, and hard [ie, illegal] drugs) and delinquent behaviors (arrest, handgun use, gang affiliation, petty and major theft, property destruction, and assaultive behavior). RESULTS Exposure to a 1% deviation from mean regional unemployment rates at the age of 1 year was associated with an increase in the odds ratios of engaging in marijuana use (1.09 [95% CI, 1.04-1.14]), smoking (1.07 [1.03-1.11]), alcohol use (1.06 [1.02-1.10]), arrest (1.17 [1.09-1.25]), gang affiliation (1.09 [1.00-1.19]), and petty (1.06 [1.01-1.10]) and major theft (1.11 [1.05-1.18]). No significant associations were noted with use of hard drugs, property destruction, and assaultive behavior. CONCLUSIONS The macroeconomic environment during infancy can have serious long-term effects on substance use and delinquent behavior. These potential long-term effects can play an important role in policy making for adolescent mental health care.


Antifungal effects of Melaleuca alternifolia (tea tree) oil and its components on Candida albicans, Candida glabrata and Saccharomyces cerevisiae.
The aim of this study was to investigate the mechanism of action of tea tree oil and its components against Candida albicans, Candida glabrata and Saccharomyces cerevisiae. Yeast cells were treated with tea tree oil or components, at one or more concentrations, for up to 6 h. During this time, alterations in permeability were assessed by measuring the leakage of 260 nm absorbing materials and by the uptake of Methylene Blue dye. Membrane fluidity was measured by 1,6-diphenyl-1,3,5-hexatriene fluorescence. The effects of tea tree oil on glucose-induced medium acidification were quantified by measuring the pH of cell suspensions in the presence of both tea tree oil and glucose. The treatment of C. albicans with tea tree oil and components at concentrations of between 0.25 and 1.0% (v/v) altered both permeability and membrane fluidity. Membrane fluidity was also increased when C. albicans was cultured for 24 h with 0.016%-0.06% (v/v) tea tree oil, as compared with control cells. For all three organisms, glucose-induced acidification of the external medium was inhibited in a dose-dependent manner in the presence of 0.2%, 0.3% and 0.4% tea tree oil. Data from this study support the hypothesis that tea tree oil and components exert their antifungal actions by altering membrane properties and compromising membrane-associated functions.


The feasibility of a modified shoe for multi-segment foot motion analysis: a preliminary study.
The majority of multi-segment kinematic foot studies have been limited to barefoot conditions, because shod conditions have the potential for confounding surface-mounted markers. The aim of this study was to investigate whether a shoe modified with a webbed upper can accommodate multi-segment foot marker sets without compromising kinematic measurements under barefoot and shod conditions. Thirty participants (15 controls and 15 participants with midfoot pain) underwent gait analysis in two conditions; barefoot and wearing a shoe (shod) in a random order. The shod condition employed a modified shoe (rubber plimsoll) with a webbed upper, allowing skin mounted reflective markers to be visualised through slits in the webbed material. Three dimensional foot kinematics were captured using the Oxford multi-segment foot model whilst participants walked at a self-selected speed. The foot pain group showed greater hindfoot eversion and less hindfoot dorsiflexion than controls in the barefoot condition and these differences were maintained when measured in the shod condition. Differences between the foot pain and control participants were also observed for walking speed in the barefoot and in the shod conditions. No significant differences between foot pain and control groups were demonstrated at the forefoot in either condition. Subtle differences between pain and control groups, which were found during barefoot walking are retained when wearing the modified shoe. The novel properties of the modified shoe offers a potential solution for the use of passive infrared based motion analysis for shod applications, for instance to investigate the kinematic effect of foot orthoses.


Drosophila syntaxin is required for cell viability and may function in membrane formation and stabilization.
The role of the Drosophila homologue of syntaxin-1A (syx) in neurotransmission has been extensively studied. However, developmental Northern analyses and in situ hybridization experiments show that SYX mRNA is expressed during all stages and in many tissues. We have isolated new mutations in syx that reveal roles for syx outside the nervous system. In the ovary, SYX is present in the germarium, but it is predominantly localized to nurse cell membranes. Mitotic recombination experiments in the germline show SYX is essential for oogenesis and may participate in membrane biogenesis in the nurse cells. In the early embryo, a large contribution of maternally deposited RNA is present, and the protein is localized at cell membranes during cellularization. After the maternal contribution is depleted, zygotically produced SYX assists secretion events occurring late in embryogenesis, such as cuticle deposition and neurotransmitter release. However, SYX is also required in larval imaginal discs, as certain hypomorphic mutant combinations exhibit rough eyes and wing notch defects indicative of cell death. Furthermore, recombinant clones that lack syx cause cell lethality in the developing eye. We propose that, similar to its roles in cuticle secretion and neurotransmitter release, SYX may mediate membrane assembly events throughout Drosophila development.


β-Catenin C-terminal signals suppress p53 and are essential for artery formation.
Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Differential requirements for p53 inhibitors Mdm2 and Mdm4 during development suggest that these control mechanisms are context-dependent. Artery formation requires investment of nascent endothelial tubes by smooth muscle cells (SMCs). Here, we find that embryos lacking SMC β-catenin suffer impaired arterial maturation and die by E12.5, with increased vascular wall p53 activity. β-Catenin-deficient SMCs show no change in p53 levels, but greater p53 acetylation and activity, plus impaired growth and survival. In vivo, SMC p53 inactivation suppresses phenotypes caused by loss of β-catenin. Mechanistically, β-catenin C-terminal interactions inhibit Creb-binding protein-dependent p53 acetylation and p53 transcriptional activity, and are required for artery formation. Thus in SMCs, the β-catenin C-terminus indirectly represses p53, and this function is essential for embryogenesis. These findings have implications for angiogenesis, tissue engineering and vascular disease.


Changing soil legacies to direct restoration of plant communities.
It is increasingly acknowledged that soil biota may influence interactions among plant species; however, little is known about how to change historical influences of previous land management on soil biota, the so-called 'biotic soil legacy effect'. We used a two-phase plant community-soil feedback approach to study how plant species typical to original (i.e. undisturbed) and degraded fen meadows may influence effects of the soil community on Carex species that are dominant in fen meadows. In phase 1, soil from original, degraded, successfully and unsuccessfully restored fen meadows was conditioned by growing plants typical to original or to degraded fen meadows. In phase 2, interactions between Carex and neighbouring plant species were studied to quantify plant community-soil feedback effects in different neighbour plant mixtures. Soil conditioning with plants typical to original fen meadows resulted in significantly more Carex biomass than with plants typical to degraded fen meadows. These effects were strongest when the soil originated from unsuccessfully restored fen meadows. However, biomass of plants typical of degraded fen meadows was also higher in soil conditioned by typical fen meadow plants. We conclude that soil legacy effects of plants from degraded fen meadows can be altered by growing typical fen meadow plant species in that soil, as this enhances priority effects that favour growth of other typical fen meadow plants. As also plant species from degraded fen meadows benefitted from soil conditioning, further studies are needed to reveal if plant species can be chosen that change negative soil legacy effects for rare and endangered fen meadow plant species, but not for plant species that are typical to degraded fen meadows.


