New Inhaled Antimicrobial Formulations for Use in the Cystic Fibrosis Patient Population.
To review the current literature on inhaled antibiotic therapies currently in clinical trials for cystic fibrosis (CF) patients. A literature search was performed using PubMed (1975 to September 2015), International Pharmaceutical Abstracts (1970 to September 2015), and MEDLINE (1946 to September 2015) to identify studies for inclusion. The following search terms were used: cystic fibrosis, inhaled amikacin, inhaled liposomal amikacin, inhaled vancomycin, and/or inhaled levofloxacin. All English-language phase II to III studies evaluating efficacy and/or safety, case reports, and retrospective studies of inhaled amikacin, inhaled vancomycin, and inhaled levofloxacin in CF patients were included. Currently available inhaled antibiotics, tobramycin and aztreonam, have demonstrated improvement in respiratory function of CF patients. Newer agents have shown potentially similar efficacy, with improvement in ease of use. Limited data suggest that inhaled liposomal amikacin and levofloxacin are both noninferior to tobramycin in terms of improvements in respiratory function. Inhaled levofloxacin has a lower rate of hospitalizations secondary to respiratory exacerbations and a reduction in the Pseudomonas aeruginosa sputum density compared with inhaled tobramycin. Inhaled vancomycin use has been documented in case reports and 2 small retrospective eradication trials, although data are limited to support its use. The horizon of inhaled antibiotic choices for CF patients is promising. The introduction of different drug classes and formulations to treat resistant Gram-negative and Gram-positive organisms increases the number of options for patients for both eradication and treatment of chronic colonization.


The impact of midlife educational, work, health, and family experiences on men's early retirement.
In empirical studies on predictors of retirement, midlife experiences have often remained implicit or been neglected. This study aims to improve our understanding of retirement by examining the impact of midlife educational, work, health, and family experiences on early retirement intentions and behavior. We distinguish theoretically and empirically between financial and nonfinancial preretirement factors through which midlife experiences could affect retirement. Using panel data of 1,229 Dutch male older workers, we estimated linear regression models to explain retirement intentions and logistic regression models to explain retirement behavior. Midlife experiences in all studied life spheres are related to retirement intentions. Educational investments, job changes, late transitions into parenthood, and late divorces are associated with weaker intentions to retire early. Midlife health problems are related to stronger early retirement intentions. For midlife work and family experiences, the relationships are (partly) mediated by the preretirement financial opportunity structure. In the educational, work, and health spheres, the preretirement nonfinancial situation has a mediating effect. Only some of the predictors of retirement intentions also predicted retirement behavior. Given the destandardization of life courses, information on distal life experiences might become even more important toward understanding retirement in the future.


Plastic restriction of HIV-1 replication in human macrophages derived from M1/M2 polarized monocytes.
M1/M2 cytokine-dependent polarization of primary human MDMs has been shown to contain CCR5-dependent (R5) HIV-1 replication. In this study, a similar effect was achieved when monocytes were first polarized toward M1 or M2 and were infected 7 d after their differentiation into MDMs, regardless of whether the cytokines were removed 18 h after cell stimulation or were left in culture. Unlike polarized MDMs, no significant down-regulation of CD4 from the cell surface was observed in MDMs derived from M1/M2-polarized monocytes. A second stimulation of MDMs differentiated from M1/M2 monocytes with the opposite polarizing cytokines converted the virus replication profile according to the new stimuli. The expression of M1 and M2 markers (i.e., APOBEC3A and DC-SIGN, respectively) was induced by MDM stimulation with the opposite cytokines, although it also persisted in cells according to their first stimulatory condition. Thus, stimulation of monocytes with M1- and M2-inducing cytokines leads to a restriction of HIV-1 replication when these cells are infected several days later as differentiated MDMs. These observations imply that activation of circulating monocytes significantly influences their capacity to either support or restrict HIV-1 replication, once extravasated, and eventually to become infected as tissue macrophages.


Comparative biology of sperm factors and fertilization-induced calcium signals across the animal kingdom.
Fertilization causes mature oocytes or eggs to increase their concentrations of intracellular calcium ions (Ca²⁺) in all animals that have been examined, and such Ca²⁺ elevations, in turn, provide key activating signals that are required for non-parthenogenetic development. Several lines of evidence indicate that the Ca²⁺ transients produced during fertilization in mammals and other taxa are triggered by soluble factors that sperm deliver into oocytes after gamete fusion. Thus, for a broad-based analysis of Ca²⁺ dynamics during fertilization in animals, this article begins by summarizing data on soluble sperm factors in non-mammalian species, and subsequently reviews various topics related to a sperm-specific phospholipase C, called PLCζ, which is believed to be the predominant activator of mammalian oocytes. After characterizing initiation processes that involve sperm factors or alternative triggering mechanisms, the spatiotemporal patterns of Ca²⁺ signals in fertilized oocytes or eggs are compared in a taxon-by-taxon manner, and broadly classified as either a single major transient or a series of repetitive oscillations. Both solitary and oscillatory types of fertilization-induced Ca²⁺ signals are typically propagated as global waves that depend on Ca²⁺ release from the endoplasmic reticulum in response to increased concentrations of inositol 1,4,5-trisphosphate (IP₃). Thus, for taxa where relevant data are available, upstream pathways that elevate intraoocytic IP3 levels during fertilization are described, while other less-common modes of producing Ca²⁺ transients are also examined. In addition, the importance of fertilization-induced Ca²⁺ signals for activating development is underscored by noting some major downstream effects of these signals in various animals.


Ethical and policy issues in cluster randomized trials: rationale and design of a mixed methods research study.
Cluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities--rather than individual themselves--are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders. We will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.


