Tracking prions: the neurografting approach.
The physical nature of the agent that causes transmissible spongiform encephalopathies (the 'prion'), is the subject of passionate controversy. Investigation of it has benefited tremendously from the use of transgenic and knockout technologies. However, prion diseases present several other enigmas, including the mechanism of brain damage and how the affinity of the agent for the central nervous system is controlled. Here we show that such questions can be effectively addressed in transgenic and knockout systems, and that pathogenesis may be clarified even before we can be certain about the nature of the infectious agent. Availability of mice overexpressing the Prnp gene (which encodes the normal prion protein) and Prnp knockout mice allows for selective reconstitution experiments aimed at expressing PrP in specific portions of the brain or in selected populations of hemato- and lymphopoietic origin. We summarize how such studies can offer insights into how prions administered to peripheral sites can gain access to central nervous tissue, and into the molecular requirements for spongiform brain damage.


Emergence of carp edema virus in cultured ornamental koi carp, Cyprinus carpio koi, in India.
A disease outbreak was reported in adult koi, Cyprinus carpio koi, from a fish farm in Kerala, India, during June 2015. The clinical signs were observed only in recently introduced adult koi, and an existing population of fish did not show any clinical signs or mortality. Microscopic examination of wet mounts from the gills of affected koi revealed minor infestation of Dactylogyrus sp. in a few koi. In bacteriological studies, only opportunistic bacteria were isolated from the gills of affected fish. The histopathological examination of the affected fish revealed necrotic changes in gills and, importantly, virus particles were demonstrated in cytoplasm of gill epithelial cells in transmission electron microscopy. The tissue samples from affected koi were negative for common viruses reported from koi viz. cyprinid herpesvirus 3, spring viraemia of carp virus, koi ranavirus and red sea bream iridovirus in PCR screening. However, gill tissue from affected koi carp was positive for carp edema virus (CEV) in the first step of nested PCR, and sequencing of PCR amplicons confirmed infection with CEV. No cytopathic effect was observed in six fish cell lines following inoculation of filtered tissue homogenate prepared from gills of affected fish. In bioassay, the symptoms could be reproduced by inoculation of naive koi with filtrate from gill tissue homogenate of CEV-positive fish. Subsequently, screening of koi showing clinical signs similar to koi sleepy disease from different locations revealed that CEV infection was widespread. To our knowledge, this is the first report of infection with CEV in koi from India.


The third Trp-Lys-Ser (WKS) tripeptide motif in tissue factor is associated with a function site.
The tripeptide sequence Trp-Lys-Ser (WKS) is repeated three times in the extracellular ligand binding domain of human Tissue Factor (TF). Using site-directed mutagenesis, we replaced each of the WKS motifs in human TF by Arg-Lys-Gly (RKG), the least conserved replacement for the motif found in murine TF. This substitution in the first repeat W14KS, as well as a Trp14----Arg substitution, resulted in a structurally altered protein, whereas a conservative hydrophobic Trp14----Phe substitution resulted in a functionally normal protein. This suggests that Trp14 may contribute to a hydrophobic core rather than involvement of this motif in function. Replacement of the W45KS and W158KS motifs was associated with no detectable structural alterations; however, function was diminished with the RKG replacement of the third repeat. Mutant proteins with Lys159----Ala and Tyr157----Ala substitutions exhibited loss of function, whereas Tyr156----Ala and Ser160----Ala substitutions flanking the YWK sequence resulted in functional proteins. These data demonstrate that the W158KS motif in human TF is associated with a functional site and identify Lys159 in this motif as a functionally important residue.


Tolerancing of board-level-free-space optical interconnects.
For optical interconnects to become a mature technology they must be amenable to electronic packaging technology. Two main obstacles to including free-space optical interconnects are alignment and heat-dissipation issues. Here we study the issues of alignment tolerancing that are due to assembly and manufacturing variations (passive-element tolerancing) over long board-level distances (>10 cm) for free-space optical interconnects. We also combine these variations with active optoelectronic device variations (active-element tolerancing). We demonstrate a computer-aided analysis procedure that permits one to determine both active- and passive-element tolerances needed to achieve some system-level specification, such as yield or cost. The procedure that we employ relies on developing a detailed design of the system to be studied in a standard optical design program, such as code v. Using information from this model, we can determine the integrated power falling on the detector, which we term optical throughput, by performing Gaussian propagation or general Fresnel propagation (if significant vignetting occurs). This optical throughput can be used to determine system-level performance criteria, such as bit-error rate. With this computer-aided analysis technique, a sensitivity analysis of all the variations under study is made on a system with realistic board-level interconnect distances to find each perturbation's relative effects (with other perturbations set to 0) on the power falling on the detector. This information is used to set initial tolerances for subsequent tolerancing analysis and design runs. A tolerancing analysis by Monte Carlo techniques is applied to determine if the yield or cost (yield is denned as the percentage of systems that have acceptable system performance) is acceptable. With a technique called parametric sampling, a subsequent tolerancing design run can be applied to optimize this yield or cost with little increase in computation. We study a design example and show that most of the tolerances can be achieved with current technology.


Targeting apoptosis: preclinical and early clinical experience with mapatumumab, an agonist monoclonal antibody targeting TRAIL-R1.
In spite of the advances in survival with chemotherapy and radiotherapy, many cancer patients continue to experience failure with treatments. Advances in molecular oncology and the development of numerous targeted therapies, used by themselves or in combination with at present available treatments such as chemotherapy and radiation, will hopefully improve the fate of these patients. It has been well understood for many years now that deregulation of apoptosis is a major hallmark of cancer cells. Mapatumumab, a fully human agonistic monoclonal antibody to TNF-related apoptosis-inducing ligand receptor 1, has been developed to induce apoptosis in cancer cells although having minimal effects on normal cells. This paper reviews the preclinical and early clinical data of this exciting new agent and discusses options for future development of mapatumumab, mostly in combinations with other therapies.


Timing and origin of the first cortical axons to project through the corpus callosum and the subsequent emergence of callosal projection cells in mouse.
A precise knowledge of the timing and origin of the first cortical axons to project through the corpus callosum (CC) and of the subsequent emergence of callosal projection cells is essential for understanding the early ontogeny of this commissure. By using a series of mouse embryos and fetuses of the hybrid cross B6D2F2/J weighing from 0.36 g to 1.0 g (embryonic day E15.75-E17.25), we examined the spatial and temporal distribution of callosal projection cells by inserting crystals of the lipophilic dye (DiI: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into the contralateral white matter just lateral to the midsagittal plane. Around 0.4 g or E15.8, retrogradely labeled cells were found restricted to a discrete cluster continuously distributed from the most ventral part of presumptive cingulate cortex to the hippocampus. During subsequent development, however, the tangential distribution of these labeled cells in ventromedial cortex did not extend further dorsally, and in fetuses where the CC became distinct from the hippocampal commissure (HC), labeled axons of cells in the ventral cingulate cortex were observed to intersect the callosal pathway and merge with labeled axons of the HC derived from cells in the hippocampus. The first cortical axons through the CC crossed the midline at about 0.64 g or E16.4, and these axons originated from a scattered neuronal population in the dorsal to lateral part of the presumptive frontal cortex. The earliest callosal cells were consistently located in the cortical plate and showed an immature bipolar appearance, displaying an ovoid- or pearl-shaped perikaryon with an apical dendrite coursing in a zig-zagging manner toward the pial surface and a slender axon directed toward the underlying white matter. Callosal projection cells spread progressively with development across the tangential extent of the cerebral cortex in both lateral-to-medial and rostral-to-caudal directions. In any cortical region, the first labeled cells appeared in the cortical plate and their number in the subplate was insignificant compared to that in the cortical plate. Thus, these results clarify that the CC is pioneered by frontal cortical plate cells, and the subsequent ontogeny of callosal projection cells proceeds according to the gradient of cortical maturation.


Calcium-regulated exocytosis in neuroendocrine cells: intersectin-1L stimulates actin polymerization and exocytosis by activating Cdc42.
Actin cytoskeleton remodeling is a critical step of regulated exocytosis in many secretory cell types, including neuroendocrine cells. While the classical model considers the cortical actin network as a physical barrier preventing the uncontrolled recruitment of secretory granules to the plasma membrane docking sites, recent evidence supports the idea that actin polymerization also plays a more active role in the late stages of exocytosis. However, the molecular machinery underlying this positive function of actin in the course of exocytosis remains largely unknown. Here, we propose that the neuronal guanine nucleotide exchange factor, intersectin-1L, activates the GTPase Cdc42, which in turn provides de novo actin filaments that are important for calcium-regulated exocytosis in PC12 cells.


Well-ordered mesoporous Fe2O3/C composites as high performance anode materials for sodium-ion batteries.
Sodium-ion batteries have attracted considerable attention in recent years. In order to promote the practical application of sodium-ion batteries, the electrochemical performances, such as specific capacity, reversibility, and rate capability of the anode materials, should be further improved. In this work, a Fe2O3/C composite with a well-ordered mesoporous structure is prepared via a facile co-impregnation method by using mesoporous silica SBA-15 as a hard template. When used as an anode material for sodium-ion batteries, the well-ordered mesoporous structure ensures fast mass transport kinetics. The presence of nano-sized Fe2O3 particles confined within the carbon walls significantly enhances the specific capacity of the composite. The carbon walls in the composite act not only as an active material contributing to the specific capacity, but also as a conductive matrix improving the cycling stability of Fe2O3 nanoparticles. As a result, the well-ordered mesoporous Fe2O3/C composite exhibits high specific capacity, excellent cycleability, and high rate capability. It is proposed that this simple co-impregnation method is applicable for the preparation of well-ordered mesoporous transition oxide/carbon composite electrode materials for high performance sodium-ion and lithium-ion batteries.