A novel mass assay to measure phosphatidylinositol-5-phosphate from cells and tissues.
Phosphatidylinositol-5-phosphate (PI5P) is a low abundance lipid proposed to have functions in cell migration, DNA damage responses, receptor trafficking and insulin signalling in metazoans. However, studies of PI5P function are limited by the lack of scalable techniques to quantify its level from cells and tissues in multicellular organisms. Currently, PI5P measurement requires the use of radionuclide labelling approaches that are not easily applicable in tissues or in vivo samples. In the present study, we describe a simple and reliable, non-radioactive mass assay to measure total PI5P levels from cells and tissues of Drosophila, a genetically tractable multicellular model. We use heavy oxygen-labelled ATP (18O-ATP) to label PI5P from tissue extracts while converting it into PI(4,5)P2 using an in vitro kinase reaction. The product of this reaction can be selectively detected and quantified with high sensitivity using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform. Further, using this method, we capture and quantify the unique acyl chain composition of PI5P from Drosophila cells and tissues. Finally, we demonstrate the use of this technique to quantify elevations in PI5P levels, from Drosophila larval tissues and cultured cells depleted of phosphatidylinositol 5 phosphate 4-kinase (PIP4K), that metabolizes PI5P into PI(4,5)P2 thus regulating its levels. Thus, we demonstrate the potential of our method to quantify PI5P levels with high sensitivity from cells and tissues of multicellular organisms thus accelerating understanding of PI5P functions in vivo.


Prevalence of post-traumatic stress disorder and physical health complaints among Portuguese Army Special Operations Forces deployed in Afghanistan.
Investigations conducted with several U.S. and U.K. military veterans returning from Afghanistan and Iraq have reported the existence of mental and physical health complaints. A total of 113 participants completed a self-report questionnaire that assessed post-traumatic stress disorder (PTSD) symptoms, physical health complaints, and reported illnesses. Overall, 2.7% of the participants reported symptoms compatible with a PTSD diagnosis and 8.8% have partial PTSD. The most common physical health complaints were back pain, fatigue, and muscle pain. In addition, participants experienced gastrointestinal, nervous, and respiratory diseases. PTSD symptoms further explain the variance in physical health complaints after controlling for the contribution of reported illnesses to the same variables. The prevalence of PTSD in the study sample is low, but PTSD symptoms are significantly related to physical health complaints and reported illnesses and explain the variance in physical symptoms. This fact should be considered by clinical support services, and military personnel with physical complaints should be screened for PTSD. These Portuguese results obtained from participants belonging to a well-prepared Special Operations Forces group contribute to a better understanding of the physical and mental impact of the war in Afghanistan.


Twenty-first century challenges for in vitro neurotoxicity.
During the last 40 years, studies incorporating in vitro methodologies have greatly advanced our understanding of human nerve cell biology. Attempts have been made to apply these to investigations of neurotoxicity. Due to the complexity of the nervous system, underpinned by an array of integrated interactions between a host of cell types, it is concluded that, at present, alternative neural models are most successful in determining the underlying mechanisms which can cause perturbation of normal functioning of the nervous system, both in adults and during the embryonic period. The use of tiered batteries of test models has been proposed in screening programmes for neurotoxicity, with the generation of much encouraging data in laboratories across the globe. This review aims to discuss the development of neural alternatives, considers the various model systems available, and highlights specific neuronal endpoints which can be tested, in addition to the cytotoxic evaluation of neuronal viability. Developments in molecular and stem cell biology, which are appropriate to neural tissue, and which offer the prospect of exciting advances for the next decade, are cited.


Validity of verbal autopsy for ascertaining the causes of stillbirth.
To validate the verbal autopsy tool for stillbirths of the World Health Organization (WHO) by using hospital diagnosis of the underlying cause of stillbirth (the gold standard) and to compare the fraction of stillbirths attributed to various specific causes through hospital assessment versus verbal autopsy. In a hospital in Chandigarh, we prospectively studied all stillbirths occurring from 15 April 2006 to 31 March 2008 whose cause was diagnosed within 2 days. All mothers had to be at least 24 weeks pregnant and live within 100 km of the hospital. For verbal autopsy, field workers visited mothers 4 to 6 weeks after the stillbirth. Autopsy results were reviewed by two independent obstetricians and disagreements were resolved by engaging a third expert. Causes of stillbirths as determined by hospital assessment and verbal autopsy were compared in frequency. Hospital assessment and verbal autopsy yielded the same top five underlying causes of stillbirth: pregnancy-induced hypertension (30%), antepartum haemorrhage (16%), underlying maternal illness (12%), congenital malformations (12%) and obstetric complications (10%). Overall diagnostic accuracy of verbal autopsy diagnosis versus hospital-based diagnosis for all five top causes of stillbirth was 64%. The areas under the receiver operator characteristic curve (ROC) were, for congenital malformations, 0.91 (95% confidence interval, CI: 0.83-0.97); pre-gestational maternal illness, 0.75 (95% CI: 0.65-0.84); pregnancy-induced hypertension, 0.76 (95% CI: 0.69-0.81); antepartum haemorrhage, 0.76 (95% CI: 0.67-0.84) and obstetric complication, 0.82 (95% CI: 0.71-0.93). The WHO verbal autopsy tool for stillbirth can provide reasonably good estimates of common underlying causes of stillbirth in resource-limited settings where a medically certified cause of stillbirth may not be available.


Tactile acuity is reduced in people with chronic neck pain.
Tactile acuity deficits have been demonstrated in a range of persistent pain conditions and may reflect underlying cortical re-organisation. This study aimed to determine whether tactile acuity is impaired in people with chronic neck pain relative to controls, and whether deficits relate to pain location, duration and intensity. In this cross-sectional study, 20 people with chronic neck pain (5 idiopathic neck pain; 15 whiplash-associated disorder) and 20 pain-free controls underwent two-point discrimination (TPD) testing at the neck, back and arm, and point-to-point (PTP) and graphesthesia tests of tactile acuity at the neck and arm. Linear mixed effects models demonstrated a significant group*body region interaction for TPD, Graphesthesia and PTP tests (Ps < 0.001), with post hoc tests showing impaired TPD in people with neck pain relative to controls at the neck, low back, and arm (P ≤ 0.001). Graphesthesia and PTP was also impaired at the neck (P < 0.001) but not the arm (P ≥ 0.48). TPD correlated with intensity and duration of pain (Pearson's r = 0.48, P < 0.05; Pearson's r = 0.77, P < 0.01). There was no sig difference between the two neck pain groups for any tactile acuity measure (TPD: P = 0.054; Graphesthesia; P = 0.67; Point to Point: P = 0.77), however, low power limited confidence in this comparison. People with chronic neck pain demonstrated tactile acuity deficits in painful and non-painful regions when measured using the TPD test, with the magnitude of deficits appearing greatest at the neck. The study also revealed a positive relationship between TPD and pain intensity/duration, further supporting the main study finding.


The family talk intervention in palliative care: a study protocol.
In palliative care contexts, support programs for families with a severely ill parent and minor children are few, and even fewer have been evaluated scientifically. The aims of this study are to examine feasibility and potential effects of a modified version of the Family Talk Intervention (FTI) in palliative care. This ongoing family-centered intervention has a quasi-experimental design comparing one intervention and one comparison group. The intervention includes severely ill parents who have minor children (aged 6-19 yrs) and are receiving advanced homecare in Stockholm, Sweden between March 2017 and March 2018. The main goal of the FTI is to support family communication through psycho-education and narrative theory. The modified FTI consists of six meetings with family members, and is held by two interventionists. Each family sets up needs-based goals for the intervention. For evaluation purposes, data are collected by questionnaire before the intervention, within two months after baseline, and one year after baseline. Interviews will be conducted within two months after FTI is completed. Notes taken by one of the interventionists during the family meetings will also be used. Questionnaire data analysis will focus on patterns over time using descriptive statistics. For interview data and notes, content analysis will be used. This study will add knowledge about palliative care for parents who have minor children. It will contribute by testing use of FTI in palliative care, and point out directions for future evaluations of FTI in palliative care settings. ClinicalTrials.gov Identifier NCT03119545 , retrospectively registered in April 18, 2017.


Structural insights into adiponectin receptors suggest ceramidase activity.
Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembrane-domain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.