Erotomania revisited: clinical course and treatment.
Erotomania is a rare disorder in which an individual has a delusional belief that a person of higher social status falls in love and makes amorous advances towards him/her. Little is known about the background, classification, treatment, or outcome of individuals with this disorder. The purpose of this study was to evaluate current criteria for diagnosing and classifying primary and secondary erotomania in addition to examining course, outcome, and impact on victims of erotomania. Semistructured interviews covering personal and family details in addition to treatment and outcome to date were performed on a series of erotomanic patients identified in a defined area. Evaluation of diagnosis used DSM-IV and other criteria. Fifteen erotomanic subjects (11 female, four male) were identified. Most were isolated, without a partner or full-time occupation. Forty percent had a first-degree relative with a psychiatric history and of those half had a first-degree relative with a mono-delusional disorder. Less than half of the objects of their affection, mainly noncelebrities, were subject to harassment. Subjects with primary erotomania and erotomania secondary to other psychiatric diagnoses were identified using DSM-IV criteria. Ellis and Mellsop's criteria were found to be useful in assessing erotomania but we could not replicate Seeman's fixed and recurrent groups. Treatment and outcome was better than expected particularly for those with primary erotomania and erotomanics with a diagnosis of bipolar affective disorder. In this series, erotomanic symptoms largely occurred in the context of other psychiatric disorders, although subjects with pure erotomanic symptoms were seen. Subjects were less dangerous and engaged in less harassment of victims than the literature suggests. Subjects were often isolated, unemployed, and with few social contacts. Strong family psychiatric histories were seen particularly with regard to mono-delusional disorders raising the possibility of genetic inheritance. An adaptation of Ellis and Mellsop's criteria was suggested for the diagnosis of primary and secondary erotomania. Response to treatment and prognosis was good, particularly for primary erotomania and erotomania secondary to bipolar affective disorder.


Axial and limb muscle development: dialogue with the neighbourhood.
Skeletal muscles are part of the musculoskeletal system which also includes nerves, tendons, connective tissue, bones and blood vessels. Here we review the development of axial and limb muscles in amniotes within the context of their surrounding tissues in vivo. We highlight the reciprocal dialogue mediated by signalling factors between cells of these adjacent tissues and developing muscles and also demonstrate its importance from the onset of muscle cell differentiation well into foetal development. Early embryonic tissues secrete factors which are important regulators of myogenesis. However, later muscle development relies on other tissue collaborators, such as developing nerves and connective tissue, which are in turn influenced by the developing muscles themselves. We conclude that skeletal muscle development in vivo is a compelling example of the importance of reciprocal interactions between developing tissues for the complete and coordinated development of a functional system.


Molecular cloning of Drosophila mus308, a gene involved in DNA cross-link repair with homology to prokaryotic DNA polymerase I genes.
Mutations in the Drosophila mus308 gene confer specific hypersensitivity to DNA-cross-linking agents as a consequence of defects in DNA repair. The mus308 gene is shown here to encode a 229-kDa protein in which the amino-terminal domain contains the seven conserved motifs characteristic of DNA and RNA helicases and the carboxy-terminal domain shares over 55% sequence similarity with the polymerase domains of prokaryotic DNA polymerase I-like enzymes. This is the first reported member of this family of DNA polymerases in a eukaryotic organism, as well as the first example of a single polypeptide with homology to both DNA polymerase and helicase motifs. Identification of a closely related gene in the genome of Caenorhabditis elegans suggests that this novel polypeptide may play an evolutionarily conserved role in the repair of DNA damage in eukaryotic organisms.


Rat liver preproalbumin: in vitro synthesis and partial amino acid sequence.
Rat liver poly(A)-containing RNA greatly stimulated incorporation of radioactive amino acids into protein when added to a wheat germ in vitro translation system. Approximately 7% of the labeled synthetic product was precipitated following indirect immunoprecipitation with antisera to rat serum albumin. Analysis of this material, and of the cyanogen bromide fragments derived from it, by sodium dodecyl sulfate/polyacrylamide gel electrophoresis revealed that it contained an NH2-terminal extension of about 2500 daltons when compared to rat serum albumin. Automated sequence determination of purified cell-free product labeled with various radioactive amino acids revealed the presence of 18 additional amino acids NH2-terminal to the sequence of rat proalbumin. The partial sequence of this extension was found to be: Met-X-X-X-X-Phe-Leu-Leu-Leu-Leu-Phe-X-X-X-X-X-Phe-X-proalbumin. On the basis of this evidence, the immunoprecipitable cell-free product was designated preproalbumin.


Regulation of p53-dependent apoptosis, transcriptional repression, and cell transformation by phosphorylation of the 55-kilodalton E1B protein of human adenovirus type 5.
The adenovirus type 5 55-kDa E1B protein (E1B-55kDa) cooperates with E1A gene products to induce cell transformation. E1A proteins stimulate DNA synthesis and cell proliferation; however, they also cause rapid cell death by p53-dependent and p53-independent apoptosis. It is believed that the role of the E1B-55kDa protein in transformation is to protect against p53-dependent apoptosis by binding to and inactivating p53. It has been shown previously that the 55-kDa polypeptide abrogates p53-mediated transactivation and that mutants defective in p53 binding are unable to cooperate with E1A in transformation. We have previously mapped phosphorylation sites near the carboxy terminus of the E1B-55kDa protein at Ser-490 and Ser-491, which lie within casein kinase II consensus sequences. Conversion of these sites to alanine residues greatly reduced transforming activity, and although the mutant 55-kDa protein was found to interact with p53 at normal levels, it was somewhat defective for suppression of p53 transactivation activity. We now report that a nearby residue, Thr-495, also appears to be phosphorylated. We demonstrate directly that the wild-type 55-kDa protein is able to block E1A-induced p53-dependent apoptosis, whereas cells infected by mutant pm490/1/5A, which contains alanine residues at all three phosphorylation sites, exhibited extensive DNA fragmentation and classic apoptotic cell death. The E1B-55kDa product has been shown to exhibit intrinsic transcriptional repression activity when localized to promoters, such as by fusion with the GAL4 DNA-binding domain, even in the absence of p53. Such repression activity was totally absent with mutant pm490/1/5A. These data suggested that inhibition of p53-dependent apoptosis may depend on the transcriptional repression function of the 55-kDa protein, which appears to be regulated be phosphorylation at the carboxy terminus.


Vibrio sp. dhg as a platform for the biorefinery of brown macroalgae.
Although brown macroalgae holds potential as an alternative feedstock, its utilization by conventional microbial platforms has been limited due to the inability to metabolize one of the principal sugars, alginate. Here, we isolate Vibrio sp. dhg, a fast-growing bacterium that can efficiently assimilate alginate. Based on systematic characterization of the genomic information of Vibrio sp. dhg, we establish a genetic toolbox for its engineering. We also demonstrate its ability to rapidly produce ethanol, 2,3-butanediol, and lycopene from brown macroalgae sugar mixture with high productivities and yields. Collectively, Vibrio sp. dhg can be used as a platform for the efficient conversion of brown macroalgae sugars into diverse value-added biochemicals.