Application of the adult international germ cell classification system to pediatric malignant non-seminomatous germ cell tumors: a report from the Children's Oncology Group.
The purpose of this analysis is to explore whether the International Germ Cell Classification Consensus (IGCCC) tumor marker criteria, developed for adult males with metastatic malignant germ cell tumors (MGCT), are prognostic among pediatric patients and whether tumor marker data may be relevant in pediatric risk stratification. The IGCCC was applied to 436 pediatric germ cell patients treated on Pediatric Intergroup Studies from 1990 to 1996. Multivariable Cox proportional hazards model identified prognostic variables; survival rates among IGCCC risk groups were compared using the log-rank test. Concordance and relative performance of IGCCC versus COG risk stratification was evaluated. Applying the IGCCC, 21% of pediatric patients were good risk (GR), 35% intermediate risk (IR), and 44% poor risk (PR). Only modest concordance between IGCCC and COG stratification systems was noted (49%). Nonetheless, the IGCCC identified a group of PR patients who had significantly worse event-free survival (EFS) versus GR/IR patients (6-year EFS 80% vs. 91%), which was similar to the difference observed using the COG system (6-year EFS 77% vs. 90%). The IGCCC performed well within subgroups for which the IGCCC is not intended (prepubertal, female, and non-metastatic patients). Applying the IGCCC system to pediatric patients produces a different stratification than does the application of the COG system, although both are prognostic. Development of a de novo pediatric prognostic classification is warranted.


[Analysis of agreement between self-reported and observed information on pubertal development among school girls].
To test the reliability of the self-classification concerning levels of breast and public hair development among female adolescents of different socioeconomic groups. A total of 445 female adolescents attending three secondary schools located in Ribeirão Preto, State of S. Paulo, Brazil, were studied. After being familiarised with Tanner's tables of breast and public hair development, the adolescents were asked to self classify themselves according to these variables. The results were compared to those obtained by a physical examination carried out soon after. Agreement rates between referred and observed information on breast development varied from 57.3% to 65.2%. For public hair the values varied from 65.4% to 73.5%. Total agreement rates for breast and public hair development, when considered simultaneously, reached values below 50.0% in the three schools. However, high agreement rates were observed for some critical degrees, such as B2, B4 and PH4. Significant events, such as the beginning of pubertal development, the menarche and the showing down of the body's development growth could be determined with acceptable levels of agreement. The low agreement rates observed for the simultaneous analysis of the degree of both breast and public hair show the need for the perfecting of methodologies that can replace the physical examination of adolescents, once reliable information about pubertal development is obtained in field studies.


Adenosine-activated mast cells induce IgE synthesis by B lymphocytes: an A2B-mediated process involving Th2 cytokines IL-4 and IL-13 with implications for asthma.
Adenosine provokes bronchoconstriction in asthmatics through acute activation of mast cells, but its potential role in chronic inflammation has not been adequately characterized. We hypothesized that adenosine up-regulates Th2 cytokines in mast cells, thus promoting IgE synthesis by B lymphocytes. We tested this hypothesis in human mast cells (HMC-1) expressing A(2A), A(2B), and A(3) adenosine receptors. The adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA) (10 microM) increased mRNA expression of IL-1beta, IL-3, IL-4, IL-8, and IL-13, but not IL-2 and IFN-gamma. Up-regulation of IL-4 and IL-13 was verified using RT-PCR and ELISA; 10 microM NECA increased IL-13 concentrations in HMC-1 conditioned medium 28-fold, from 7.6 +/- 0.3 to 215 +/- 4 pg/ml, and increased IL-4 concentrations 6-fold, from 19.2 +/- 0.1 to 117 +/- 2 pg/ml. This effect was mediated by A(2B) receptors because neither the selective A(2A) agonist 2-p-(2-carboxyethyl)phenethylamino-NECA nor the selective A(3) agonist N(6)-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine reproduced it, and the selective A(2B) antagonist 3-isobutyl-8-pyrrolidinoxanthine prevented it. Constitutive expression of CD40 ligand on HMC-1 surface was not altered by NECA. Human B lymphocytes cocultured for 12 days with NECA-stimulated HMC-1 produced 870 +/- 33 pg IgE per 10(6) B cells, whereas lymphocytes cocultured with nonstimulated HMC-1, or cultured alone in the absence or in the presence of NECA, produced no IgE. Thus, we demonstrated induction of IgE synthesis by the interaction between adenosine-stimulated mast cells and B lymphocytes, and suggest that this mechanism is involved in the amplification of the allergic inflammatory responses associated with asthma.


Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.
The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.


Anxiety symptoms in psychotic disorders.
BackgroundThe prevalence of anxiety symptoms among Australians with psychotic disorders was examined as part of the Survey of High Impact Psychosis (SHIP).MethodsA two-phase design was used. Of 7,955 people who were screen positive for psychosis and eligible, 1825 participants (18-34 years and 35-64 years) were interviewed. Data were collected on symptomatology, substance use, cognitive ability, functioning, disability, physical health, mental health service utilisation, medication use, education, employment and housing. Anxiety symptomatology was divided into generalized anxiety, panic, phobic, social anxiety and obsessive-compulsive symptoms.ResultsThe most common ICD-10 diagnoses were schizophrenia or schizoaffective disorder (63.0%) and bipolar (mania) disorder (17.5%). Overall, 59.8% (n = 1092) of participants reported experiencing anxiety symptoms in the previous 12 months. Female gender was highly associated with all domains of anxiety. Smoking was significantly associated with all domains of anxiety, except generalized anxiety. The presence of any depressive symptoms in the previous 12 months was significantly associated with all anxiety symptoms. Medication side-effects were associated with phobic and obsessive-compulsive symptoms. Social dysfunction was associated with social anxiety, and less so for obsessive-compulsive symptoms.ConclusionsAnxiety symptoms are common in people with psychotic disorders. Appropriate screening and treatment should be a clinical priority.


The proportion of correct diagnoses is low in emergency patients with nonspecific complaints presenting to the emergency department.
To determine the proportion of correct emergency department (ED) diagnoses and of hospital discharge diagnoses, in comparison with final diagnoses at the end of a 30-day follow-up, in patients presenting with nonspecific complaints (NSCs) to the ED; to determine differences between male and female patients in the proportion of missed diagnoses. Prospective observational study. Diagnoses made at the ED, hospital discharge diagnoses, and final diagnoses were compared. Of 22,782 nontrauma patients presenting to the ED from May 2007 until May 2009, 9,926 were triaged as emergency severity index level 2 or 3, of whom 789 presented with NSCs. After exclusion of 217 patients, 572 were included for final analysis. The final diagnosis at the end of follow-up was taken to be the correct "gold standard" diagnosis. In 263 (46.0%) patients, this corresponded to the primary ED diagnosis, and in 292 (51%) patients to the hospital discharge diagnosis. The most frequent final diagnoses were urinary tract infections (n=49), electrolyte disorders (n=40) and pneumonia (n=37), and were correctly diagnosed at the ED in 23, 21 and 27 patients, respectively. Of the twelve most common diagnoses (corresponding to 354 patients), functional impairment was most frequently missed. Among these 354 patients, diagnoses were significantly more often missed in women than in men (142 of 231 [62%] women vs 57 of 123 [46%] men, p=0.004). Patients presenting to the ED with NSCs present a diagnostic challenge. New diagnostic tools are needed to help in the diagnosis of these patients.


Identification and characterization of Shigella boydii 20 serovar nov., a new and emerging Shigella serotype.
Analysis of 163 putative Shigella isolates from Canada and the USA showed biochemical reactions consistent with Shigella species, although none of the isolates reacted with antiserum raised against any of the well-established or provisional Shigella serotypes. All these isolates, provisionally designated serotype SH108, were positive for the ipaH gene and the invasion-associated locus. All fermented mannitol, were serologically indistinguishable from each other and showed no reaction in antisera prepared against Escherichia coli serotypes O1 to O181. PCR-RFLP analysis of the genes involved in O-antigen synthesis revealed a common pattern among these isolates that was distinct from recognized Shigella serotypes and E. coli. Between 1999 and 2003, isolates from across Canada were submitted to the National Laboratory for Enteric Pathogens for antibiotic susceptibility testing, phage typing and PFGE. These assays revealed heterogeneity among the members of this serotype. Antimicrobial susceptibility testing with seven antibiotics identified six profiles, with 90 % (45/50) of the isolates resistant to four or more antibiotics and 72 % (36/50) resistant to five or more. All isolates were typable using a panel of 16 phages, with 11 different phage types (PTs) represented. The most common PTs found were PT 3 (64 %), PT 6 (10 %) and PT 16 (6 %). Analysis of XbaI-restricted genomic DNA revealed 16 highly related patterns that were not readily distinguishable from those obtained for some other Shigella serotypes. The World Health Organization Collaborating Center for Shigella has added serotype SH108 to the Shigella scheme as S. boydii serotype 20 (serovar nov.). Strain SH108 (isolate 99-4528) is the reference strain for this serotype.


Resilience and vision impairment in older people.
Some people fare better than others when faced with adversity; they appear to be more 'resilient'. This article explores the concept of resilience in the context of vision impairment using two linked sets of narrative interview data from 2007 to 2010. Three case studies were analysed in detail using a framework approach based upon a social-ecological model of resilience and vision impairment. Within the model a range of assets and resources are identified which influence an individual's capacity for resilience. A set of criteria were used to establish the extent to which each individual appeared to be resilient at each point in time. Analysis revealed that it is not merely the presence or absence of individual, social, and community resources - but how these resources interact with each other - that influences resilience and can create a risk to wellbeing. To possess only some of these resources is not sufficient; there is a co-dependency between these resources which requires the presence of other resources for resilience to be achieved. Resilience is not a fixed state; individuals can become more or less resilient as their circumstances and resources change over time. We suggest that the concept of resilience has much to offer the field of vision impairment as it allows the identification of enablers as well as areas of barriers to improving people's health and wellbeing and suggests further opportunities for service providers to engage with clients, even those who appear to be supported, as people's social, economic and emotional landscapes continue to change over time, rather than identifying deficit.