Flipping Patients and Frames: The Patient in Relational Medicine.
Medicine has evolved in two opposite directions. Evidence-based medicine focuses more on laboratory and computer data than on the patient. Yet experimental data also provide growing evidence for the importance of the patient's social-psychological "demand" side of medicine, to complement the doctor's bio-cognitive "supply" side. The patient's mindset has major diagnostic and therapeutic effects. The patient's experience is shaped by perceptions of four dimensions: meaning, agency, self-image, and temporal focus. The patient's perceptions are linked in part to the therapeutic context, through the interaction between doctor and patient. In that proximal setting, the dimensions can be reshaped, for better and worse. These dynamics point to the inherently interactional nature of medicine and to the significant role of medical social sciences in the therapeutic context.


Differences in Characteristics and Outcomes Between Asian and Non-Asian Patients in the TIAregistry.org.
This study provides the contemporary causes and prognosis of transient ischemic attack (TIA) and minor stroke in Asians and the direct comparisons with non-Asians. The TIAregistry.org enrolled 4789 patients (1149 Asians and 3640 non-Asians) with a TIA or minor ischemic stroke within 7 days of onset. Every participating facility had systems dedicated to urgent intervention of TIA/stroke patients by specialists. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome. Approximately 80% of patients were evaluated within 24 hours of symptom onset. At 1 year, there were no differences in the rates of composite cardiovascular events (6.8% versus 6.0%; P=0.38) and stroke (6.0% versus 4.8%; P=0.11) between Asians and non-Asians. Asians had a lower risk of cerebrovascular disease (stroke or TIA) than non-Asians (adjusted hazard ratio, 0.79; 95% confidence interval, 0.63-0.98; P=0.03); the difference was primarily driven by a lower rate of TIA in Asians (4.2% versus 8.3%; P<0.001). Moderately severe bleeding was more frequent in Asians (0.8% versus 0.3%; P=0.02). In multivariable analysis, multiple acute infarcts (P=0.005) and alcohol consumption (P=0.02) were independent predictors of stroke recurrence in Asians, whereas intracranial stenosis (P<0.001), ABCD2 score (P<0.001), atrial fibrillation (P=0.008), extracranial stenosis (P=0.03), and previous stroke or TIA (P=0.03) were independent predictors in non-Asians. The short-term stroke risk after a TIA or minor stroke was lower than expected when urgent evidence-based care was delivered, irrespective of race/ethnicity or region. However, the predictors of stroke were different for Asians and non-Asians.


Evaluating human basal metabolism: the erroneous and misleading use of so-called "prediction equations".
Prediction (regression) equations are widely used, but their reliability as predictive tools is questionable as they provide contradicting results. The key point is that values calculated by regression equations are not precisely defined numbers but lie within a range of possible values in the standard deviation interval, none of which can be considered as the most probable. Ignoring this point leads to illicit/improper calculations, generating wrong results, which may have adverse consequences for human health. To demonstrate this, we applied the equations of Harris and Benedict in a reverse method, i.e. calculating (predicting) the daily energy expenditure in the same subjects used to obtain the equations and comparing values with the original measured data. We used the Bland-Altman and frequency distribution analyses. We found large differences in both individual data and population characteristics, showing that prediction equations are not predictive tools.


Chronic kidney disease in Asia: Protocol for a collaborative overview.
The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the prognostic implications and treatment patterns in Asian region. We have established the Asian Renal Collaboration (ARC) with the goal of consolidating region-wide data regarding CKD. This collaborative project will synthesize data and perform meta-analyses of observational studies conducted in Asia. Studies will be identified through a systematic literature search including abstracts, proceedings of meetings, electronic databases such as MEDLINE and EMBASE. Personal enquiry among collaborators and experts in the region will identify additional studies, or other data sources such as registries. Both cross-sectional and longitudinal studies that describe the prevalence of CKD and its complications will be included, as will longitudinal studies that describe important clinical outcomes for people with CKD. Individual participant data will be sought, where possible, from each of the studies included in the collaboration for baseline parameters and subsequent outcomes, in order to maximize flexibility and consistency of data analyses. This study is an initiative offering a unique opportunity to obtain information about the prevalence and manifestations of CKD in Asia, as well as its risk factors. The ARC will also provide insights into important outcomes including progression of CKD, CKD complications, cardiovascular disease and death. These findings will improve our understanding of kidney disease in Asia, and thus help inform service provision, preventive care and further research across the region.


Epilepsy in poor regions of the world.
Epilepsy is a common disorder, particularly in poor areas of the world, and can have a devastating effect on people with the disorder and their families. The burden of epilepsy in low-income countries is more than twice that found in high-income countries, probably because the incidence of risk factors is higher. Many of these risk factors can be prevented with inexpensive interventions, but there are only a few studies that have assessed the effect of reducing risk factors on the burden of epilepsy. The mortality associated with epilepsy in low-income countries is substantially higher than in less impoverished countries and most deaths seem to be related to untreated epilepsy (eg, as a result of falls or status epilepticus), but the risk factors for death have not been adequately examined. Epilepsy is associated with substantial stigma in low-income countries, which acts as a barrier to patients accessing biomedical treatment and becoming integrated within society. Seizures can be controlled by inexpensive antiepileptic drugs, but the supply and quality of these drugs can be erratic in poor areas. The treatment gap for epilepsy is high (>60%) in deprived areas, but this could be reduced with low-cost interventions. The substantial burden of epilepsy in poor regions of the world can be reduced by preventing the risk factors, reducing stigma, improving access to biomedical diagnosis and treatment, and ensuring that there is a continuous supply of good quality antiepileptic drugs.


Sanpodo: a context-dependent activator and inhibitor of Notch signaling during asymmetric divisions.
Asymmetric cell divisions generate sibling cells of distinct fates ('A', 'B') and constitute a fundamental mechanism that creates cell-type diversity in multicellular organisms. Antagonistic interactions between the Notch pathway and the intrinsic cell-fate determinant Numb appear to regulate asymmetric divisions in flies and vertebrates. During these divisions, productive Notch signaling requires sanpodo, which encodes a novel transmembrane protein. Here, we demonstrate that Drosophila sanpodo plays a dual role to regulate Notch signaling during asymmetric divisions - amplifying Notch signaling in the absence of Numb in the 'A' daughter cell and inhibiting Notch signaling in the presence of Numb in the 'B' daughter cell. In so doing, sanpodo ensures the asymmetry in Notch signaling levels necessary for the acquisition of distinct fates by the two daughter cells. These findings answer long-standing questions about the restricted ability of Numb and Sanpodo to inhibit and to promote, respectively, Notch signaling during asymmetric divisions.


The Omp85-related chloroplast outer envelope protein OEP80 is essential for viability in Arabidopsis.
beta-Barrel proteins of the Omp85 (Outer membrane protein, 85 kD) superfamily exist in the outer membranes of Gram-negative bacteria, mitochondria, and chloroplasts. Prominent Omp85 proteins in bacteria and mitochondria mediate biogenesis of other beta-barrel proteins and are indispensable for viability. In Arabidopsis (Arabidopsis thaliana) chloroplasts, there are two distinct types of Omp85-related protein: Toc75 (Translocon at the outer envelope membrane of chloroplasts, 75 kD) and OEP80 (Outer Envelope Protein, 80 kD). Toc75 functions as a preprotein translocation channel during chloroplast import, but the role of OEP80 remains elusive. We characterized three T-DNA mutants of the Arabidopsis OEP80 (AtOEP80) gene. Selectable markers associated with the oep80-1 and oep80-2 insertions segregated abnormally, suggesting embryo lethality of the homozygous genotypes. Indeed, no homozygotes were identified among >100 individuals, and heterozygotes of both mutants produced approximately 25% aborted seeds upon self-pollination. Embryo arrest occurred at a relatively late stage (globular embryo proper) as revealed by analysis using Nomarski optics microscopy. This is substantially later than arrest caused by loss of the principal Toc75 isoform, atToc75-III (two-cell stage), suggesting a more specialized role for AtOEP80. Surprisingly, the oep80-3 T-DNA (located in exon 1 between the first and second ATG codons of the open reading frame) did not cause any detectable developmental defects or affect the size of the AtOEP80 protein in chloroplasts. This indicates that the N-terminal region of AtOEP80 is not essential for the targeting, biogenesis, or functionality of the protein, in contrast with atToc75-III, which requires a bipartite targeting sequence.