Structural tympanic membrane changes in secretory otitis media and cholesteatoma.
Otitis media may predispose for retraction pathologic abnormality later in life. A weakening of the collagen fiber bundles in the lamina propria of the tympanic membrane (TM) is a prerequisite for the formation of a retraction pocket. Various collagen types have different tensile strength. The collagen-type distribution in the TM during otitis media and cholesteatoma has not been reported before. The collagen contents of TM biopsies from child patients with longstanding secretory otitis media without retraction pockets were compared with pars tensa cholesteatomas using immunohistochemical staining for collagen Types I to IV. The histology was also investigated using transmission electron microscopy. The outer epithelium was in some biopsies thickened with evidence of edema. The biopsies showed an intact lamina propria with positive immunohistochemical staining for collagen Types I to III and showed normal collagen fiber bundles on electron microscopy. The outer epithelium of the cholesteatomas showed marked thickness variations and signs of edema. There was a presence of normal collagen fiber bundles in smaller parts of all cholesteatomas, positive for collagen Types I to II. In other parts, only scattered collagen fibers were found. Tympanic membrane biopsies from patients with longstanding secretory otitis media may show a thickening of the outer epithelium. Collagen Types I to III are present in the lamina propria, and no ultrastructural changes of the collagen fiber bundles are observed. Collagen is found in cholesteatomas in the remnants of the lamina propria, with positive staining for collagen Types I and II, whereas Type III seems to be lacking.


Clinical and intra-operative factors affecting the outcome of arthrocentesis in disc displacement without reduction: A retrospective study.
Temporomandibular disorder (TMD) is a group of disease which affects the temporomandibular joint (TMJ) and supporting tissues of the musculoskeletal structures. Arthrocentesis is an effective treatment modality for TMD, especially in patients who suffer from pain and limited mouth opening. The aim of this study was to investigate the effects of pre-operative and intra-operative variables on the clinical outcome of arthrocentesis therapy. The records of 83 patients diagnosed as disc displacement (DD) without reduction according to DC/TMD, and treated with arthrocentesis were selected. Sex, age, bruxism history, pain intensity and maximum mouth opening (MMO) were recorded as pre-operative variables. Extravasation and the amount of irrigation were recorded as intra-operative variables. The success of the arthrocentesis procedure was determined as MMO <35 mm and pain intensity lower than 3, at third-month follow-up. At 3-month follow-up, clinical evaluation showed a significant reduction in TMJ pain and an increase in MMO (P < 0.05). It was found that patients with an unsuccessful outcome are those who had a more restricted MMO and severe pain before the procedure. Extravasation was found to be a significant factor that affects the success of the procedure. The success of arthrocentesis in TMJ DD without reduction is adversely affected by the severity of the pre-operative clinical symptoms. Extravasation is also a factor that has a negative effect on the success of the procedure.


Ecotoxicological risk assessment due to the presence of bisphenol A and caffeine in surface waters in the Sinos River Basin - Rio Grande do Sul - Brazil.
Bisphenol A (BPA) is an emerging contaminant, regularly detected in aquatic ecosystems, considered as an endocrine disrupting compound (EDC). Caffeine is another chemical related to human activity, often found in surface waters. The objective of this study was to evaluate the ecotoxicological risk due to BPA and caffeine in water samples from the Sinos River basin, Rio Grande do Sul, Brazil. Water samples were collected at three sites monthly from May 9 th, 2016 to April 11th, 2017 (n = 36). BPA concentrations in water samples collected were in the range of not detected to 517 ng L-1 and caffeine concentrations in the range of 41.7 to 28,439.6 ng L-1. The concentration of BPA in the analyzed samples had a moderate correlation with caffeine (rs = 0.402). High ecotoxicological risk for BPA was characterized in 77.77% of samples, with 11.11% presenting medium and 11.1% presenting low risk. For caffeine 13.9%, 50% and 36.11% of the samples presented high, medium and low risk, respectively. Caffeine concentrations in water can be used as predictors of BPA concentrations above 10 ng L-1, the lower concentration of ecotoxicological risk, with specificity of 66.7% and sensitivity of 70.4%. The assessment of aquatic risks has shown that both investigated compounds pose risks to organisms in the studied surface waters, mouth of the Pampa stream, mouth of the Luiz Rau stream and catchment point for public supply in Lomba Grande.


A key enzyme of the Leloir pathway is involved in pathogenicity of Leptosphaeria maculans toward oilseed rape.
Agrobacterium tumefaciens-mediated random insertional mutagenesis was used to investigate pathogenicity determinants in Leptosphaeria maculans. One tagged nonpathogenic mutant, termed m186, is analyzed in detail here. Microscopic analyses of infected plant tissues revealed that m186 is specifically blocked at the invasive growth phase after an unaffected initial penetration stage and is unable to switch to the necrotrophic lifestyle. In addition, m186 exhibits an altered cell wall and seems to be affected in its ability to produce cell-wall-degrading enzymes. The T-DNA insertion occurs in the intergenic region between two head-to-tail genes, leading to a constitutive upregulation of their expression. Complementation experiments showed that only one of these two genes, Lmepi, fully accounts for the mutant phenotype. Bioinformatics and expression analyses along with functional studies suggested that the Lmepi gene encodes for the highly conserved UDP-glucose-4-epimerase, a key enzyme of the Leloir pathway involved in galactose metabolism. For the third time, this study highlights the intimate connection between primary metabolism and pathogenicity in L. maculans. This finding, along with similar data obtained from the related species Stagonospora nodorum, indicates the importance of in planta nutrition for the success of infection of plants by fungi belonging to class Dothideomycete.


Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia.
A critical component of cognitive impairments in schizophrenia can be characterized as a disturbance in cognitive control, or the ability to guide and adjust cognitive processes and behavior flexibly in accordance with one's intentions and goals. Cognitive control impairments in schizophrenia are consistently linked to specific disturbances in prefrontal cortical functioning, but the underlying neurophysiologic mechanisms are not yet well characterized. Synchronous gamma-band oscillations have been associated with a wide range of perceptual and cognitive processes, raising the possibility that they may also help entrain prefrontal cortical circuits in the service of cognitive control processes. In the present study, we measured induced gamma-band activity during a task that reliably engages cognitive control processes in association with prefrontal cortical activations in imaging studies. We found that higher cognitive control demands were associated with increases in induced gamma-band activity in the prefrontal areas of healthy subjects but that control-related modulation of prefrontal gamma-band activity was absent in schizophrenia subjects. Disturbances in gamma-band activity in patients correlated with illness symptoms, and gamma-band activity correlated positively with performance in control subjects but not in schizophrenia patients. Our findings may provide a link between previously reported postmortem abnormalities in thalamofrontocortical circuitry and alterations in prefrontal activity observed in functional neuroimaging studies. They also suggest that deficits in frontal cortical gamma-band synchrony may contribute to the cognitive control impairments in schizophrenia.


Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy.
Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment. We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care.


Effect of new generation surface sealants on the marginal permeability of Class V resin composite restorations.
This study evaluated, in vitro, the effectiveness of 5 surface sealants (Biscover, Optiguard, Seal-n-Shine, PermaSeal and DuraFinish); 1 pit and fissure sealant (Helioseal) and 1 dentin bonding agent (Adper Scotchbond MultiPurpose Adhesive) on the marginal sealing ability of Class V hybrid resin composite (Esthet.X) restorations. Ninety-six non-carious human molars were randomly assigned to 8 groups (n=12). Class V cavities were prepared on either the facial or lingual surfaces, with coronal margins in enamel and apical margins in cementum (dentin), and restored following manufacturers' instructions. Following finishing and polishing procedures, the covering agents were applied to each restoration and adjacent tooth surface, except for the control group restorations, which were not sealed. The teeth were thermocycled, immersed in a 1% methylene blue dye solution, sectioned and analyzed for dye penetration (leakage) using a 20x binocular microscope. Microleakage was evaluated at the coronal and apical margins using an 0-3 ordinal grading scale. Non-parametric data was analyzed at a p< or =0.05 level of significance. The Kruskal-Wallis test showed a significant difference was exhibited among groups at the coronal margins, with Helioseal pit/fissure sealant and DuraFinish surface sealant exhibiting significantly less leakage than the control and Adper Scotchbond MultiPurpose adhesive. At the apical margins, DuraFinish surface sealant showed significantly less leakage than the Biscover, Seal-n-Shine and PermaSeal surface sealants or Helioseal pit/fissure sealant, Adper Scotchbond MultiPurpose adhesive and the control group. According to the Wicoxon signed-rank test, significantly greater leakage was revealed at the apical margins compared to the enamel margins of the material groups.


Dandy-Walker syndrome. Clinical analysis of 23 cases.
A clinical analysis of 23 patients with Dandy-Walker malformation indicates that more than 85% of them were diagnosed at or before 1 year of age, and that the incidence of associated anomalies is approximately 50%, with a 17% incidence for agenesis of the corpus callosum. The significance of the presence of these anomalies is substantiated by the fact that of the seven deaths recorded, six were related to this disease and five were affected by associated anomalies. The high mortality rate (26%) is comparable to that of other series. The differential diagnosis with posterior fossa extra-axial cysts is discussed. Ten patients were primarily treated with excision of the cyst membrane; all of them required subsequent shunting to control the intracranial pressure, demonstrating the futility of this approach. None of the patients treated with lateral ventricle shunting suffered an upward herniation of the posterior fossa contents, suggesting that combined shunting of the lateral and fourth ventricles is rarely necessary. The technical advantages of posterior fossa shunting alone are outlined. Of the 16 survivors, 14 were assessed for their mental development by means of standard psychometric testing. The results of the intelligence quotient (IQ) scoring have indicated that 71% of the patients have subnormal mental development (IQ less than 83). There was no significant relationship between retardation and associated anomalies, although agenesis of the corpus callosum was related to poor intellectual development in the two patients so affected (IQ's of 50 and 73).


What have two decades of laboratory life-history evolution studies on Drosophila melanogaster taught us?
A series of laboratory selection experiments on Drosophila melanogaster over the past two decades has provided insights into the specifics of life-history tradeoffs in the species and greatly refined our understanding of how ecology and genetics interact in life-history evolution. Much of what has been learnt from these studies about the subtlety of the microevolutionary process also has significant implications for experimental design and inference in organismal biology beyond life-history evolution, as well as for studies of evolution in the wild. Here we review work on the ecology and evolution of life-histories in laboratory populations of D. melanogaster, emphasizing how environmental effects on life-history-related traits can influence evolutionary change. We discuss life-history tradeoffs - many unexpected - revealed by selection experiments, and also highlight recent work that underscores the importance to life-history evolution of cross-generation and cross-life-stage effects and interactions, sexual antagonism and sexual dimorphism, population dynamics, and the possible role of biological clocks in timing life-history events. Finally, we discuss some of the limitations of typical selection experiments, and how these limitations might be transcended in the future by a combination of more elaborate and realistic selection experiments, developmental evolutionary biology, and the emerging discipline of phenomics.


Reinforcement of perceptual inference: reward and punishment alter conscious visual perception during binocular rivalry.
Perception is an inferential process, which becomes immediately evident when sensory information is conflicting or ambiguous and thus allows for more than one perceptual interpretation. Thinking the idea of perception as inference through to the end results in a blurring of boundaries between perception and action selection, as perceptual inference implies the construction of a percept as an active process. Here we therefore wondered whether perception shares a key characteristic of action selection, namely that it is shaped by reinforcement learning. In two behavioral experiments, we used binocular rivalry to examine whether perceptual inference can be influenced by the association of perceptual outcomes with reward or punishment, respectively, in analogy to instrumental conditioning. Binocular rivalry was evoked by two orthogonal grating stimuli presented to the two eyes, resulting in perceptual alternations between the two gratings. Perception was tracked indirectly and objectively through a target detection task, which allowed us to preclude potential reporting biases. Monetary reward or punishments were given repeatedly during perception of only one of the two rivaling stimuli. We found an increase in dominance durations for the percept associated with reward, relative to the non-rewarded percept. In contrast, punishment led to an increase of the non-punished compared to a relative decrease of the punished percept. Our results show that perception shares key characteristics with action selection, in that it is influenced by reward and punishment in opposite directions, thus narrowing the gap between the conceptually separated domains of perception and action selection. We conclude that perceptual inference is an adaptive process that is shaped by its consequences.


Sympathetic activity and blood pressure increases with bladder distension in humans.
Microneurographic recordings of muscle nerve sympathetic activity, which is governed by baroreceptors and involved in blood pressure regulation, were made in the peroneal nerve in 16 healthy volunteers during physiological bladder distension. When the urge to urinate was pronounced, sympathetic outflow increased from a baseline level of 16.3 +/- 1.7 to 23.2 +/- 1.9 bursts/min (mean +/- SEM, p less than 0.01). There was a concomitant significant rise in both systolic and diastolic blood pressure, from 125 +/- 2/74 +/- 2 to 140 +/- 4/84 +/- 3 mm Hg. After micturition, sympathetic activity and blood pressure returned toward initial values. It is concluded that 1) increased sympathetic outflow contributed to the rise in blood pressure, 2) there is a vesicovascular response mediated by sympathetic vasoconstrictor neurons in humans corresponding to mechanisms observed in animals, and 3) the described functional relation between bladder distension and sympathetic vasoconstrictor activity probably plays a role in clinical conditions such as autonomic dysreflexia in humans with cervical spinal cord lesions and nocturnal micturition syncope.