Design and performance of the CDC real-time reverse transcriptase PCR swine flu panel for detection of 2009 A (H1N1) pandemic influenza virus.
Swine influenza viruses (SIV) have been shown to sporadically infect humans and are infrequently identified by the Influenza Division of the Centers for Disease Control and Prevention (CDC) after being received as unsubtypeable influenza A virus samples. Real-time reverse transcriptase PCR (rRT-PCR) procedures for detection and characterization of North American lineage (N. Am) SIV were developed and implemented at CDC for rapid identification of specimens from cases of suspected infections with SIV. These procedures were utilized in April 2009 for detection of human cases of 2009 A (H1N1) pandemic (pdm) influenza virus infection. Based on genetic sequence data derived from the first two viruses investigated, the previously developed rRT-PCR procedures were optimized to create the CDC rRT-PCR Swine Flu Panel for detection of the 2009 A (H1N1) pdm influenza virus. The analytical sensitivity of the CDC rRT-PCR Swine Flu Panel was shown to be 5 copies of RNA per reaction and 10(-1.3 - -0.7) 50% infectious doses (ID(50)) per reaction for cultured viruses. Cross-reactivity was not observed when testing human clinical specimens or cultured viruses that were positive for human seasonal A (H1N1, H3N2) and B influenza viruses. The CDC rRT-PCR Swine Flu Panel was distributed to public health laboratories in the United States and internationally from April 2009 until June 2010. The CDC rRT-PCR Swine Flu Panel served as an effective tool for timely and specific detection of 2009 A (H1N1) pdm influenza viruses and facilitated subsequent public health response implementation.


Quantitative and qualitative shifts in defensive metabolites define chemical defense investment during leaf development in Inga, a genus of tropical trees.
Selective pressures imposed by herbivores are often positively correlated with investments that plants make in defense. Research based on the framework of an evolutionary arms race has improved our understanding of why the amount and types of defenses differ between plant species. However, plant species are exposed to different selective pressures during the life of a leaf, such that expanding leaves suffer more damage from herbivores and pathogens than mature leaves. We hypothesize that this differential selective pressure may result in contrasting quantitative and qualitative defense investment in plants exposed to natural selective pressures in the field. To characterize shifts in chemical defenses, we chose six species of Inga, a speciose Neotropical tree genus. Focal species represent diverse chemical, morphological, and developmental defense traits and were collected from a single site in the Amazonian rainforest. Chemical defenses were measured gravimetrically and by characterizing the metabolome of expanding and mature leaves. Quantitative investment in phenolics plus saponins, the major classes of chemical defenses identified in Inga, was greater for expanding than mature leaves (46% and 24% of dry weight, respectively). This supports the theory that, because expanding leaves are under greater selective pressure from herbivores, they rely more upon chemical defense as an antiherbivore strategy than do mature leaves. Qualitatively, mature and expanding leaves were distinct and mature leaves contained more total and unique metabolites. Intraspecific variation was greater for mature leaves than expanding leaves, suggesting that leaf development is canalized. This study provides a snapshot of chemical defense investment in a speciose genus of tropical trees during the short, few-week period of leaf development. Exploring the metabolome through quantitative and qualitative profiling enables a more comprehensive examination of foliar chemical defense investment.


Predicting ozone levels : A statistical model for predicting ozone levels in the Shuaiba Industrial Area, Kuwait.
This paper presents a statistical model that is capable of predicting ozone levels from precursor concentrations and meteorological conditions during daylight hours in the Shuaiba Industrial Area (SIA) of Kuwait. The model has been developed from ambient air quality data that was recorded for one year starting from December 1994 using an air pollution mobile monitoring station. The functional relationship between ozone level and the various independent variables has been determined by using a stepwise multiple regression modelling procedure. The model contains two terms that describe the dependence of ozone on nitrogen oxides (NOx) and nonmethane hydrocarbon precursor concentrations, and other terms that relate to wind direction, wind speed, sulphur dioxide (SO2) and solar energy. In the model, the levels of the precursors are inversely related to ozone concentration, whereas SO2 concentration, wind speed and solar radiation are positively correlated. Typically, 63 % of the variation in ozone levels can be explained by the levels of NOx. The model is shown to be statistically significant and model predictions and experimental observations are shown to be consistent. A detailed analysis of the ozone-temperature relationship is also presented; at temperatures less than 27 °C there is a positive correlation between temperature and ozone concentration whereas at temperatures greater than 27 °C a negative correlation is seen. This is the first time a non-monotonic relationship between ozone levels and temperature has been reported and discussed.


Medullary cavity diameter of metacarpal and metatarsal bones in cats. A cadaveric radiographic and computed tomographic analysis.
To compare radiography and computed tomography (CT) for the evaluation of medullary cavity diameters of metacarpal and metatarsal bones in cats and to analyse their correlation with intramedullary pin size. Radiography and CT were performed in cadavers (n = 12). The mid-diaphysis was determined and the medullary cavity diameter was measured by two observers. Each bone was osteotomized at the mid-diaphysis, Kirschner wires were inserted, and pin size was documented. Intra- and interobserver variability was evaluated (hierarchical analysis of variance). Radiography and CT were compared (correlation analysis, a t-test for dependent samples, a Bland-Altman analysis) and pin size, radiography and CT were compared (regression and correlation analysis). Intra-observer variability was low for radiographs and CT, with an estimated median variation of 0.10 mm for radiographs and 0.12 mm for CT. Inter-observer variability was low, with a median variation of 0.03 mm for radiographs and 0.21 mm for CT. There was a high correlation between radiography and CT for the assessment of the medullary cavity diameter. A high correlation was found between pin size and measurement on radiographs, and between pin size and measurements on CT. In two cats, pin insertion was difficult or impossible. Mid-diaphyseal measurements are applicable methods for the assessment of the medullary cavity diameter in feline metacarpal and metatarsal bones regarding intramedullary pins. In some cats the medullary cavity diameter may be too small for intramedullary pinning techniques, which can be identified preoperatively on radiographs.


CDKAL1-related single nucleotide polymorphisms are associated with insulin resistance in a cross-sectional cohort of Greek children.
Five novel loci recently found to be associated with body mass in two GWAS of East Asian populations were evaluated in two cohorts of Swedish and Greek children and adolescents. These loci are located within, or in the proximity of: CDKAL1, PCSK1, GP2, PAX6 and KLF9. No association with body mass has previously been reported for these loci in GWAS performed on European populations. The single nucleotide polymorphisms (SNPs) with the strongest association at each loci in the East Asian GWAS were genotyped in two cohorts, one obesity case control cohort of Swedish children and adolescents consisting of 496 cases and 520 controls and one cross-sectional cohort of 2293 nine-to-thirteen year old Greek children and adolescents. SNPs were surveyed for association with body mass and other phenotypic traits commonly associated with obesity, including adipose tissue distribution, insulin resistance and daily caloric intake. No association with body mass was found in either cohort. However, among the Greek children, association with insulin resistance could be observed for the two CDKAL1-related SNPs: rs9356744 (β = 0.018, p = 0.014) and rs2206734 (β = 0.024, p = 0.001). CDKAL1-related variants have previously been associated with type 2 diabetes and insulin response. This study reports association of CDKAL1-related SNPs with insulin resistance, a clinical marker related to type 2 diabetes in a cross-sectional cohort of Greek children and adolescents of European descent.


Dietary supplementation with omega-3 polyunsaturated fatty acid-rich oils protects against visible-light-induced retinal damage in vivo.
The effects of administering omega-3 (ω-3) polyunsaturated fatty acid (PUFA)-rich oils on visible-light-induced retinal damage were investigated in rabbits. The mole percentages of α-linolenic acid in sea buckthorn berry oil, sea buckthorn oil (SO), sea buckthorn seed oil and flaxseed oil (FO) were 2.12%, 12.98%, 31.56% and 55.41%, respectively. Algal oil (AO) contains 33.34% docosahexaenoic acid. SO has the highest total phenolic content (63.42 ± 0.59 mg SAE per 100 g) amongst these oils. The administration of SO, FO and AO provided structural and functional protection to the retina. In the retina, we observed a significant increase in the levels of DHA in the AO group compared with the normal group. The mechanism of retinal protection by SO, FO and AO involves up-regulating the expression of nuclear factor erythroid-2 related factor 2 and haem oxygenase-1. The levels of interleukin-1 β, tumour necrosis factor-alpha, interleukin-8, and cyclooxygenase 2 in the retina were significantly reduced with AO treatment. The administration of AO resulted in the down-regulation of nuclear factor kappa B mRNA expression. In addition, the treatment with AO significantly attenuated the light-induced apoptosis and angiogenesis in the retina. These results suggest that dietary ω-3 PUFA-rich oils protect against visible-light-induced retinal damage.


Structure of the influenza C virus CM2 protein transmembrane domain obtained by site-specific infrared dichroism and global molecular dynamics searching.
The 115-residue protein CM2 from Influenza C virus has been recently characterized as a tetrameric integral membrane glycoprotein. Infrared spectroscopy and site-directed infrared dichroism were utilized here to determine its transmembrane structure. The transmembrane domain of CM2 is alpha-helical, and the helices are tilted by beta = (14.6 +/- 3.0) degrees from the membrane normal. The rotational pitch angle about the helix axis omega for the 1-(13)C-labeled residues Gly(59) and Leu(66) is omega = (218 +/- 17) degrees, where omega is defined as zero for a residue pointing in the direction of the helix tilt. A detailed structure was obtained from a global molecular dynamics search utilizing the orientational data as an energy refinement term. The structure consists of a left-handed coiled-coil with a helix crossing angle of Omega = 16 degrees. The putative transmembrane pore is occluded by the residue Met(65). In addition hydrogen/deuterium exchange experiments show that the core is not accessible to water.


Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes.
Zinc supplementation for the treatment of diarrhoea has been shown to decrease the duration and severity of the diarrhoeal episode, diarrhoea hospitalization rates and, in some studies, all-cause mortality. Using multiple outcome measures, we sought to estimate the effect of zinc for the treatment of diarrhoea on diarrhoea mortality and subsequent pneumonia mortality. We conducted a systematic review of efficacy and effectiveness studies. We used a standardized abstraction and grading format and performed meta-analyses for all outcomes with >or=2 data points. The estimated effect on diarrhoea mortality was determined by applying the standard Child Health Epidemiology Reference Group rules for multiple outcomes. We identified 13 studies for abstraction. Zinc supplementation decreased the proportion of diarrhoeal episodes which lasted beyond 7 days, risk of hospitalization, all-cause mortality and diarrhoea mortality. Using diarrhoea hospitalizations as the closest and most conservative possible proxy for diarrhoea mortality, zinc for the treatment of diarrhoea is estimated to decrease diarrhoea mortality by 23%. Zinc is an effective therapy for diarrhoea and will decrease diarrhoea morbidity and mortality when introduced and scaled-up in low-income countries.


Plasma eicosapentaenoic acid is negatively associated with all-cause mortality among men and women in a population-based prospective study.
Omega-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties, whereas omega-6 PUFAs appear to have proinflammatory properties. We aimed to assess plasma omega-3 and omega-6 PUFA status in relation to all-cause mortality in an Australian community-based study. We hypothesized that omega-3 PUFA would be inversely associated, and omega-6 PUFA positively associated with all-cause mortality. Plasma phospholipid omega-3 (eicosapentaenoic acid [EPA], docosapentaenoic acid [DPA], docosahexaenoic acid, α-linolenic acid, and total) and omega-6 PUFAs (linoleic acid, arachidonic acid, and total) were measured among 1008 adults (44% men) in 1996. Plasma PUFA composition was quantified using gas chromatography. During 17-year follow-up, 98 men and 81 women died. After adjustment for potential confounding factors, plasma EPA was inversely associated with all-cause mortality overall (adjusted hazard ratio [HR] per 1-SD increase, 0.81; 95% confidence interval [CI], 0.68-0.95), in men (HR, 0.78; 95% CI, 0.62-0.98), and in women (HR, 0.78; 95% CI, 0.65-0.94), separately. Inverse associations with mortality among men were also seen for DPA (HR, 0.76; 95% CI, 0.60-0.97) and α-linolenic acid (HR, 0.73; 95% CI, 0.57-0.94). No omega-6 PUFAs were significantly associated with mortality. Our findings of reduced all-cause mortality in men and women who have high EPA in plasma, and in men with high plasma DPA and α-linolenic acid, partially support our hypothesis that omega-3 PUFAs help reduce mortality but provide no evidence that omega-6 PUFAs may increase mortality.


Promoter Polymorphism of Toll-Like Receptor 4 is Associated with a Decreased Risk of Coronary Artery Disease: A Case-Control Study in the Chinese Han Population.
BACKGROUND Coronary artery disease (CAD) is considered a chronic inflammatory disease of the blood vessels. Toll-like receptor 4 (TLR4) is a transmembrane receptor involved in inflammatory reactions. The aim of this study was to determine the association between polymorphisms in the promoter region and 3'-untranslated region (3'-UTR) of TLR4, and the associated CAD risk. MATERIAL AND METHODS This study enrolled 424 participants with CAD and 424 controls without CAD. The polymorphisms in the promoter region and 3'-UTR of TLR4 were identified from the HapMap database, including rs10116253, rs10983755, and rs11536889. Genomic DNA was extracted from peripheral blood. Polymerase chain reaction-restriction fragment length polymorphism was performed to identify genotype polymorphisms. Relative luciferase activity was measured using the dual-luciferase reporter assay system. RESULTS TLR4 rs10116253 in the promoter region was associated with CAD risk. The variant (CC+TC) genotypes of rs10116253 were associated with a decreased CAD risk (OR 95% CI 0.73 (0.54-0.98), p=0.034). In the stratification analyses, the variant (CC+TC) genotypes of rs10116253 were observed to have a relationship with decreased CAD risk in the male subgroup (OR: 95% CI 0.68 (0.48-0.98), p=0.041). Moreover, the variant CC and (CC+TC) genotypes of rs10116253 were correlated with a decreased CAD risk in participants younger than 60-year-old (TC: OR (95% CI 0.62 (0.39-0.98), p=0.042; TC+CC: OR 95% CI 0.63 (0.41-0.98), p=0.039). Regarding rs10116253, the luciferase activity of the mutant C allele construct was lower than that of the wild T allele construct (5.215±0.009 vs. 5.304±0.041; p=0.087). CONCLUSIONS The results provided evidence of an association between the TLR4 rs10116253 in the promoter region and a reduced risk of CAD.


A highly sensitive and rapidly responding fluorescent probe based on a rhodol fluorophore for imaging endogenous hypochlorite in living mice.
Hypochlorous (HOCl) acid is generated as a defense tool in the immune system and plays a vital role in killing a wide range of pathogens. There is therefore great interest in developing fluorescent probes that can endogenously respond to the change in concentration of HOCl in vivo. To address this challenge, we here present a rapidly responding fluorescent probe RO610 to image endogenous HOCl in living mice. The development of RO610 was based on a novel water-soluble and pH-independent fluorescent xanthene dye, 2'-formylrhodol ROA, which exhibits highly selective and sensitive responses to HOCl/ClO- over other reactive species. Moreover, adding a little more than 5 equiv. of ClO- to the solution of RO610 resulted in a clearly observable fluorescence enhancement (48-fold) within 30 s. Based on these properties, RO610 was used to detect ClO- in A549 cells without interference by other oxidants. It was applied for the imaging of endogenous HOCl in living nude mice with satisfactory results.


Hu-1: Major histocompatibility locus in man.
A single locus with 15 or more alleles controls reactivity in mixed leukocyte culture tests. Genes at this locus also control most of the specificities measured by cytotoxic antiserums to leukocytes. Both of these tests can be used to predict survival of skin grafts. It is proposed that this is the major histocompatibility locus in man.


Meta-analysis of TP73 polymorphism and cervical cancer.
The aim of this study was to investigate the tumor protein p73 (TP73) G4C14-A4T14 polymorphism and to perform a meta-analysis to assess TP73 expression in cervical cancer and precancerous tissue. Articles containing data regarding TP73 status in cervical cancer patients and healthy controls were retrieved from PubMed, EMBASE, Cochrane, Chinese Biomedical Literature, and China National Knowledge Infrastructure databases. Then, the quality of the studies was evaluated according to inclusion and exclusion criteria. Odds ratios between the case and control groups were used as an effect evaluation index and the RevMan 5.0 software was employed to carry out the meta-analysis. Three independent investigations including 8452 cases of cervical cancer and 8326 healthy controls were included in our study following the application of inclusion and exclusion criteria. PCR genotyping revealed that the TP73 GC/GC genotype produced a 193-bp product, while the AT/AT genotype produced a 270-bp fragment, and GC/AT genotype samples produced two fragments of 193 and 270 bp. Meta-analysis showed that TP73 expression in cervical cancer was significantly higher than that in normal cervical squamous epithelium (P < 0.05). This elevated expression may play an important role in the occurrence and development of cervical cancer. Therefore, TP73 testing might be useful in the screening and diagnosis of cervical cancer and precancerous lesions.


Protocol for the Femoroacetabular Impingement Trial (FAIT): a multi-centre randomised controlled trial comparing surgical and non-surgical management of femoroacetabular impingement.
Femoroacetabular Junction Impingement (FAI) describes abnormalities in the shape of the femoral head-neck junction, or abnormalities in the orientation of the acetabulum. In the short term, FAI can give rise to pain and disability, and in the long-term it significantly increases the risk of developing osteoarthritis. The Femoroacetabular Impingement Trial (FAIT) aims to determine whether operative or non-operative intervention is more effective at improving symptoms and preventing the development and progression of osteoarthritis. FAIT is a multicentre superiority parallel two-arm randomised controlled trial comparing physiotherapy and activity modification with arthroscopic surgery for the treatment of symptomatic FAI. Patients aged 18 to 60 with clinical and radiological evidence of FAI are eligible. Principal exclusion criteria include previous surgery to the index hip, established osteoarthritis (Kellgren-Lawrence ≥ 2), hip dysplasia (centre-edge angle < 20°), and completion of a physiotherapy programme targeting FAI within the previous 12 months. Recruitment will take place over 24 months and 120 patients will be randomised in a 1:1 ratio and followed up for three years. The two primary outcome measures are change in hip outcome score eight months post-randomisation (approximately six-months post-intervention initiation) and change in radiographic minimum joint space width 38 months post-randomisation. ClinicalTrials.gov: NCT01893034. Cite this article: Bone Joint Res 2014;3:321-7.


Clinical efficacy of a computerised device (STA™) and a pressure syringe (VarioJect INTRA™) for intraligamentary anaesthesia.
To evaluate the impact of experience whilst using different devices for intraligamentary anaesthesia, dental students tested clinical anaesthetic efficacy of a mechanical (PDL-S) and a computer-controlled (CCLAD) application system in restorative patients. In a prospective study, 41 Patients in need of restorative treatment in lower posterior mandible were randomised into three groups (PDL-S: teeth n = 22; CCLAD: teeth n = 20; inferior alveolar nerve block (IANB): teeth n = 20). Dental last year students conducted anaesthesia and dental treatment. Primary objectives were differences in pain during treatment [numeric rating scale (NRS)] as well as in anaesthetic efficacy (complete/sufficient vs. insufficient/no effect) between PDL-S and CCLAD. Pain of injection, need for second injections, amount of anaesthetic solution and duration of local numbness were assessed. IANB as gold standard was compared to each system descriptively. PDL-S had a significant lower pain during treatment (P = 0.017) but a similar anaesthetic efficacy (P = 0.175) compared to the CCLAD system. Concerning pain of injection (P = 0.42), quantity of second injections (P = 0.232), amount of used solution (P = 0.073) as well as duration of local numbness (P = 0.253), no differences were seen. When comparing both periodontal ligament injection (PDL)-systems with IANB, pain rating was higher when using CCLAD. Injection pain, amount of used solution as well as soft tissue anaesthesia was less for PDL-S and CCLAD. Both PDL techniques showed a good success for dental routine treatments. Although, compared to the mechanic device, the CCLAD system might need more clinical daily experience. We recommend including specific trainings in intraligamentary anaesthesia in the dental curriculum.