The dose-dependent effects of halothane on right ventricular contraction pattern and regional inotropy in swine.
The right ventricle (RV) is comprised of two embryologically distinct units, the inflow and outflow tracts, which normally contract sequentially and differ in the magnitude of increased inotropy during sympathetic nervous stimulation. The present study examined the dose-response effects of halothane on the RV contraction pattern and regional contractility in seven open-chest pigs instrumented for measurement of inflow and outflow tract pressures and segment lengths. The RV contraction pattern was evaluated by comparing the phase of inflow and outflow tract shortening, and regional contractility was determined by calculation of preload recruitable stroke work (PRSW) slope. Using this methodology, an inflow-outflow tract contraction phase difference of -27 degrees (inflow tract shortened earlier) was evident at baseline, but was abolished by 1.0 and 1.5 minimum alveolar anesthetic concentration (MAC) halothane; PRSW slope of both the inflow and outflow tracts, however, demonstrated similar dose-related change. To determine whether alterations in cardiac sympathovagal balance played a role in the RV response to halothane, an additional four animals were studied after pretreatment with hexamethonium, propranolol, and atropine. In these animals, there was no difference in the regional contraction phase either at baseline or during halothane administration, and dose-related depression of PRSW by halothane was again similar in both regions. However, when halothane effects on regional PRSW in animals with autonomic blockade were compared to those of neurally intact animals, a 20% greater depression of outflow tract PRSW by 0.5 MAC halothane was evident. This study demonstrates that halothane abolishes the normal sequential pattern of RV contraction without exerting markedly variant negative inotropic effects within different regions of the RV, and provides evidence to suggest that alterations in cardiac sympathovagal balance may contribute to the effect of halothane on RV contraction dynamics.


MOSFET-Embedded microcantilevers for measuring deflection in biomolecular sensors.
A promising approach for detecting biomolecules follows their binding to immobilized probe molecules on microfabricated cantilevers; binding causes surface stresses that bend the cantilever. We measured this deflection, which is on the order of tens of nanometers, by embedding a metal-oxide semiconductor field-effect transistor (MOSFET) into the base of the cantilever and recording decreases in drain current with deflections as small as 5 nanometers. The gate region of the MOSFET responds to surface stresses and thus is embedded in silicon nitride so as to avoid direct contact with the sample solution. This approach, which offers low noise, high sensitivity, and direct readout, was used to detect specific binding events with biotin and antibodies.


Preservation of otologic homografts.
Techniques for preservation of homografts for replacement of tympanic membranes, ossicles, closure of the oval window, and canalplasty remain controversial. Review of 300 articles reveals no evidence opposing the harvesting of grafts from living patients or cadavers, or the prolonged storage of these materials in antibacterial solutions. It appears to be important to store the grafting material long enough to reduce antigenicity. Numerous techniques and materials are being used with success. Additional research on antigens, histologic fate of grafts, long-term success, and complications is essential to determine ideal grafting materials, preservatives, and techniques.


STAT3-induced long noncoding RNAs in multiple myeloma cells display different properties in cancer.
Interleukin-6 (IL-6)-activated Signal Transducer and Activator of Transcription 3 (STAT3) facilitates survival in the multiple myeloma cell line INA-6 and therefore represents an oncogenic key player. However, the biological mechanisms are still not fully understood. In previous studies we identified microRNA-21 as a STAT3 target gene with strong anti-apoptotic potential, suggesting that noncoding RNAs have an impact on the pathogenesis of human multiple myeloma. Here, we describe five long noncoding RNAs (lncRNAs) induced by IL-6-activated STAT3, which we named STAiRs. While STAiRs 1, 2 and 6 remain unprocessed in the nucleus and show myeloma-specific expression, STAiRs 15 and 18 are spliced and broadly expressed. Especially STAiR2 and STAiR18 are promising candidates. STAiR2 originates from the first intron of a tumor suppressor gene. Our data support a mutually exclusive expression of either STAiR2 or the functional tumor suppressor in INA-6 cells and thus a contribution of STAiR2 to tumorigenesis. Furthermore, STAiR18 was shown to be overexpressed in every tested tumor entity, indicating its global role in tumor pathogenesis. Taken together, our study reveals a number of STAT3-induced lncRNAs suggesting that the interplay between the coding and noncoding worlds represents a fundamental principle of STAT3-driven cancer development in multiple myeloma and beyond.


A long-term evaluation of the mandibular Schwarz appliance and the acrylic splint expander in early mixed dentition patients.
The aim of this prospective longitudinal clinical study was to evaluate the short-term and long-term changes in dental-arch dimensions in patients treated with either an acrylic splint rapid maxillary expander alone (RME-only) or a rapid maxillary expander combined with a mandibular removable Schwarz plate (RME-Sz) in the early mixed dentition, followed later by fixed appliances in the permanent dentition. The dental casts of 27 RME-only patients were compared with those of 23 RME-Sz patients and 16 untreated controls (CTRL) with constricted maxillary arches at 4 times: pretreatment (T1), after expansion but before fixed appliance therapy (T2), after fixed appliance therapy (T3), and at long-term observation (T4). The mean ages for the treated groups were approximately 9 years at T1, 12 years at T2, 14 years at T3, and 20 years at T4. Arch width, arch depth, arch perimeter, and molar angulation were assessed in all subjects at all observation times. T1-T2, T2-T3, T3-T4, and T1-T4 changes were compared statistically in the treated groups with respect to the CTRL. Treatment with an RME-only or an RME-Sz followed by fixed appliances produced significant short-term and long-term increases in maxillary arch widths compared with the CTRL. The RME-Sz led to significantly more favorable results than the RME-only protocol: (1) significantly greater increases in the transverse width of the mandibular arch and mandibular arch perimeter in the long term, and (2) uprighting of the mandibular posterior teeth buccally, thus allowing for an amount of maxillary expansion that was clinically effective for the correction of moderate tooth size-arch size discrepancies. In the overall observation interval, the significant increases in maxillary and mandibular arch perimeters in the RME-Sz group were 3.8 and 3.7 mm, respectively, when compared with the CTRL. The RME-only protocol produced modest long-term increases in maxillary arch perimeter (2.6 mm); the average long-term increase in mandibular arch perimeter (2.0 mm) in the RME-only group was not statistically significant. The RME-Sz led to significantly more favorable results than the RME-only protocol.


Automatic measurement of key ski jumping phases and temporal events with a wearable system.
We propose a new method, based on inertial sensors, to automatically measure at high frequency the durations of the main phases of ski jumping (i.e. take-off release, take-off, and early flight). The kinematics of the ski jumping movement were recorded by four inertial sensors, attached to the thigh and shank of junior athletes, for 40 jumps performed during indoor conditions and 36 jumps in field conditions. An algorithm was designed to detect temporal events from the recorded signals and to estimate the duration of each phase. These durations were evaluated against a reference camera-based motion capture system and by trainers conducting video observations. The precision for the take-off release and take-off durations (indoor < 39 ms, outdoor = 27 ms) can be considered technically valid for performance assessment. The errors for early flight duration (indoor = 22 ms, outdoor = 119 ms) were comparable to the trainers' variability and should be interpreted with caution. No significant changes in the error were noted between indoor and outdoor conditions, and individual jumping technique did not influence the error of take-off release and take-off. Therefore, the proposed system can provide valuable information for performance evaluation of ski jumpers during training sessions.