Family strain and its relation to psychosocial dysfunction in children and adolescents after liver transplantation.
Parental functioning is essential to children's development. Therefore, this cross-sectional single-center study examined the prevalence of family strain in 181 parents and its associations to psychosocial functioning in their children after LT. Median age at LT was one yr. Mean time elapsed since LT was 5.8 yr. The IFS, and the SDQ were applied to parents. Family strain in the present sample was comparable to that in the German normative group of families with a chronically ill or disabled child, but families of LT recipients showed a significantly higher financial impact, impact on coping, and impact on siblings (p < 0.001). Younger age of patients at survey, a more severe clinical course, child's restrictions, and financial losses following LT were determined as significant predictors of family strain (R(2) = 0.42). Parents reported less family strain after living-related compared with deceased donation. Family strain was significantly correlated to psychosocial dysfunction in children post-LT. Present findings demonstrate a risk of maladjustment to the post-LT condition in families. They emphasize the importance of psychological assessment of parents and patients during transplant and follow-up to ensure the best achievable long-term outcome of patients.


Predictors of Relapse and Functioning in First-Episode Psychosis: A Two-Year Follow-Up Study.
First-episode psychosis has an annual incidence rate of 24.6 to 40.9 per 100,000 population, and most individuals develop chronic disorders, such as schizophrenia or affective psychosis. The first two to five years are thought to be key determinants of long-term functional and clinical prognosis. This study aimed to determine the two-year course of illness in first-episode psychosis, including diagnosis, relapse, and functioning and factors related to these variables. A total of 140 patients who experienced a first episode of psychosis were recruited and evaluated between 2008 and 2012 in a first-episode psychosis program in Barcelona, Spain. Regression models were used to determine factors predicting relapse and functioning. A general trend was noted toward improved functioning and less severe psychotic symptoms. However, after two years, one-third of the patients had a diagnosis of schizophrenia and more than 40% had a diagnosis of affective psychosis. Rates of relapse were 31% after one year and 43% at two years. Cannabis use after illness onset and poor insight were the best predictors of relapse. Being male and severity of negative symptoms at baseline predicted worse functioning at two years. Patients with first-episode psychosis were found to have high relapse rates during the first years after illness onset. Further studies evaluating treatment strategies focused on reducing cannabis use and improving insight in first-episode psychosis should be encouraged.


Pannexin 1 channels: new actors in the regulation of catecholamine release from adrenal chromaffin cells.
Chromaffin cells of the adrenal gland medulla synthesize and store hormones and peptides, which are released into the blood circulation in response to stress. Among them, adrenaline is critical for the fight-or-flight response. This neurosecretory process is highly regulated and depends on cytosolic [Ca(2+)]. By forming channels at the plasma membrane, pannexin-1 (Panx1) is a protein involved in many physiological and pathological processes amplifying ATP release and/or Ca(2+) signals. Here, we show that Panx1 is expressed in the adrenal gland where it plays a role by regulating the release of catecholamines. In fact, inhibitors of Panx1 channels, such as carbenoxolone (Cbx) and probenecid, reduced the secretory activity induced with the nicotinic agonist 1,1-dimethyl-4-phenyl-piperazinium (DMPP, 50 μM) in whole adrenal glands. A similar inhibitory effect was observed in single chromaffin cells using Cbx or (10)Panx1 peptide, another Panx1 channel inhibitors. Given that the secretory response depends on cytosolic [Ca(2+)] and Panx1 channels are permeable to Ca(2+), we studied the possible implication of Panx1 channels in the Ca(2+) signaling occurring during the secretory process. In support of this possibility, Panx1 channel inhibitors significantly reduced the Ca(2+) signals evoked by DMPP in single chromaffin cells. However, the Ca(2+) signals induced by caffeine in the absence of extracellular Ca(2+) was not affected by Panx1 channel inhibitors, suggesting that this mechanism does not involve Ca(2+) release from the endoplasmic reticulum. Conversely, Panx1 inhibitors significantly blocked the DMPP-induce dye uptake, supporting the idea that Panx1 forms functional channels at the plasma membrane. These findings indicate that Panx1 channels participate in the control the Ca(2+) signal that triggers the secretory response of adrenal chromaffin cells. This mechanism could have physiological implications during the response to stress.


The functional reach test in people with multiple sclerosis: a reliability and validity study.
Limits of stability (LOS) is a major component of balance dysfunction in people with multiple sclerosis (MS). The functional reach test (FRT) is a clinical LOS assessment; however, its psychometric properties have not been investigated in people with MS yet. Objectives: To investigate: (1) the intrarater, interrater, and test-retest reliability of the FRT in people with MS; (2) the minimum detectable change (MDC) in the FRT distances; (3) the concurrent and discriminant validity of the FRT; and (4) the cutoff distance that best discriminates people with MS from healthy people and fallers from non-fallers with MS. Forty-three people with MS and 36 healthy people participated in this study. The FRT was administered along with the instrumented LOS test, Berg Balance Scale, Four Square Step Test, Timed Up and Go Test, and Expanded Disability Status Scale. The FRT was repeated by the same rater after 2 min from the first test session to determine the intrarater reliability and was simultaneously conducted by two independent raters to determine the interrater reliability. The FRT was also repeated after 7-10 days to determine the test-retest reliability. The reliability was quantified using intraclass correlation coefficients (ICC), Bland-Altman plots, and the MDC. The validity was assessed by correlating the FRT distances with the scores of other measures and by comparing the FRT distances between the MS group and healthy people, and between the fallers and non-fallers in the MS group. The FRT demonstrated good to excellent intrarater, interrater, and test-retest reliability with an ICC (3,1) of 0.80-0.88 (p < .001), an ICC (3,2) of 0.94-0.97 (p < .001), an ICC (2,3) of 0.84-0.86 (p < .001), respectively. Bland-Altman analyses showed no systematic bias between the assessments. The MDC was 8.28 centimeters. The FRT was correlated with the other outcome measures (correlation coefficients ranged from 0.31 to 0.79, p < .05 for all). Significant differences in the FRT distances were found between people with MS and healthy people; however, no significant difference was found between the fallers and non-fallers with MS (p < .001 and p = .09, respectively). The cutoff distance of 35.5 centimeters best discriminates healthy people from people with MS while of 28.5 centimeters did not discriminate between the fallers and non-fallers with MS. The FRT is a reliable, valid, and easy-to-administer tool for assessing LOS in people with MS.