Eye movement desensitisation treatment utilises the positive visceral element of the investigatory reflex to inhibit the memories of post-traumatic stress disorder: a theoretical analysis.
Eye movement desensitisation and reprocessing (EMDR) has attracted controversy and has led to publications covering a wide range of psychological problems treated by EMDR, in particular, post-traumatic stress disorder (PTSD). There is growing clinical evidence of the effectiveness of EMDR, but a lack of a convincing theoretical basis to explain its rapid effect. This paper argues that a combination of Pavlovian and Darwinian theory provide a theoretical explanation for the therapeutic effectiveness of EMDR. We suggest that the investigatory component of the orienting reflex is an evolutionary development enabling organisms to assess their environment for both opportunities and threats. We propose that EMDR is rapidly effective because it is a clinical method of Pavlovian conditioning by which the positive visceral element of the investigatory reflex can be paired with clinically-induced noxious memories to remove their negative affect. Compared with established forms of treatment for PTSD, EMDR is rapid, with resulting clinical and economic benefits. Our suggested theoretical basis for EMDR has implications for further explanatory research and for developments in EMDR treatment.


Synthesis and Examination of Nanocomposites Based on Poly(2-hydroxyethyl methacrylate) for Medicinal Use.
Preparation of poly(2-hydroxyethyl methacrylate) (PHEMA) based nanocomposites using different approaches such as synthesis with water as the porogen, filling of polymer matrix by silica and formation of interpenetrating polymer networks with polyurethane was demonstrated. Incorporation of various biologically active compounds (BAC) such as metronidazole, decamethoxin, zinc sulphate, silver nitrate or amino acids glycine and tryptophan into nanocomposites was achieved. BAC were introduced into the polymer matrix either (1) directly, or (2) with a solution of colloidal silica, or (3) through immobilization on silica (sol-densil). Morphology of prepared materials was investigated by laser scanning microscopy and low-vacuum scanning electron microscopy. In vacuum freeze-drying, prior imaging was proposed for improving visualization of the porous structure of composites. The interaction between PHEMA matrix and silica filler was investigated by IR spectroscopy. Adsorption of 2-hydroxyethyl methacrylate and BAC from aqueous solution on the silica surface was also examined. Phase composition and thermal stability of composites were studied by the differential thermogravimetry/differential thermal analysis. Release of BAC into water medium from prepared composites were shown to depend on the synthetic method and differed significantly. Obtained PHEMA-base materials which are characterized by controlled release of BAC have a strong potential for application in manufacturing of different surgical devices like implants, catheters and drainages.


High sensitivity-troponin elevation secondary to non-coronary diagnoses and death and recurrent myocardial infarction: An examination against criteria of causality.
Myonecrosis provoked by illness unrelated to unstable coronary plaque is common, but uncertainty about a cause-effect relationship with future events challenges the appropriateness of initiating therapies known to be effective in cardiac conditions. We examined the causal relationship between troponin elevation in non-coronary diagnoses and late cardiac events using the Bradford Hills criteria for causality. Patients presenting acutely to South Australian public hospitals receiving at least one troponin between September 2011-September 2012 were included. Diagnoses were classified as coronary, non-coronary cardiac and non-cardiac using the International Classification of Diseases, version 10 Australian Modified, codes. The relationship between peak in-hospital troponin, using a high-sensitivity troponin T assay and adjudicated cardiac and non-cardiac mortality, and subsequent myocardial infarction (MI) was assessed using competing-risk flexible parametric survival models. Troponin results were available for 38,161 patients of whom, 12,645 (33.6%), 3237 (8.5%), and 22,079 (57.9%) patients were discharged with coronary, non-coronary cardiac and non-cardiac diagnoses, respectively. Troponin >14 ng/l was observed in 43.6%. The relationship between troponin and cardiac mortality was stronger among the non-coronary diagnosis group (troponin 1000 ng/l: coronary hazard ratio: 5.1 (95% confidence interval (CI) 4.0-6.6) vs non-coronary hazard ratio: 16.3 (95% CI 12.6-22.4)). The temporal hazard for cardiac death was marked within 30 days in both groups. Among non-coronary diagnoses, the hazard for recurrent MI was higher but did not vary with time. Consistency with causal criteria between secondary myonecrosis and cardiac events suggest the potential benefit for extending cardiac specific interventions to this population if supported in trials appropriately designed to address competing risks. Troponin elevation precipitated by non-coronary events is common and demonstrates an associations with late mortality that are analogous to spontaneous MI resulting from unstable coronary plaque. These observations help inform the design of randomized clinical trials exploring the benefits and risk of therapies with established benefits in other cardiac conditions. Such studies will need to appropriately account for competing risks in this population of patients.


The Effect of Money Priming on Self-Focus in the Imitation-Inhibition Task.
The self-sufficiency hypothesis suggests that priming individuals with money makes them focus more strongly on themselves than on others. However, recently, research supporting this claim has been heavily criticized and some attempts to replicate have failed. A reason for the inconsistent findings in the field may lay in the common use of explicit measures, because they tend to rely on one or just a few items and are thus prone to demand effects and low reliability. In the present research, we administered, in two experiments, the imitation-inhibition task - a robust, unobtrusive, and reliable paradigm that is sensitive to self-other focus on a trial-by-trial basis. A pilot study found an increased focus on the self as compared to others when primed with money. Building on this finding, a preregistered high-powered experiment replicated this effect, suggesting that money primes may indeed increase a focus on the self. An additionally carried out meta-analysis indicates that automatic imitation is modulated by self-other focus and that money primes lead to a smaller focus on the self than conventional methods. Overall, the found effects are rather small and several limitations, such as order effects, call for a cautious interpretation of the findings.


A healable supramolecular polymer blend based on aromatic pi-pi stacking and hydrogen-bonding interactions.
An elastomeric, healable, supramolecular polymer blend comprising a chain-folding polyimide and a telechelic polyurethane with pyrenyl end groups is compatibilized by aromatic pi-pi stacking between the pi-electron-deficient diimide groups and the pi-electron-rich pyrenyl units. This interpolymer interaction is the key to forming a tough, healable, elastomeric material. Variable-temperature FTIR analysis of the bulk material also conclusively demonstrates the presence of hydrogen bonding, which complements the pi-pi stacking interactions. Variable-temperature SAXS analysis shows that the healable polymeric blend has a nanophase-separated morphology and that the X-ray contrast between the two types of domain increases with increasing temperature, a feature that is repeatable over several heating and cooling cycles. A fractured sample of this material reproducibly regains more than 95% of the tensile modulus, 91% of the elongation to break, and 77% of the modulus of toughness of the pristine material.


Introduction of an N-Glycosylation Site into UDP-Glucuronosyltransferase 2B3 Alters Its Sensitivity to Cytochrome P450 3A1-Dependent Modulation.
Our previous studies have demonstrated functional protein-protein interactions between cytochrome P450 (CYP) 3A and UDP-glucuronosyltransferase (UGT). However, the role of carbohydrate chains of UGTs in the interaction with CYP is not well understood. To address this issue, we examined whether CYP3A1 modulates the function of UGT2B3 which lacks potential glycosylation sites. We also examined whether the introduction of N-glycosylation to UGT2B3 affects CYP3A-dependent modulation of UGT function. To introduce a potential glycosylation site into UGT2B3, Ser 316 of UGT2B3 was substituted with Asn by site-directed mutagenesis. A baculovirus-Sf-9 cell system for expressing CYP3A1 and UGT2B3/UGT2B3(S316N) was established using a Bac-to-Bac system. Glycosylation of UGT2B3(S316N) was demonstrated in this expression system. The microsomal activity of recombinant UGT was determined using 4-methylumbelliferone as a substrate. The effect of CYP3A1 co-expression on UGT function was examined by comparing the kinetic profiles between single (UGT alone) and double expression (UGT plus CYP) systems. The kinetics of the two expression systems fitted a Michaelis-Menten equation. When the 4-MU concentration was varied, co-expression of CYP3A1 lowered the Vmax of UGT2B3-mediated conjugation. Conversely, for UGT2B3(S316N), the Vmax in the dual expression system was higher than that in the single expression system. The data obtained demonstrate that the introduction of N-glycosylation to UGT2B3 alters its sensitivity to CYP3A1-dependent modulation while CYP3A1 enhanced UGT2B3(S316N) activity, and wild-type UGT2B3 was suppressed by CYP3A1. These data suggest that N-glycosylation of UGT is one of the determinants regulating the interaction between CYP3A and UGT.