Effect of Porcine circovirus 2 (PCV-2) maternally derived antibodies on performance and PCV-2 viremia in vaccinated piglets under field conditions.
Nowadays, the most common presentation of PCV-2 is the subclinical infection in piglets after weaning. The success of PCV-2 vaccination is associated with the control of the clinical disease as well as the improvement of production parameters. In consequence, the objective of the present study was to analyse the effect of PCV-2 maternally derived antibody (MDA) levels on vaccine efficacy in piglets vaccinated at three weeks of age with a commercial PCV-2 subunit vaccine. The study was performed analysing a database with 6112 wean-to-slaughter piglets from 4 different European regions. Results showed that the use of the vaccine was able to decrease the PCV-2 viremia calculated as area under the curve (AUC = 60.29 ± 3.73), increase average daily weight gain (ADWG = 0.65 ± 0.01 kg/day) and reduce mortality (7%) in vaccinated piglets compared to non-vaccinated ones (AUC of 198.27 ± 6.14, 0.62 ± 0.01 kg/day and 11% respectively). The overall difference of ADWG between both groups was close to 30 g per day (p < 0.05), also when they were split for low and high levels of MDA titres. Moreover, the animals with the highest ADWG were observed in the group of piglets vaccinated with high or extremely high antibody titres (0.66 and 0.65 kg/day respectively). Considering only animals with extremely high antibody titres, both study groups performed similar, however there was a numerical difference of 10 g/day in favour of vaccinated piglets. Likewise, lack of correlation between ADWG and MDA was observed suggesting that no maternal antibody interference was present with the tested vaccine because the vaccinated animals grew faster compared to unvaccinated control animals, regardless of the level of maternal antibodies present at the time of vaccination. The results of the present study demonstrated that the MDA against PCV-2 transferred through the colostrum intake has a protective effect against this viral infection. The vaccine used in the present study (Ingelvac CircoFLEX®) was effective when applied at three weeks of age and was not affected by the level of MDA at the time of vaccination.


UICC-ARO Symposium at the UICC 2016 World Cancer Congress How Can We Mobilize Action to Realize UHC in Asia?
The 2016 World Cancer Congress, organised by UICC, was held in Paris in November 2016, under the theme "Mobilizing action – Inspiring Change." As part of Track 4 presentations on the theme of "Strengthening cancer control: optimizing outcomes of health systems," UICC-Asian Regional Office (UICC-ARO) held a symposium to discuss the issue of mobilizing action to realize UHC in Asia. Introducing the symposium, Hideyuki Akaza noted that universal health coverage (UHC) is included in the Sustainable Development Goals and one of the key issues for achieving UHC will be how to balance patient needs with the economic burden of cancer. Speakers from Japan and Indonesia addressed various issues, including the current status and challenges for medical economic evaluation in Asia, the importance of resource stratification, prospects for precision medicine, and the outlook for cancer control and UHC in developing and emerging countries in Asia. Key issues raised included how to respond to the rising costs of treating cancer as new and increasingly expensive drugs come to the market. Speakers and participants noted that health technology assessment programs are being developed around Asia in order to evaluate the cost-effectiveness of drugs in the face of budgetary constraints within increasingly pressurized national health systems. The importance of screening and early detection was also noted as effective means that have the potential to reduce reliance on expensive drugs for advanced cancers. The symposium was chaired jointly by Hideyuki Akaza and Shinjiro Nozaki (WHO Kobe Centre).


Sleep patterns, shiftwork, and individual differences: a comparison of onshore and offshore control-room operators.
The sleep patterns of offshore control-room operators were compared with those of personnel carrying out similar work onshore, taking into account individual differences in age, number of years of shiftwork, and neuroticism. The dependent variables were self-reported sleep quality and duration for day-shift (D-S) and night-shift (N-S) work, and during leave periods (L-P). Offshore workers reported longer N-S sleep duration, and lower D-S sleep quality than those onshore, but the two groups did not differ in L-P measures. The effects of environmental differences (onshore versus offshore) on sleep patterns were more marked than those of the two different shift systems (weekly rotation and fast rotation) in operation onshore. Age was negatively related to both duration and quality of sleep; over and above age, number of years of shiftwork was negatively related to sleep duration. Neuroticism was also negatively related to sleep duration and, more strongly, to sleep quality. These findings are discussed in relation to the literature on shiftwork and sleep in general, and the characteristics of the offshore environment in particular.


A multi-ion permeation mechanism in neuronal background chloride channels.
Unitary current/voltage relationships of background Cl channels of rat hippocampal neurons were determined for varied gradients and absolute concentrations of NaCl. The channels revealed permeabilities for both Cl and Na ions. A hyperlinear increase of unitary conductance, observed for a symmetrical increase of salt concentration from 300 and 600 mM, indicated a multi-ion permeation mechanism. A variety of kinetic models of permeation were tested against the experimental current/voltage relationships. Models involving a pore occupied by mixed complexes of up to five ions were necessary to reproduce all measurements. A minimal model included four equilibrium states and four rate-limiting transitions, such that the empty pore accepts first an anion and then can acquire one or two cation/anion pairs. Three transport cycles are formed: a slow anion cycle (between the empty and single-anion states), a slow cation cycle (between the one- and three-ion states), and a fast anion cycle (between the three- and five-ion states). Thus, permeant anions are required for cation permeation, and several bound anions and cations promote a high rate of anion permeation. The optimized free-energy and electrical charge parameters yielded a self-consistent molecular interpretation, which can account for the particular order in which the pore accepts ions from the solutions. Although the model describes the mixed anion/cation permeability of the channel observed at elevated concentrations, it predicts a high selectivity for Cl anion at physiological ionic conditions.


Acute hypoxia modifies regulation of neuroglobin in the neonatal mouse brain.
Among endogenous adaptive systems to hypoxia, neuroglobin, a recently discovered heme protein, was suggested as a novel oxygen-dependent neuroprotectant. We aimed to characterize i) maturational age-related regulation of neuroglobin in the developing mouse brain under normoxic and hypoxic conditions, and ii) the role of hypoxia-inducible transcription factors (HIFs) as possible mediators of O(2)-dependent regulation of neuroglobin in vitro and in vivo. During early stages of postnatal brain maturation (P0-P14) neuroglobin mRNA levels significantly increased in developing mouse forebrains. By immunohistochemical analysis we confirmed expression of neuroglobin protein in the cytoplasm of developing neurons but not glial cells under normoxic conditions. Exposure of the immature brains (P0, P7) to acute (8% O(2), 6h) and chronic systemic hypoxia (10% O(2), 7 days) led to differential activation of neuroglobin varying with maturational stage (P0, P7) and severity of hypoxia. This observation may indicate that neuroglobin is involved in adaptive responses of immature neurons to acute hypoxia during an early stage of mouse brain maturation (P0). In response to activation of the HIF system by prolyl-4-hydroxylase inhibitor (FG-4497), neuroglobin mRNA expression was significantly up-regulated in primary mouse cortical neurons (DIV6) exposed to normoxia and hypoxia (1% O(2)) compared to non-treated controls. In conclusion, present results strongly indicate that cerebral regulation of neuroglobin is related to maturational stage and that hypoxia-induced neuroglobin up-regulation is modified by the HIF system.


A unitary anesthetic binding site at high resolution.
Propofol is the most widely used injectable general anesthetic. Its targets include ligand-gated ion channels such as the GABA(A) receptor, but such receptor-channel complexes remain challenging to study at atomic resolution. Until structural biology methods advance to the point of being able to deal with systems such as the GABA(A) receptor, it will be necessary to use more tractable surrogates to probe the molecular details of anesthetic recognition. We have previously shown that recognition of inhalational general anesthetics by the model protein apoferritin closely mirrors recognition by more complex and clinically relevant protein targets; here we show that apoferritin also binds propofol and related GABAergic anesthetics, and that the same binding site mediates recognition of both inhalational and injectable anesthetics. Apoferritin binding affinities for a series of propofol analogs were found to be strongly correlated with the ability to potentiate GABA responses at GABA(A) receptors, validating this model system for injectable anesthetics. High resolution x-ray crystal structures reveal that, despite the presence of hydrogen bond donors and acceptors, anesthetic recognition is mediated largely by van der Waals forces and the hydrophobic effect. Molecular dynamics simulations indicate that the ligands undergo considerable fluctuations about their equilibrium positions. Finally, apoferritin displays both structural and dynamic responses to anesthetic binding, which may mimic changes elicited by anesthetics in physiologic targets like ion channels.