Construction of four low-dimensional NIR-luminescence-tunable Yb(III) complexes.
Four low-dimensional ytterbium(iii)-organic compounds through hydrothermal reactions of quinoline-2,3-dicarboxylic acid (2,3-H2qldc) and oxalic acid (H2ox) with Yb2O3, namely, [Yb(2,3-qldc)(ox)1/2(H2O)3·(H2O)4]n (1), [Yb(2,3-qldc)(ox)1/2(H2O)2·(H2O)2]n (2), [Yb(2,3-Hqldc)(ox)(H2O)2·(H2O)]n (3) and [Yb(2,3-Hqldc)(ox)(H2O)·(H2O)2]n (4), were first synthesized and characterized by elemental analysis (EA), infrared spectroscopy (IR), thermogravimetric analysis (TG), and single-crystal X-ray diffraction. When the reactant ratio of 2,3-H2qldc : H2ox : Yb2O3 is 2 : 1 : 1, 1-D chain-like complex 1 with three coordinated water molecules around the Yb(iii) ion was obtained in mixed solvents of H2O and CH3OH (v : v = 10 : 1) at 70 °C, and with the increase of temperature to 100 °C, the same reactants gave 2-D 6(3) topological layer-like complex 2 with two coordinated water molecules in the coordination sphere of the Yb(iii) ion. However, when the reactant ratio was changed to 1 : 1 : 1, two 2-D 6(3) topological layer-like complexes 3 (70 °C) and 4 (100 °C) were obtained at different temperatures, in which the coordination water molecules in 3 and 4 are two and one, respectively. Obviously, these results reveal that the reaction temperature and reactant ratios play critical roles in the structural direction of these low-dimensional compounds. Interestingly, with the gradual loss of coordination water molecules to the Yb(iii) ion, the near infrared (NIR) emission of four Yb(iii)-based compounds 1-4 can be gradually strengthened with increasing order of 1 < 3 < 2 < 4, indicating that these ytterbium(iii) complexes have tunable near infrared luminescence.


Mammary epithelial paracellular permeability in atopic and non-atopic mothers versus childhood atopy.
Sodium/potassium (Na/K) ratios are considered to be a marker of mammary epithelial paracellular permeability. The aim of the present study was to investigate the association between maternal atopy and Na/K ratios in breast milk and the association between Na/K ratios in breast milk and the development of atopy in the offspring. Early and mature milk samples were obtained from 30 atopic and 43 non-atopic women. We found no differences in the Na/K ratios between atopic and non-atopic women. At 18 months of age, 22 (30%) of the children had a positive skin prick test (SPT) and 26 (36%) had symptoms of atopic diseases. Overall, high levels of Na/K compared with low and slightly raised levels of Na/K in the maternal milk tended to be associated with a positive SPT and atopic disease. However, if the mother was atopic, high levels of Na/K in early or mature milk were associated with a significantly increased risk of a positive SPT or atopic disease in the offspring [RR = 4.8 (1.9-12)] whereas no such association was observed in non-atopic mothers [RR = 0.8 (0.4-1.7), p for interaction = 0.001]. Thus, high Na/K levels in the breast milk may be associated with the development of atopy and atopic diseases in the offspring of atopic mothers.


Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and disease activity in Systemic Lupus Erythematosus.
A recent metabolomic screen of sera from patients with Systemic Lupus Erythematosus (SLE) found reduction of antioxidants and substrates for energy generation. These metabolic alterations may underlie one of the most common features of SLE--fatigue. The metabolomic studies also noted reduced omega-3 fatty acids, which are powerful anti- oxidants. This deficiency may be causally related to oxidative stress, inflammation, disease activity, and fatigue in SLE. Supplementation of omega-3 fatty acids using fish oil in SLE has been shown to reduce oxidative stress in other studies. The objective of this study is to evaluate the effect of fish oil supplementation on clinical measures of fatigue, quality of life, and disease activity as part of a randomized clinical trial. Fifty SLE patients recruited in outpatient clinics were randomized 1:1 to fish oil supplementation or olive oil placebo, and blinded to their treatment group. At baseline and after 6 months of treatment, RAND Short Form-36 (RAND SF-36), Fatigue Severity Scale (FSS), SLE Disease Activity Index (SLEDAI), and Physician Global Assessment (PGA) were completed; serum was also collected for soluble mediator analysis. Thirty-two patients completed the study. PGA improved significantly in the fish oil group compared with the placebo group (p = 0.015). The RAND SF-36 Energy/fatigue and Emotional well-being scores demonstrated improvement trends (p = 0.092 and 0.070). No clear difference was seen in FSS and SLEDAI (p = 0.350 and p = 0.417). Erythrocyte sedimentation rate and serum IL-12 were reduced (p = 0.008 and p = 0.058); while serum IL-13 was increased by fish oil supplementation (p = 0.033). In this randomized, placebo-controlled 6-month trial, SLE patients randomized to fish oil supplementation demonstrated improvement in their PGA, RAND SF-36, and some circulating inflammatory markers. ClinicalTrials.gov Identifier: NCT02021513 (registered 13 December 2013).


Boldine, a natural aporphine alkaloid, inhibits telomerase at non-toxic concentrations.
In a preliminary screening study of natural alkaloids, boldine, an aporphine alkaloid, showed an interesting dose and time dependent anti-proliferative effect in several cancer cell lines. Cytotoxicity of boldine in human fibroblasts was considerably lower than the telomerase positive embryonic kidney HEK293 and breast cancer MCF-7 and MDA-MB-231 cells. Whether boldine can inhibit telomerase was investigated here using a modified quantitative real-time telomere repeat amplification protocol (q-TRAP). This test showed that boldine inhibits telomerase in cells treated with sub-cytotoxic concentrations. Telomerase inhibition occurs via down-regulation of hTERT, the catalytic subunit of the enzyme. Boldine changed the splicing variants of hTERT towards shorter non-functional transcripts as well. A direct interaction of boldine with the enzyme may also be involved, though thermal FRET method did not detect any substantial interaction between boldine and synthetic telomere sequences. This study advocates boldine as a valuable candidate for telomerase-targeted cancer care. This study suggests that derivatives of boldine could be potent anti-cancer drugs.


Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity.
Single doses of the traditional herbal treatment Panax ginseng have recently been shown to elicit cognitive improvements in healthy young volunteers. The mechanisms by which ginseng improves cognitive performance are not known. However, they may be related to the glycaemic properties of some Panax species. Using a double-blind, placebo-controlled, balanced crossover design, 30 healthy young adults completed a 10 min test battery at baseline, and then six times in immediate succession commencing 60 min after the day's treatment (placebo, 200mg G115 or 400mg G115). The 10 min battery comprised a Serial Threes subtraction task (2 min); a Serial Sevens task (2 min); a Rapid Visual Information Processing task (5 min); then a 'mental fatigue' visual analogue scale. Blood glucose was measured prior to each day's treatment, and before, during and after the post-dose completions of the battery. Both the 200mg and 400mg treatments led to significant reductions in blood glucose levels at all three post-treatment measurements (p 0.005 in all cases). The most notable behavioural effects were associated with 200mg of ginseng and included significantly improved Serial Sevens subtraction task performance and significantly reduced subjective mental fatigue throughout all (with the exception of one time point in each case) of the post-dose completions of the 10 min battery (p 0.05). Overall these data suggest that Panax ginseng can improve performance and subjective feelings of mental fatigue during sustained mental activity. This effect may be related to the acute gluco-regulatory properties of the extract.


Proceedings from the Ice Hockey Summit on Concussion: a call to action.
The objective of this proceeding is to integrate the concussion in sport literature and sport science research on safety in ice hockey to develop an action plan to reduce the risk, incidence, severity, and consequences of concussion in ice hockey. A rationale paper outlining a collaborative action plan to address concussions in hockey was posted for review two months prior to the Ice Hockey Summit: Action on Concussion. Focused presentations devoted specifically to concussion in ice hockey were presented during the Summit and breakout sessions were used to develop strategies to reduce concussion in the sport. This proceedings and a detailed scientific review (a matrix of solutions) were written to disseminate the evidence-based information and resulting concussion reduction strategies. The manuscripts were reviewed by the authors, advisors and contributors to ensure that the opinions and recommendations reflect the current level of knowledge on concussion in hockey. Six components of a potential solution were articulated in the Rationale paper and became the topics for breakout groups that followed the professional, scientific lectures. Topics that formed the core of the action plan were: metrics and databases; recognizing, managing and return to play; hockey equipment and ice arenas; prevention and education; rules and regulations; and expedient communication of the outcomes. The attendees in breakout sessions identified action items for each section. The most highly ranked action items were brought to a vote in the open assembly, using an Audience Response System (ARS). The strategic planning process was conducted to assess: Where are we at?; Where must we get to?; and What strategies are necessary to make progress on the prioritized action items? Three prioritized action items for each component of the solution and the percentage of the votes received are listed in the body of this proceeding.


Headache and musculoskeletal complaints among subjects with self reported whiplash injury: the HUNT-2 study.
To evaluate the life-time prevalence of self reported whiplash injury and the relationship to chronic musculoskeletal complaints (MSCs) and headache in a large unselected adult population. Between 1995 and 1997, all inhabitants 20 years and older in Nord-Trondelag county in Norway were invited to a comprehensive health survey. Out of 92,936 eligible for participation, a total of 59,104 individuals (63.6%) answered the question about whiplash injury (whiplash). Among these, 46,895 (79.3%) responded to the questions of musculoskeletal complaints and headache. The total life-time prevalence of self reported whiplash injury was 2.9%, for women 2.7% and for men 3.0%. There was a significant association between self reported whiplash injury and headache (OR = 2.1; 95% CI 1.8-2.4), and chronic MSCs (OR = 3.3; 95% CI 2.8-3.8), evident for all ten anatomical sites investigated. The association was most pronounced for those with a combination of headache and chronic MSC for both men (OR = 4.8; 95% CI 3.6-6.2) and women (OR = 5.2; 95% CI 3.7-7.1). Subjects with self reported whiplash injury had significantly more headache and musculoskeletal complaints than those without, and may in part be due to selective reporting. The causal mechanism remains unclear and cannot be addressed in the present study design.


The Envy of Scholars: Applying the Lessons of the Framingham Heart Study to the Prevention of Chronic Kidney Disease.
During the past 50 years, a dramatic reduction in the mortality rate associated with cardiovascular disease has occurred in the US and other countries. Statistical modeling has revealed that approximately half of this reduction is the result of risk factor mitigation. The successful identification of such risk factors was pioneered and has continued with the Framingham Heart Study, which began in 1949 as a project of the US National Heart Institute (now part of the National Heart, Lung, and Blood Institute). Decreases in total cholesterol, blood pressure, smoking, and physical inactivity account for 24%, 20%, 12%, and 5% reductions in the mortality rate, respectively. Nephrology was designated as a recognized medical professional specialty a few years later. Hemodialysis was first performed in 1943. The US Medicare End-Stage Renal Disease (ESRD) Program was established in 1972. The number of patients in the program increased from 5,000 in the first year to more than 500,000 in recent years. Only recently have efforts for risk factor identification, early diagnosis, and prevention of chronic kidney disease (CKD) been undertaken. By applying the approach of the Framingham Heart Study to address CKD risk factors, we hope to mirror the success of cardiology; we aim to prevent progression to ESRD and to avoid the cardiovascular complications associated with CKD. In this paper, we present conceptual examples of risk factor modification for CKD, in the setting of this historical framework.


Sites important for PLCbeta2 activation by the G protein betagamma subunit map to the sides of the beta propeller structure.
The betagamma subunits of the heterotrimeric GTP-binding proteins (G proteins) that couple heptahelical, plasma membrane-bound receptors to intracellular effector enzymes or ion channels directly regulate several types of effectors, including phospholipase Cbeta and adenylyl cyclase. The beta subunit is made up of two structurally different regions: an N-terminal alpha helix followed by a toroidal structure made up of 7 blades, each of which is a twisted beta sheet composed of four anti-parallel beta strands (Wall, M. A., Coleman, D. E., Lee, E., Iñiguez-Lluhi, J. A., Posner, B. A., Gilman, A. G., and Sprang, S. R. (1995) Cell 83, 1047-1058; Lambright, D. G., Sondek, J., Bohm, A., Skiba, N. P., Hamm, H. E., and Sigler, P. B. (1996) Nature 379, 311-319). We have previously shown that sites for activation of PLCbeta2, PLCbeta3, and adenylyl cyclase II overlap on the "top" surface of the propeller, where Galpha also binds (Li, Y., Sternweis, P. M., Charnecki, S., Smith, T. F., Gilman, A. G., Neer, E. J., and Kozasa, T. (1998) J. Biol. Chem. 273, 16265-16272). The present study was undertaken to identify the regions on the side of the torus that might be important for effector interactions. We made mutations in each of the outer beta strands of the G protein beta1 propeller, as well as mutations in the loops that connect the outer strands to the adjacent beta strands. Our results suggest that activation of PLCbeta2 involves residues in the outer strands of blades 2, 6, and 7 of the propeller. We tested three of the mutations that most severely affected PLCbeta2 activity against two forms of adenylyl cyclase (ACI and ACII). Both inhibition of ACI and activation of ACII were unaffected by these mutations, suggesting that if ACI and ACII contact the outer strands, the sites of contact are different from those for PLCbeta2. We propose that distinct sets of contacts along the sides of the propeller will define the specificity of the interaction of betagamma with effectors.