The effects of abused inhalants on mouse behavior in an elevated plus-maze.
Previous research has shown that abused inhalants (i.e., the volatile solvents) share some of the pharmacological properties of drugs used in the treatment of anxiety. In an attempt to further examine commonalities in the effects of inhalants and central nervous system depressant drugs, the behavioral effects of inhaled 1,1,1-trichloroethane, toluene, methoxyflurane and the convulsant vapor flurothyl were examined and compared to those of diazepam in the elevated plus-maze, a test used to predict antianxiety effects. After inhalant exposure or diazepam injection, mice were placed in the center of an elevated plus-maze and the number of entries and time spent in each type of arm (open versus closed) were measured during 5-min tests. Exposure to increasing concentrations of toluene produced concentration-related increases in the total number of open arm entries and the total time spent on the open arms, a pattern of behavioral effects similar to that produced by diazepam. A similar pattern was observed for increasing concentrations of 1,1,1-trichloroethane and methoxyflurane but changes in open arm activity were only observed at concentrations that increased locomotor activity. Conversely, only decreases in open arm time and number of entries were observed for flurothyl. The increasing evidence for commonalities in the behavioral effects of volatile solvents and depressant drugs may provide a foundation for understanding the neurobehavioral basis of inhalant abuse.


Individual differences in brain structure underpin empathizing-systemizing cognitive styles in male adults.
Individual differences in cognitive style can be characterized along two dimensions: 'systemizing' (S, the drive to analyze or build 'rule-based' systems) and 'empathizing' (E, the drive to identify another's mental state and respond to this with an appropriate emotion). Discrepancies between these two dimensions in one direction (S>E) or the other (E>S) are associated with sex differences in cognition: on average more males show an S>E cognitive style, while on average more females show an E>S profile. The neurobiological basis of these different profiles remains unknown. Since individuals may be typical or atypical for their sex, it is important to move away from the study of sex differences and towards the study of differences in cognitive style. Using structural magnetic resonance imaging we examined how neuroanatomy varies as a function of the discrepancy between E and S in 88 adult males from the general population. Selecting just males allows us to study discrepant E-S profiles in a pure way, unconfounded by other factors related to sex and gender. An increasing S>E profile was associated with increased gray matter volume in cingulate and dorsal medial prefrontal areas which have been implicated in processes related to cognitive control, monitoring, error detection, and probabilistic inference. An increasing E>S profile was associated with larger hypothalamic and ventral basal ganglia regions which have been implicated in neuroendocrine control, motivation and reward. These results suggest an underlying neuroanatomical basis linked to the discrepancy between these two important dimensions of individual differences in cognitive style.


Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis.
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2-dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.


Patterns of localization and cytoskeletal association of two vegetally localized RNAs, Vg1 and Xcat-2.
In Xenopus, localization of a rare class of mRNAs during oogenesis is believed to initiate pattern formation in the early embryo. We have determined the pattern of RNA localization for one of these RNAs, Xcat-2, which encodes a putative RNA-binding protein related to Drosophila nanos (Mosquera, L., Forristall, C., Zhou, Y. and King, M. L. (1993) Development 117, 377-386). Xcat-2 is exclusively localized to the mitochondrial cloud in stage I oocytes, moves with this body into the vegetal cortex during stage II and, later, partitions into islands consistent with it being a component of the germ plasm. As previously shown, Vg1 is not localized to the vegetal cortex until stage IV and distributes to all vegetal blastomeres during development. We found a direct correlation between the localized condition of these RNAs and their recovery in a detergent-insoluble fraction. We present evidence suggesting that differential RNA binding to a cytoskeletal component(s) in the vegetal cortex determines the pattern of inheritance for that RNA in the embryo.


Repair of 104 failed anti-reflux operations.
To assess whether reoperative surgery for failed Nissen fundoplication is beneficial and to classify all mechanisms of failure recognized. Antireflux surgery is often necessary, but a 10% failure rate is commonplace. We report results for patients undergoing reoperative surgery and present a nomenclature of mechanisms of failure. A total of 104 patients, who had a previous fundoplication for gastroesophageal reflux disease (GERD), underwent reoperative surgery. Manometry (n = 86), endoscopy (n = 101), pH monitoring (n = 27), upright esophagram (n = 90), gastric emptying (n = 26), and symptom assessment (n = 104) were performed prior to reoperative surgery. Patients were also assessed before and during reoperation for mechanism of failure using a newly proposed classification. The operative approach was laparoscopic in 58 patients, via open laparotomy in 12, and a thoracotomy in 34 patients. Follow-up was conducted by phone interview and was completed in 97 patients (97%; 3 were deceased) with a mean follow-up of 32 months (range, 1-146 months). The conversion rate to laparotomy for laparoscopic patients was 8%. The perioperative complication rate was 32%. One patient died of respiratory insufficiency after a laparotomy. Seven patients required additional surgery for correction of persistent or recurrent symptoms. The short and long-term complication rate was similar for the different operative approachs. Symptom resolution (rare or absent) occurred in 74% of patients with dysphagia, 75% with heartburn, 85% with regurgitation, and 94% with chest pain. The overall post-reoperative patient satisfaction was 7 on a scale of 1 to 10 and 3 on a scale of 1 to 4 when patients were asked to grade the operative result. There was no difference in the symptom resolution for patients operated upon by the laparoscopic approach as compared with laparotomy, but those patients undergoing a Collis gastroplasty had poorer results. The preoperative accuracy of assessment for mechanism of failure was 78%. A nomenclature of mechanisms of failure is included to aide reoperative assessment and new mechanisms of failure are described. Reoperative surgery results for GERD are satisfactory. A variety of operative approaches proved equally effective. Poorer results were observed in patients with more advanced disease.


Photodynamic molecular beacon as an activatable photosensitizer based on protease-controlled singlet oxygen quenching and activation.
Molecular beacons are FRET-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets, thus are useful tools for in vivo cancer imaging. Photodynamic therapy (PDT) is a cell-killing process by light activation of a photosensitizer (PS) in the presence of oxygen. The key cytotoxic agent is singlet oxygen ((1)O(2)). By combining these two principles (FRET and PDT), we have introduced a concept of photodynamic molecular beacons (PMB) for controlling the PS's ability to generate (1)O(2) and, ultimately, for controlling its PDT activity. The PMB comprises a disease-specific linker, a PS, and a (1)O(2) quencher, so that the PS's photoactivity is silenced until the linker interacts with a target molecule, such as a tumor-associated protease. Here, we report the full implementation of this concept by synthesizing a matrix metalloproteinase-7 (MMP7)-triggered PMB and achieving not only MMP7-triggered production of (1)O(2) in solution but also MMP7-mediated photodynamic cytotoxicity in cancer cells. Preliminary in vivo studies also reveal the MMP7-activated PDT efficacy of this PMB. This study validates the core principle of the PMB concept that selective PDT-induced cell death can be achieved by exerting precise control of the PS's ability to produce (1)O(2) by responding to specific cancer-associated biomarkers. Thus, PDT selectivity will no longer depend solely on how selectively the PS can be delivered to cancer cells. Rather, it will depend on how selective a biomarker is to cancer cells, and how selective the interaction of PMB is to this biomarker.


Nail-assisted percutaneous plating of pediatric femoral fractures.
Traditional operative treatments for pediatric femoral shaft fractures may result in an unacceptable complication rate, especially in patients with complex fractures. Despite requiring the use of fluoroscopy and presenting some technical difficulty, minimally invasive percutaneous plating is an alternative operative method. We retrospectively reviewed 13 consecutive femoral fractures in children (mean age, 9 years) who were treated by a modified technique of percutaneous plating. Six of the fractures were comminuted. Nine children had associated injuries, including four with head trauma. The primary indication for use of percutaneous plating in this pediatric series was a complex fracture in which flexible nailing would be suboptimal. The results were evaluated by a modification of Flynn's criteria. All fractures united without bone grafts (mean, 11 weeks). No patients had residual radiographic angulations greater than 10 degrees or a leg-length discrepancy greater than 5 mm. All patients had excellent final outcomes. There were no major complications such as deep infection or refracture. The technique provided adequate stability for early functional treatment and predictable healing with maintenance of leg length and alignment. Provisional reduction and stabilization of complex pediatric femoral fractures can facilitate definitive percutaneous plating.


G-quadruplexes induce apoptosis in tumor cells.
Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor activity in nude mice carrying prostate and breast tumor xenografts. However, the molecular basis for their antitumor activity remains unclear. In the current study, we showed that a variety of telomeric G-tail oligodeoxynucleotides (TG-ODNs) exhibited antiproliferative activity against many tumor cells in culture. Systematic mutational analysis of the TG-ODNs suggests that the antiproliferative activity depends on the G-quadruplex conformation of these TG-ODNs. TG-ODNs were also shown to induce poly(ADP-ribose) polymerase-1 cleavage, phosphatidylserine flipping, and caspase activation, indicative of induction of apoptosis. TG-ODN-induced apoptosis was largely ataxia telangiectasia mutated (ATM) dependent. Furthermore, TG-ODN-induced apoptosis was inhibited by the c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125. Indeed, TG-ODNs were shown to activate the JNK pathway in an ATM-dependent manner as evidenced by elevated phosphorylation of JNK and c-Jun. Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNK-dependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs.


The anti-idiotypic antibody 1F7 stimulates monocyte interleukin-10 production and induces endotoxin tolerance.
Pathogens that establish chronic infection elicit immune responses with suppressive cytokines dominating over pro-inflammatory cytokines. Chronic hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection and simian immunodeficiency virus (SIV) infection are associated with high levels of antiviral antibodies expressing a common idiotype specifically recognized by the 1F7 monoclonal antibody (mAb). The 1F7 mAb is a murine IgMκ antibody raised against immunoglobulin pooled from the plasma of multiple HIV-infected individuals. In this study, we investigated direct effects of the 1F7 mAb itself on peripheral blood mononuclear cells (PBMC). Isolated monocytes or PBMC from healthy controls were incubated with the 1F7 mAb or IgMκ mAb control. Cytokine production was measured in cell culture supernatants by ELISA and cells producing interleukin-10 (IL-10) were identified by subset depletion and intracellular flow cytometry. Endotoxin tolerance was assessed by exposing monocytes to lipopolysaccharide (LPS) following 1F7 mAb or IgMκ mAb control pre-treatment and comparing tumor necrosis factor (TNF)-α levels in cell culture supernatants. The 1F7 mAb stimulated monocytes and CD36+ lymphocytes to produce IL-10 in a time and dose-dependent manner. Treatment of monocytes with 1F7 mAb also reduced their subsequent responsiveness to LPS stimulation. Induction of antibodies expressing the 1F7 idiotype by chronic pathogens may facilitate IL-10 production and progression to chronic infection. Direct effects of IL-10 from human monocytes stimulated by 1F7-like antibodies, followed by monocyte transition to an alternatively activated phenotype illustrated by endotoxin tolerance, are two complementary features favouring a tolerogenic or non-responsive immunological environment.