Crystal and molecular structure of r(CGCGAAUUAGCG): an RNA duplex containing two G(anti).A(anti) base pairs.
Non-Watson-Crick base pair associations contribute significantly to the stabilization of RNA tertiary structure. The conformation adopted by such pairs appears to be a function of both the sequence and the secondary structure of the RNA molecule. G.A mispairs adopt G(anti).A(anti) configurations in some circumstances, such as the ends of helical regions of rRNAs, but in other circumstances probably adopt an unusual configuration in which the inter-base hydrogen bonds involve functional groups from other bases. We investigated the structure of G.A pairs in a synthetic RNA dodecamer, r(CGCGAAUUAGCG), which forms a duplex containing two such mismatches. The structure of the RNA duplex was determined by single crystal X-ray diffraction techniques to a resolution in the range 7.0-1.8A, and found to be an A-type helical structure with 10 Watson-Crick pairs and two G.A mispairs. The mispairs adopt the G(anti).A(anti) conformation, held together by two obvious hydrogen bonds. Unlike analogous base pairs seen in a DNA duplex, they do not exhibit a high propeller twist and may therefore be further stabilized by weak, reverse, three-center hydrogen bonds. G(anti).A(anti) mispairs are held together by two hydrogen of guanine and the N6 and N1 of adenine. If the mispairs do not exhibit high propeller twist they may be further stabilized by inter-base reverse three-centre hydrogen bonds. These interactions, and other hydrogen bonds seen in our study, may be important in modelling the structure of RNA molecules and their interactions with other molecules.


Large-scale fabrication of titanium-rich perovskite PZT submicro/nano wires and their electromechanical properties.
We report a 2-step approach to prepare tetragonal perovskite PbZr(0.1)Ti(0.9)O(3) submicro/nano wires in gram scale and with over 95% wire content. Non-perovskite precursor wires were first fabricated by hydrothermal processing. A subsequent annealing in a PbO atmosphere at 600 degrees C converted these wires into perovskite structures which retain the one-dimensional shape. Binding of the perovksite nanowires to a conductive substrate could be achieved by a similar heat treatment of the non-perovskite precursor wires on a flat Pt coated substrate. Taking advantage of the strong mechanical attachment and good electrical contact between the wires and the metallic layer, piezoresponse force microscopy (PFM) was used to measure the local piezoelectric and ferroelectric properties of the individual wires. Enhanced piezoelectric response relative to sputtered epitaxial PbZr(0.2)Ti(0.8)O(3) film and squared hysterisis loop with sharp switching indicate pronounced electro-mechanical and ferroelectric behavior. The 90 degree domain structure of the as-prepared perovskite PZT wires was confirmed by both PFM and transmission electron microscopy investigations.


Role of prethymic cells in acquisition of self-tolerance.
The sequential character of T-lymphocyte development as it pertains to the stage at which self-tolerance is acquired was investigated. Three phases were studied, defined here as prethymic, intrathymic, and postthymic as determined by the timing of thymus implantation. The model utilized was the temporal pattern of skin graft rejection in thymusless BALB/c nude mice implanted with allogeneic, C57BL/6J, or syngeneic thymuses before or after skin grafting; in some instances, F(1) hybrid spleen cells were also given to newborns or young adults. These experiments in nude mice showed that, (a) self-tolerance could be established despite the absence of the host's own haplotype in the implanted thymus; (b) recently emigrated postthymic cells could already discriminate self from non-self; (c) specific neonatal tolerance could be induced in nudes by inoculation of F(1) hybrid cells; (d) nudes showed a higher capacity for induction of neonatal tolerance than did normal littermates. These findings indicate that the process of self-tolerance in the T cell's lineage begins during the prethymic state early in ontogeny.


The major outer membrane protein of Haemophilus ducreyi consists of two OmpA homologs.
The major outer membrane protein (MOMP) of Haemophilus ducreyi is an OmpA homolog that migrates on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels as three species with apparent molecular weights ranging from 37,000 to 43,000. Monoclonal antibodies directed against this macromolecule were used to identify recombinant clones containing fragments of the gene encoding this protein. Nucleotide sequence analysis of these fragments confirmed that the MOMP encoded by the intact gene (momp) was a member of the OmpA family of outer membrane proteins. Construction of an isogenic H. ducreyi mutant unable to express the MOMP led to the discovery of a second outer membrane protein which migrated at the same rate on SDS-PAGE gels as the MOMP. N-terminal amino acid sequence analysis of this second protein revealed that its N terminus was nearly identical to that of the MOMP and also had homology with members of the OmpA family. Nucleotide sequence analysis of the region downstream from the momp gene revealed the presence of a partial open reading frame encoding a predicted OmpA-like protein. A modification of anchored PCR technology was used to obtain the nucleotide sequence of this downstream gene which was shown to encode a second OmpA homolog (OmpA2). The N-terminal amino acid sequence of OmpA2 was identical to that of the OmpA-like protein detected in the momp mutant. The H. ducreyi MOMP and OmpA2 proteins, which comigrated on SDS-PAGE gels and which were encoded by the tandem arranged momp and ompA2 genes, were 72% identical.


The room-temperature superstructure of ZrP2O7 is orthorhombic: there are no unusual 180 degrees P-O-P bond angles.
The structure of room-temperature ZrP2O7 is shown to be orthorhombic by a combination of high-resolution synchrotron powder diffraction and single-crystal synchrotron diffraction data. Small nontwinned single crystals were obtained by synthesizing the compound using solvothermal methods at temperatures below the cubic to orthorhombic phase transition. The average P-O-P angle is 146 degrees. DFT calculations (B3LYP/AUG-cc-pVDZ) on the isolated P2O7(4-) anion yield a P-O-P angle of 153.42 degrees and indicate that the barrier to inversion is of the order 3.6 kJ mol(-1).


Autonomous Exploration for Radioactive Hotspots Localization Taking Account of Sensor Limitations.
Effective radioactive hotspot localization and detection is limited by sensor characteristics (i.e., the long acquisition time and poor angular resolution AR of a gamma camera) that significantly degrade the performance of autonomous exploration in terms of the completion time and accuracy. The goal of this research is to study effective exploration algorithms that take into account these specific sensor limitations. These exploration algorithms are adapted and implemented based on behaviour-based and multi-criteria decision making MCDM approaches on an autonomous robot. The algorithms were also tested in simulation and validated by experiments performed on a real robot. According to the results, the algorithms demonstrate the ability to mitigate the unfavourable effects of the limitations.


Sequence and expression of the gene encoding the respiratory nitrous-oxide reductase from Paracoccus denitrificans. New and conserved structural and regulatory motifs.
The structural gene for the respiratory nitrous-oxide reductase from Paracoccus denitrificans has been cloned using a probe derived from the structural gene, nosZ, for this enzyme from Pseudomonas stutzeri. The cloned gene could be expressed surprisingly well (presumably yielding an apo-protein) using an expression vector in Escherichia coli. Sequencing the nosZ gene from P. denitrificans has shown that the periplasmic nitrous-oxide reductase of this organism is highly similar in sequence to previously derived primary sequences for the enzyme from three other organisms. As with the other reductases, an unusually long signal sequence is deduced and a common motif of GXXRRXXLG near the beginning of this sequence is present. The results of N-terminal sequencing of the mature nitrous-oxide reductase from the closely related organism Thiosphaera pantotropha indicate that processing of the P. denitrificans precursor occurs between amino acids at positions 57 and 58. The predicted signal peptide is therefore of the same length and of similar overall structure to that previously described for the P. denitrificans methylamine dehydrogenase small subunit (MauA). The P. denitrificans sequence for the mature nitrous-oxide reductase reduces from 14 to 11 and 6 to 4, respectively, the number of conserved histidine and methionine residues compared to previous sequences. Three cysteine and four tryptophan residues, previously identified as conserved amongst nitrous-oxide reductases, are found in the Paracoccus enzyme. A comparison of the sequence of the C-terminal region of the nitrous-oxide-reductase sequence with that for the CuA region of subunit II of the cytochrome aa3 from P. denitrificans reveals considerable sequence similarities. Upstream of the structural gene for nosZ are sequences TTGAAGCTTAACCAG (centred at position -21 with respect to the start codon) and CCCGGTGGTCATCAAG (centred at position -126). Although both could be FNR (ANR) boxes, the latter is far more probable to have this role because only it is likely to be upstream of a promoter site. This is the first indication at the DNA sequence level for the existence of this regulatory system in P. denitrificans. Analysis of the flanking DNA sequences revealed reading frames upstream and downstream of the nosZ gene showing similarity to the nosR and nosD genes, respectively, of Pseudomonas species. An S30 in vitro transcription/translation system was developed for P. denitrificans which permitted the expression of the cloned gene for nitrous-oxide reductase and which will be of general value in other studies of this organism.


Tracking image correlation: combining single-particle tracking and image correlation.
The interactions and coordination of biomolecules are crucial for most cellular functions. The observation of protein interactions in live cells may provide a better understanding of the underlying mechanisms. After fluorescent labeling of the interacting partners and live-cell microscopy, the colocalization is generally analyzed by quantitative global methods. Recent studies have addressed questions regarding the individual colocalization of moving biomolecules, usually by using single-particle tracking (SPT) and comparing the fluorescent intensities in both color channels. Here, we introduce a new method that combines SPT and correlation methods to obtain a dynamical 3D colocalization analysis along single trajectories of dual-colored particles. After 3D tracking, the colocalization is computed at each particle's position via the local 3D image cross correlation of the two detection channels. For every particle analyzed, the output consists of the 3D trajectory, the time-resolved 3D colocalization information, and the fluorescence intensity in both channels. In addition, the cross-correlation analysis shows the 3D relative movement of the two fluorescent labels with an accuracy of 30 nm. We apply this method to the tracking of viral fusion events in live cells and demonstrate its capacity to obtain the time-resolved colocalization status of single particles in dense and noisy environments.


Identification of the tyrosine nitration sites in human endothelial nitric oxide synthase by liquid chromatography-mass spectrometry.
The formation of nitric oxide (NO) in biological systems has led to the discovery of a number of post- translational protein modifications that can affect biological conditions such as vasodilation. Studies both from our laboratory and others have shown that beside its effect on cGMP generation from soluble guanylate cylcase, NO can produce protein modifications through both S-nitrosylation of cysteine residues. Previously, we have identified the potential S-nitrosylation sites on endothelial NO synthase (eNOS). Thus, the goal of this study was to further increase our understanding of reactive nitrogen protein modifications of eNOS by identifing tyrosine residues within eNOS that are susceptible to nitration in vitro. To accomplish this, nitration was carried out using tetranitromethane followed by tryptic digest of the protein. The resulting tryptic peptides were analyzed by liquid chromatography/mass spectrometry (LC/MS) and the position of nitrated tyrosines in eNOS were identified. The eNOS sequence contains 30 tyrosine residues and our data indicate that multiple tyrosine residues are capable of being nitrated. We could identify 25 of the 30 residues in our tryptic digests and 19 of these were susceptible to nitration. Interstingly, our data identified four tyrosine residues that can be modified by nitration that are located in the region of eNOS responsible for the binding to heat shock protein 90 (Hsp90), which is responsible for ensuring efficient coupling of eNOS.


Circles South East: the first 10 years 2002-2012.
This article describes the first 10 years of the implementation of Circles of Support and Accountability (Circles) in the management of sexual offenders in South-East England by Circles South East (CSE). The Circles of 71 core members are reviewed in detail, with reference to demographic data, offense and sentencing histories, risk assessment data, and considerations regarding Multi-Agency Public Protection Arrangements. A group of 71 comparison subjects who were referred to CSE and deemed suitable for but did not receive the service was identified. Follow-up behaviors of both groups are examined (including all forms of reconviction, breach of orders, and prison recall). Over a comparable follow-up period of 55 months, the incidence of violent and contact sexual reconviction in the comparison group was significantly higher than for the Circles cohort. Comparisons are made between expected and actual levels of sexual reconviction, with the Circles cohort showing lower than expected rate of sexual reconviction but not to a statistically significant degree.


Longitudinal associations between psychological well-being and the consumption of fruits and vegetables.
Psychological well-being is associated with longevity and reduced risk of disease, but possible mechanisms are understudied. Health behaviors like eating fruits and vegetables may link psychological well-being with better health; however, most evidence is cross-sectional. This study investigated psychological well-being's longitudinal association with fruit and vegetable consumption across as many as 7 years. Participants were 6,565 older adults from the English Longitudinal Study of Ageing, which includes men and women aged 50 years or older. Psychological well-being was assessed with 17 items from the Control, Autonomy, Satisfaction, Pleasure Scale. Fruit and vegetable consumption was initially assessed during 2006-2007 and then approximately every 2 years through 2012-2013. Covariates included sociodemographic factors, health status, and other health behaviors. Mixed linear models showed that higher baseline levels of psychological well-being were associated with more fruit and vegetable consumption at baseline (β = 0.05, 95% confidence interval [CI] [0.02, 0.08]) and that fruit and vegetable consumption declined across time (β = -0.01, 95% CI [-0.02, -0.004]). Psychological well-being interacted significantly with time such that individuals with higher baseline psychological well-being had slower declines in fruit and vegetable consumption (β = 0.01, 95% CI [0.01, 0.02]). Among individuals who initially met recommendations to consume 5 or more servings of fruits and vegetables (N = 1,719), higher baseline psychological well-being was associated with 11% reduced risk of falling below recommended levels during follow-up (hazard ratio = 0.89, 95% CI [0.83, 0.95]). Findings suggest that psychological well-being may be a precursor to healthy behaviors such as eating a diet rich in fruits and vegetables. (PsycINFO Database Record


Incidence of pediatric and neonatal intensive care unit-acquired infections.
To compare the cumulative incidence of infections acquired in the pediatric intensive care unit (PICU) and neonatal intensive care unit (NICU). Estimation of the cumulative incidence of infections with data obtained from the Pediatric Prevention Network (PPN) point-prevalence survey and observed rates from the National Nosocomial Infections Surveillance (NNIS) system. Ten hospitals participated in both the PPN survey and NNIS system. All patients present on the PPN survey dates (August 4, 1999, or February 1, 2000) in the NICUs or PICUs of the PPN hospitals were included in the survey. Point prevalences for PICU-acquired and for NICU-acquired infections at these hospitals were calculated from the survey data. The cumulative incidence rates were estimated from the point prevalence rates using a standard formula and a standard method for calculating the time to recovery (ie, on the basis of the assumption that discontinuance of antimicrobial therapy indicates recovery from infection); alternate methods to judge the time to recovery from infection were also explored. The average cumulative incidence of intensive care unit-acquired infection for NICUs and PICUs combined (all units), as measured by NNIS, was 14.1 cases per 100 patients; in comparison, the prevalence was 14.06 cases for 100 patients (median difference, -0.95 cases per 100 patients; 95% confidence interval, -4.6 to 5.0 cases per 100 patients), and the estimated cumulative incidence using the standard method of calculating the time to recovery was 13.8 cases per 100 patients (median difference, -1.5 cases per 100 patients; 95% confidence interval, -9.1 to 2.9 cases per 100 patients). Estimates of cumulative incidence using alternate methods for calculation of time to recovery did not perform as well (range, 4.9-100.9 cases per 100 patients). The average incidence density for all units, as measured by the NNIS system, was 6.8 cases per 1,000 patient-days, and the estimate of incidence density using the standard method of calculating the time to recovery was 3.6 cases per 1,000 patient-days (median difference, 4.3 cases per 1,000 patient-days; 95% confidence interval, 0.9 to 9.2 cases per 1,000 patient-days). Estimated incidence densities using alternate methods for determining recovery time correlated closely with observed incidence densities. In this patient population, the simple point prevalence provided the best estimate of cumulative incidence, followed by use of a standard formula and a standard method of calculating the time to recovery. Estimation of incidence density using alternate methods performed well. The standard formula and method may provide an even better estimate of cumulative incidence than does simple prevalence in general populations.


MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults.
To determine whether volumes of hippocampus and amygdala are abnormal in people with autism. Neuropathologic studies of the limbic system in autism have found decreased neuronal size, increased neuronal packing density, and decreased complexity of dendritic arbors in hippocampus, amygdala, and other limbic structures. These findings are suggestive of a developmental curtailment in the maturation of the neurons and neuropil. Measurement of hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled gradient-recalled echo MRI scans in 14 non-mentally retarded autistic male adolescents and young adults and 14 individually matched, healthy community volunteers. Amygdala volume was significantly smaller in the autistic subjects, both with (p = 0.006) and without (p = 0.01) correcting for total brain volume. Total brain volume and absolute hippocampal volume did not differ significantly between groups, but hippocampal volume, when corrected for total brain volume, was significantly reduced (p = 0.04) in the autistic subjects. There is a reduction in the volume of amygdala and hippocampus in people with autism, particularly in relation to total brain volume. The histopathology of autism suggests that these volume reductions are related to a reduction in dendritic tree and neuropil development, and likely reflect the underdevelopment of the neural connections of limbic structures with other parts of the brain, particularly cerebral cortex.


Distribution of Salmonella serovars and phage types on 80 Ontario swine farms in 2004.
The objective of this study was to describe the distribution of Salmonella spp. on Ontario grower-finisher pig farms. Eighty swine farms were visited from January through July 2004. On each farm, fecal samples were collected from 5 pens, 2 rectal samples and 1 pooled sample from fresh manure on the floor per pen. Salmonella was isolated from 91 (11%) of the 800 rectal samples and 73 (18%) of the 397 pooled samples. Overall, Salmonella was recovered from 37 (46%) of the 80 farms. On each positive farm, Salmonella was cultured from 1 to 7 pigs or 1 to 5 pens. Of the 37 farms, 18, 13, 5, and 1 yielded 1, 2, 3, and 4 serovars, respectively. The most common serovars were S. Typhimurium var. Copenhagen, S. Infantis, S. Typhimurium, S. Derby, S. Agona, S. Havana, and S. enterica subsp. I:Rough-O. The 3 most frequent phage types were PT 104, PT 104a, and PT 104b. There was a statistically fair agreement between samples collected directly from pigs and pooled pen samples in determining the Salmonella status at the pen and farm level (kappa = 0.6, P < 0.0001). However, in 62 pens, Salmonella status, serovars, or phage types differed between the pig and pooled pen samples. The distribution of Salmonella on the swine farms in this study indicates that, in developing an intervention strategy, priority should be given to farms positive for S. Typhimurium var. Copenhagen. Also, the variation in Salmonella status between pig and pooled pen samples deserves consideration in a sampling strategy.


Nanoparticle-Based Histidine-Rich Protein-2 Assay for the Detection of the Malaria Parasite Plasmodium falciparum.
A nanoparticle-based assay for detection and quantification of Plasmodium falciparum histidine-rich protein 2 (HRP2) in urine and serum is reported. The assay uses magnetic beads conjugated with anti-HRP2 antibody for protein capture and concentration, and antibody-conjugated quantum dots for optical detection. Western blot analysis demonstrated that magnetic beads allow the concentration of HRP2 protein in urine by 20-fold. The concentration effect was achieved because large volume of urine can be incubated with beads, and magnetic separation can be easily performed in minutes to isolate beads containing HRP2 protein. Magnetic beads and quantum dots conjugated to anti-HRP2 antibodies allows the detection of low concentrations of HRP2 protein (0.5 ng/mL), and quantification in the range of 33-2,000 ng/mL corresponding to the range associated with non-severe to severe malaria. This assay can be easily adapted to a noninvasive point-of-care test for classification of severe malaria.


The Beneficial Effects of Cognitive Training With Simple Calculation and Reading Aloud (SCRA) in the Elderly Postoperative Population: A Pilot Randomized Controlled Trial.
Background: There has been little research conducted regarding cognitive treatments for the elderly postsurgical population. Patients aged ≥60 years have an increased risk of postoperative cognitive decline, a condition in which cognitive functions are negatively affected. This cognitive decline can lead to a decline in quality of life. In order to maintain a high quality of life, the elderly postsurgical population may benefit from treatment to maintain and/or improve their cognitive functions. This pilot study investigates the effect of simple calculation and reading aloud (SCRA) cognitive training in elderly Japanese postsurgical patients. Methods: Elderly patients undergoing non-cardiovascular thoracic surgery under general anesthesia were recruited (n = 12). Subjects were randomly divided into two groups-one that receives 12 weeks of SCRA intervention, and a waitlisted control group. Before and after the intervention, we measured cognitive function [Mini-Mental Status Exam-Japanese (MMSE-J), Frontal Assessment Battery (FAB), computerized Cogstate Brief Battery (CBB)] and emotional state [General Health Questionnaire-12 (GHQ-12), Geriatric Depression Scale (GDS), Quality of Life Scale-5 (QOL-5)]. Results: Group difference analyses using ANCOVA with permutation test showed that the intervention SCRA group had a significant improvement in FAB motor programming sub-score, GDS, and QOL-5 compared to the control group. Within-group analyses using Wilcoxon signed-rank test to compare baseline and follow-up showed that the SCRA intervention group total FAB scores, FAB motor programming sub-scores, and QOL-5 scores were significantly improved. Discussion: This pilot study showed that there are important implications for the beneficial effects of SCRA intervention on cognitive function and emotional state in the postoperative elderly population; however, further investigations are necessary to reach any conclusions. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000019832).


CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants.
While microvascular injury is associated with chronic rejection, the cause of tissue ischemia during alloimmune injury is not yet elucidated. We investigated the contribution of T lymphocytes and complement to microvascular injury-associated ischemia during acute rejection of mouse tracheal transplants. Using novel techniques to assess microvascular integrity and function, we evaluated how lymphocyte subsets and complement specifically affect microvascular perfusion and tissue oxygenation in MHC-mismatched transplants. To characterize T cell effects on microvessel loss and recovery, we transplanted functional airway grafts in the presence and absence of CD4(+) and CD8(+) T cells. To establish the contribution of complement-mediated injury to the allograft microcirculation, we transplanted C3-deficient and C3-inhibited recipients. We demonstrated that CD4(+) T cells and complement are independently sufficient to cause graft ischemia. CD8(+) T cells were required for airway neovascularization to occur following CD4-mediated rejection. Activation of antibody-dependent complement pathways mediated tissue ischemia even in the absence of cellular rejection. Complement inhibition by CR2-Crry attenuated graft hypoxia, complement/antibody deposition on vascular endothelium and promoted vascular perfusion by enhanced angiogenesis. Finally, there was a clear relationship between the burden of tissue hypoxia (ischemia×time duration) and the development of subsequent airway remodeling. These studies demonstrated that CD4(+) T cells and complement operate independently to cause transplant ischemia during acute rejection and that sustained ischemia is a precursor to chronic rejection.