Processing of major histocompatibility class I-restricted antigens in the endoplasmic reticulum.
We have introduced long precursor peptides directly into the endoplasmic reticulum (ER) of a mutant cell line (T2-Db) that lacks the ability to transport peptides from the cytosol to the ER in a transporter associated with antigen processing (TAP) dependent way. This was done by expressing various influenza A-derived peptides containing the naturally processed epitope ASNENMDAM (366-374) preceded by the influenza hemagglutinin ER translocation sequence. Peptides derived from these minigenes that became associated with Db were isolated and identified by combined reversed phase liquid chromatography and detection by cytotoxic T lymphocytes. Our results establish that NH2-terminal extensions of at least 40 residues can be trimmed from peptides entering the ER, but that proteolysis of larger proteins may be limited.


Ecological meltdown in the Firth of Clyde, Scotland: two centuries of change in a coastal marine ecosystem.
The Firth of Clyde is a large inlet of the sea that extends over 100 km into Scotland's west coast. We compiled detailed fisheries landings data for this area and combined them with historical accounts to build a picture of change due to fishing activity over the last 200 years. In the early 19th century, prior to the onset of industrial fishing, the Firth of Clyde supported diverse and productive fisheries for species such as herring (Clupea harengus, Clupeidae), cod (Gadus morhua, Gadidae), haddock (Melanogrammus aeglefinus, Gadidae), turbot (Psetta maxima, Scophthalmidae) and flounder (Platichthys flesus, Pleuronectidae). The 19th century saw increased demand for fish, which encouraged more indiscriminate methods of fishing such as bottom trawling. During the 1880s, fish landings began to decline, and upon the recommendation of local fishers and scientists, the Firth of Clyde was closed to large trawling vessels in 1889. This closure remained in place until 1962 when bottom trawling for Norway lobster (Nephrops norvegicus, Nephropidae) was approved in areas more than three nautical miles from the coast. During the 1960s and 1970s, landings of bottomfish increased as trawling intensified. The trawl closure within three nautical miles of the coast was repealed in 1984 under pressure from the industry. Thereafter, bottomfish landings went into terminal decline, with all species collapsing to zero or near zero landings by the early 21st century. Herring fisheries collapsed in the 1970s as more efficient mid-water trawls and fish finders were introduced, while a fishery for mid-water saithe (Pollachius virens, Gadidae) underwent a boom and bust shortly after discovery in the late 1960s. The only commercial fisheries that remain today are for Nephrops and scallops (Pecten maximus, Pectinidae). The Firth of Clyde is a marine ecosystem nearing the endpoint of overfishing, a time when no species remain that are capable of sustaining commercial catches. The evidence suggests that trawl closures helped maintain productive fisheries through the mid-20th century, and their reopening precipitated collapse of bottomfish stocks. We argue that continued intensive bottom trawling for Nephrops with fine mesh nets will prevent the recovery of other species. This once diverse and highly productive environment will only be restored if trawl closures or other protected areas are re-introduced. The Firth of Clyde represents at a small scale a process that is occurring ocean-wide today, and its experience serves as a warning to others.


Serum sex hormone-binding globulin, a determinant of cardiometabolic disorders independent of abdominal obesity and insulin resistance in elderly men and women.
Serum sex hormone-binding globulin (SHBG) is related to cardiometabolic disorders; but whether or not this relationship is purely secondary to hyperinsulinemia and/or obesity, which down-regulates SHBG, is unknown. The aim of the study was to investigate the association of SHBG and total testosterone with atherogenic dyslipidemias, metabolic syndrome (MS), and diabetes among predominantly elderly Turkish adults. After appropriate exclusions, 777 randomly selected male and female subjects with available measurements of both variables were eligible and were analyzed cross-sectionally, with diabetic subjects analyzed separately. Free testosterone was calculated. Metabolic syndrome was identified by the modified criteria of the Adult Treatment Panel III. Metabolic syndrome was identified in half the sample, which had a median age of 58 years. The odds of low SHBG concentrations (<45 nmol/L in men, <55 nmol/L in women) for the likelihood of 2 types of dyslipidemias, MS, and diabetes were examined by regression analyses in standard models including age, smoking status, presence of abdominal obesity, and insulin resistance (homeostasis model assessment of insulin resistance). In both sexes, low SHBG was associated independently with high triglyceride/low high-density lipoprotein dyslipidemia and with MS, at significant 2.2- to 4.5-fold odds ratios, independent of waist circumference or homeostasis model assessment of insulin resistance index. Low SHBG among women was additionally associated with the likelihood of hypertriglyceridemia with elevated apolipoprotein B and-at borderline significance-with that of diabetes, again when adjusted for the same confounders. In an elderly population with prevalent MS, low SHBG levels significantly associate with high triglyceride/low high-density lipoprotein dyslipidemia, MS, and, in women alone, diabetes and a dyslipidemia marking small dense low-density lipoprotein particles, all independent of abdominal obesity and insulin resistance. Low SHBG may be an important independent factor for cardiometabolic risk, particularly in women.


Usual source of care and unmet health care needs: interaction of disability with race and ethnicity.
Having a usual source of care (USC) and having unmet health care needs have been found to vary in relation to sociodemographic differences in the US population, including race, ethnicity, and disability status. People in underserved racial and ethnic groups who also have a disability may experience a complex mix of health care advantages and disparities. However, little is known about this intersection. To determine how disability status, combined with membership in an underserved racial or ethnic group, is associated with having a USC and unmet health care needs. We conducted multivariate regression analyses of 2002-2010 data from the Medical Expenditure Panel Survey, focused on working age adults (18-64 y). Although most racial and ethnic groups were less likely to have a USC than non-Hispanic whites, people with disabilities were more likely to have a USC; Hispanics with basic activity limitations were the only disability group with elevated odds of lacking a USC. Conversely, disability was strongly associated with unmet health care needs, but we did not find inflated impacts of both having a disability and belonging to an underserved racial or ethnic group. We found limited evidence of interaction or additive effects of disability and race/ethnicity but did confirm separate disparities for each. Ongoing research is needed to track both disability-related and racial/ethnic disparities, to determine whether increased insurance coverage, provider training, care coordination, and other efforts under the Affordable Care Act lead to reductions in disparities.


Tracing the decision-making process of physicians with a Decision Process Matrix.
Decision-making processes in a medical setting are complex, dynamic and under time pressure, often with serious consequences for a patient's condition. The principal aim of the present study was to trace and map the individual diagnostic process of real medical cases using a Decision Process Matrix [DPM]). The naturalistic decision-making process of 11 residents and a total of 55 medical cases were recorded in an emergency department, and a DPM was drawn up according to a semi-structured technique following four steps: 1) observing and recording relevant information throughout the entire diagnostic process, 2) assessing options in terms of suspected diagnoses, 3) drawing up an initial version of the DPM, and 4) verifying the DPM, while adding the confidence ratings. The DPM comprised an average of 3.2 suspected diagnoses and 7.9 information units (cues). The following three-phase pattern could be observed: option generation, option verification, and final diagnosis determination. Residents strove for the highest possible level of confidence before making the final diagnoses (in two-thirds of the medical cases with a rating of practically certain) or excluding suspected diagnoses (with practically impossible in half of the cases). The following challenges have to be addressed in the future: real-time capturing of emerging suspected diagnoses in the memory of the physician, definition of meaningful information units, and a more contemporary measurement of confidence. DPM is a useful tool for tracing real and individual diagnostic processes. The methodological approach with DPM allows further investigations into the underlying cognitive diagnostic processes on a theoretical level and improvement of individual clinical reasoning skills in practice.


Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity.
Can we identify compound(s) with reported phosphodiesterase inhibitor (PDEI) activity that could be added to human spermatozoa in vitro to enhance their motility without compromising other sperm functions? We have identified several compounds that produce robust and effective stimulation of sperm motility and, importantly, have a positive response on patient samples. For >20 years, the use of non-selective PDEIs, such as pentoxifylline, has been known to influence the motility of human spermatozoa; however, conflicting results have been obtained. It is now clear that human sperm express several different phosphodiesterases and these are compartmentalized at different regions of the cells. By using type-specific PDEIs, differential modulation of sperm motility may be achieved without adversely affecting other functions such as the acrosome reaction (AR). This was a basic medical research study examining sperm samples from normozoospermic donors and subfertile patients attending the Assisted Conception Unit (ACU), Ninewells Hospital Dundee for diagnostic semen analysis, IVF and ICSI. Phase 1 screened 43 commercially available compounds with reported PDEI activity to identify lead compounds that stimulate sperm motility. Samples were exposed (20 min) to three concentrations (1, 10 and 100 µM) of compound, and selected candidates (n = 6) progressed to Phase 2, which provided a more comprehensive assessment using a battery of in vitro sperm function tests. All healthy donors and subfertile patients were recruited at the Medical Research Institute, University of Dundee and ACU, Ninewells Hospital Dundee (ethical approval 08/S1402/6). In Phase 1, poor motility cells recovered from the 40% interface of the discontinuous density gradient were used as surrogates for patient samples. Pooled samples from three to four different donors were utilized in order to reduce variability and increase the number of cells available for simultaneous examination of multiple compounds. During Phase 2 testing, semen samples from 23 patients attending for either routine diagnostic andrology assessment or IVF/ICSI were prepared and exposed to selected compounds. Additionally, 48 aliquots of prepared samples, surplus to clinical use, were examined from IVF (n = 32) and ICSI (n = 16) patients to further determine the effects of selected compounds under clinical conditions of treatment. Effects of compounds on sperm motility were assessed by computer-assisted sperm analysis. A modified Kremer test using methyl cellulose was used to assess sperm functional ability to penetrate into viscous media. Sperm acrosome integrity and induction of apoptosis were assessed using the acrosomal content marker PSA-FITC and annexin V kit, respectively. In Phase 1, six compounds were found to have a strong effect on poor motility samples with a magnitude of response of ≥ 60% increase in percentage total motility. Under capacitating and non-capacitating conditions, these compounds significantly (P ≤ 0.05) increased the percentage of total and progressive motility. Furthermore, these compounds enhanced penetration into a cervical mucus substitute (P ≤ 0.05). Finally, the AR was not significantly induced and these compounds did not significantly increase the externalization of phosphatidylserine (P = 0.6, respectively). In general, the six compounds maintained the stimulation of motility over long periods of time (180 min) and their effects were still observed after their removal. In examinations of clinical samples, there was a general observation of a more significant stimulation of sperm motility in samples with lower baseline motility. In ICSI samples, compounds #26, #37 and #38 were the most effective at significantly increasing total motility (88, 81 and 79% of samples, respectively) and progressive motility (94, 93 and 81% of samples, respectively). In conclusion, using a two-phased drug discovery screening approach including the examination of clinical samples, 3/43 compounds were identified as promising candidates for further study. This is an in vitro study and caution must be taken when extrapolating the results. Data for patients were from one assessment and thus the robustness of responses needs to be established. The n values for ICSI samples were relatively small. We have systematically screened and identified several compounds that have robust and effective stimulation (i.e. functional significance with longevity and no toxicity) of total and progressive motility under clinical conditions of treatment. These compounds could be clinical candidates with possibilities in terms of assisted reproductive technology options for current or future patients affected by asthenozoospermia or oligoasthenozoospermia. This study was funded primarily by the MRC (DPFS) but with additional funding from the Wellcome Trust, Tenovus (Scotland), University of Dundee, NHS Tayside and Scottish Enterprise. The authors have no competing interests. A patent (#WO2013054111A1) has been published containing some of the information presented in this manuscript.


Stress and heart disease: evidence of associations between unemployment and heart disease from the OPCS Longitudinal Study.
The OPCS Longitudinal Study has been used to study both overall and cause-specific mortality patterns in 1971-1981 among men and women directly or indirectly affected by unemployment in April 1971. Groups studied included men seeking work in 1971, the wives of men seeking work in 1971 and other women in the same households as a man seeking work in 1971. The findings of this project are summarized here and attention is focused on mortality from circulatory diseases, in particular ischaemic heart disease. The study provides evidence which could be seen as supporting hypotheses about relationships between stress and overall mortality, with a marked excess for suicides. The evidence with respect to ischaemic heart disease is positive but less convincing with excess mortality from this cause principally occurring among younger unemployed men and among the wives of men who were seeking work in 1971. Given the sharp contrasts in the pattern and levels of unemployment between 1971 and 1981 it is difficult to extrapolate from these findings to the present day.


Efficacy and safety of photodynamic therapy versus Nd-YAG laser resection in NSCLC with airway obstruction.
A prospective controlled randomized trial was performed in order to assess the effectiveness and safety of photodynamic therapy versus laser resection in 31 patients with partial or complete tracheobronchial obstruction due to inoperable non-small cell lung cancer. Fourteen patients received dihaematoporphyrin ether and argon dye laser photoradiation, and 17 patients received Nd-YAG laser resection. Endoluminal obstruction of >75% was found in 77.4% of the patients. Among the symptoms, cough was more severe in the Nd-YAG group (p=0.02). Patients in both groups experienced symptomatic relief after treatment (p=0.003). Patients in the photodynamic therapy (PDT) group showed a significantly longer time until treatment failure (p=0.03) and longer median survival (p=0.007). Bronchitis and photosensitization (both in the PDT group) were the most common adverse effects. There was one death, probably related to treatment, in the PDT group. Photodynamic therapy and neodymium-yttrium aluminium garnet laser resection showed similar effectiveness and safety in the palliation of symptoms. The more prolonged survival in the photodynamic therapy group may have been due to differences in tumour stage between the groups. The degree of obstruction improved after treatment in both groups. In conclusion, photodynamic therapy is a valid method of palliation in partially or totally obstructing non-small cell lung carcinoma.


Histopathology and immunophenotype of the spleen during acute antibody-mediated rejection.
Splenectomy has been reported to have a beneficial effect in treating Acute antibody-mediated rejection (ABMR). This reason for this often rapid and profound beneficial effect is not readily apparent from what is known about normal splenic immunoarchitecture. While the spleen is rich in mature B cells, it has not been noted to be a repository for direct antibody-secreting cells. We present a case of a Native American female who received a renal transplant and developed a severe episode of ABMR. The patient was initially refractory to both plasmapheresis and IVIG. The patient underwent an emergent splenectomy with almost immediate improvement in her renal function and a rapid drop in her DR51 antibodies. Immunohistochemical stains of the spleen demonstrated abundant clusters of CD138+ plasma cells (>10% CD138 cells as opposed to 1% CD138 cells as seen in traumatic controls). Though this is a single case, these findings offer a rationale for the rapid ameliorative effect of splenectomy in cases of antibody rejection. It is possible that the spleen during times of excessive antigenic stress may rapidly turn over B cells to active antibody-secreting cells or serve as a reservoir for these cells produced at other sites.


Practical Relativistic Bit Commitment.
Bit commitment is a fundamental cryptographic primitive in which Alice wishes to commit a secret bit to Bob. Perfectly secure bit commitment between two mistrustful parties is impossible through an asynchronous exchange of quantum information. Perfect security is, however, possible when Alice and Bob each split into several agents exchanging classical information at times and locations suitably chosen to satisfy specific relativistic constraints. In this Letter we first revisit a previously proposed scheme [C. Crépeau et al., Lect. Notes Comput. Sci. 7073, 407 (2011)] that realizes bit commitment using only classical communication. We prove that the protocol is secure against quantum adversaries for a duration limited by the light-speed communication time between the locations of the agents. We then propose a novel multiround scheme based on finite-field arithmetic that extends the commitment time beyond this limit, and we prove its security against classical attacks. Finally, we present an implementation of these protocols using dedicated hardware and we demonstrate a 2 ms-long bit commitment over a distance of 131 km. By positioning the agents on antipodal points on the surface of Earth, the commitment time could possibly be extended to 212 ms.


U.S.-Mexico cross-border workforce training needs: survey implementation.
Since the tragic events experienced on September 11, 2001, and other recent events such as the hurricane devastation in the southeastern parts of the country and the emergent H1N1 season, the need for a competent public health workforce has become vitally important for securing and protecting the greater population. The primary objective of the study was to assess the training needs of the U.S. Mexico border states public health workforce. The Arizona Center for Public Health Preparedness of the Mel and Enid Zuckerman College of Public Health at The University of Arizona implemented a border-wide needs assessment. The online survey was designed to assess and prioritize core public health competencies as well as bioterrorism, infectious disease, and border/binational training needs. Approximately 80% of the respondents were employed by agencies that serve both rural and urban communities. Respondents listed 23 different functional roles that best describe their positions. Approximately 35% of the respondents were primarily employed by state health departments, twenty-seven percent (30%) of the survey participants reported working at the local level, and 19% indicated they worked in other government settings (e.g. community health centers and other non-governmental organizations). Of the 163 survey participants, a minority reported that they felt they were well prepared in the Core Bioterrorism competencies. The sections on Border Competency, Surveillance/Epidemiology, Communications/Media Relations and Cultural Responsiveness, did not generate a rating of 70% or greater on the importance level of survey participants. The study provided the opportunity to examine the issues of public health emergency preparedness within the framework of the border as a region addressing both unique needs and context. The most salient findings highlight the need to enhance the border competency skills of individuals whose roles include a special focus on emergency preparedness and response along the US-Mexico border.


NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway.
The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.


Interferometric tomography for flow visualization of density fields in supersonic jets and convective flow.
Tomographic methods are used for the investigation of three-dimensional compressible flow fields by means of interferometric methods. A modified algebraic reconstruction technique algorithm is applied. The algorithm proved to give reliable reconstructions from experimentally measured projection data in the case of an unrestricted angular view. The method was used for the reconstruction of density distributions of weakly perturbed supersonic free jets exiting from a deformed Laval nozzle. Even small perturbations of the jet resulted in significant three-dimensional effects. Reconstruction of a multiple system of jets emanating from a sievelike nozzle showed mutual interactions between the constituent jets. For the investigation of unsteady flows a setup for the recording of holographic interferograms was designed. Here, because of experimental restrictions, only a limited angular range of views was accessible. In the context of this limited-view geometry, reconstructions revealed considerable distortions for objects containing steep gradients.


Understanding childbirth as a complex salutogenic phenomenon: The EU COST BIRTH Action Special Collection.
In 2014, the EU funded a four-year European Cooperation in Science and Technology (COST) Action to address the topic of childbirth. The COST Birth Action was a cross-European network, that brought together over 120 scientists, practitioners, activists and policy makers from 34 countries to work on intrapartum care. The central aim was to advance the state of research and practice in a specific area of great clinical and social importance, intrapartum care. The Action used inter and trans-disciplinary approaches to address birth from multiple perspectives and drew on complexity theory and the concept of salutogenesis (wellbeing). This special collection presents six papers produced from the Action and gives a sense of the range and depth of the work conducted. The Collection illustrates the knowledge that can be generated when a diverse group of people come together with a similar goals and perspectives.