Cytotoxicity of activated natural killer cells against pediatric solid tumors.
To develop new therapies for children with solid tumors, we tested the cytotoxicity of natural killer (NK) cells expanded by coculture with K562-mb15-41BBL cells. We sought to identify the most sensitive tumor subtypes, clarify the molecular interactions regulating cytotoxicity, and determine NK antitumor potential in vivo. We tested in vitro cytotoxicity of expanded NK cells against cell lines representative of Ewing sarcoma (EWS; n = 5), rhabdomyosarcoma (n = 4), neuroblastoma (n = 3), and osteosarcoma (n = 3), and correlated the results with expression of inhibitory and activating NK receptor ligands. We also compared expanded and primary NK cells, determined the effects of activating receptor ligation and of chemotherapeutic drugs, and assessed the therapeutic effect of NK cell infusions in xenografts. In 45 experiments, EWS and rhabdomyosarcoma cell lines were remarkably sensitive to expanded NK cells, with median cytotoxicities at 1:1 effector/target ratio of 87.2% and 79.1%, respectively. Cytotoxicity was not related to levels of expression of NK receptor ligands, nor was it affected by pretreatment of target cells with daunorubicin or vincristine, but was markedly inhibited by preincubation of NK cells with a combination of antibodies against the NK-activating receptors NKGD2 and DNAM-1. Expanded NK cells were considerably more cytotoxic than unstimulated NK cells, and eradicated EWS cells engrafted in nonobese diabetic/severe combined immunodeficient Il2rgnull mice. Among pediatric solid tumors, EWS and rhabdomyosarcoma are exquisitely sensitive to expanded NK cells. The NK expansion method described here has been adapted to large-scale conditions and supports a phase I clinical study including patients with these malignancies.


Hepatitis C, illicit drug use and public health: does Canada really have a viable plan?
Some 300,000 individuals are infected with the hepatitis C virus (HCV) in Canada. HCV infection is associated with major morbidity, mortality and health care costs; these indicators are projected to rise over the next decade. The vast majority of prevalent and incident HCV infections in Canada are illicit drug use-related; thus, the HCV disease burden can only be addressed through interventions targeting this primary risk factor. Both preventive (e.g., needle exchange, methadone treatment) and therapeutic (e.g., the accessibility of HCV treatment for illicit drug users) interventions aimed at HCV in illicit drug users have been broadly expanded in Canada in recent years. However, evidence suggests that existing preventive measures only offer limited effectiveness in reducing HCV risk exposure. Also, due to restricted resources, treatment for HCV currently only reaches an extremely small proportion (i.e., <5%) of HCV-infected drug users. Thus, on the basis of current HCV incidence as well as given interventions and their impact, Canada is not achieving a net reduction in the prevalence of HCV-related to illicit drug use. In order to reduce the HCV disease burden, Canada needs to reconsider the scope, delivery and resourcing of both preventive and treatment interventions targeting the primary risk population of illicit drug users.


Advances in noninvasive myelin imaging.
Myelin is important for the normal development and healthy function of the nervous system. Recent developments in MRI acquisition and tissue modeling aim to provide a better characterization and more specific markers for myelin. This allows for specific monitoring of myelination longitudinally and noninvasively in the healthy brain as well as assessment of treatment and intervention efficacy. Here, we offer a nontechnical review of MRI techniques developed to specifically monitor myelin such as magnetization transfer (MT) and myelin water imaging (MWI). We further summarize recent studies that employ these methods to measure myelin in relation to development and aging, learning and experience, and neuropathology and psychiatric disorders. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 136-151, 2018.


Human T-cell lymphotropic virus type II in Guaraní Indians, Southern Brazil.
Human T-cell lymphotropic virus type II (HTLV-II) is found in many New World Indian groups on the American continent. In Brazil, HTLV-II has been found among urban residents and Indians in the Amazon region, in the North. Guaraní Indians in the South of Brazil were studied for HTLV-I/II infection. Among 52 individuals, three (5.76%) showed positive anti-HTLV-II antibodies (enzyme-linked immunosorbent assay and Western blot). This preliminary report is the first seroepidemiological study showing HTLV-II infection among Indians in the South of Brazil.


High-frequency dielectric relaxation of liquid crystals: THz time-domain spectroscopy of liquid crystal colloids.
Terahertz time-domain spectroscopy has been used to study the dielectric relaxation of pure 4'-n-pentyl-4-cyanobiphenyl (5CB) liquid crystal (LC) and its mixtures with 10 mum SiO2 particles in the frequency range 0.2-2 THz. For the pure sample, we find that spatial inhomogeneities consisting of oriented domains, comparable in size to our probe area (~1 mm(2)), cause a large scatter in the measured dielectric function, due to varying contributions from the ordinary and extraordinary components. In the LC/particle mixtures, ordering of the LC at the surface of the SiO2 particles results in a break-up of these domains, giving rise to a spatially much more homogeneous dielectric response. The inferred dielectric function can be interpreted using effective medium theory and the Debye relaxation model. We observe this stabilizing effect for interparticle distances < ~30 mum, setting a lower limit for the size of oriented domains in the bulk LC.


Elucidation of Quantum-Well-Specific Carrier Mobilities in Layered Perovskites.
Layered organohalide perovskite films consist of quantum wells with concentration distributions tailored to enhance long-range charge transport. Whereas cascaded energy and charge funneling behaviors have been detected with conventional optical spectroscopies, it is not clear that such dynamics contribute to the efficiencies of photovoltaic cells. In this Letter, we use nonlinear photocurrent spectroscopy to selectively target charge transport processes within devices based on layered perovskite quantum wells. The photocurrent induced by a pair of laser pulses is directly measured in this "action" spectroscopy to remove ambiguities in signal interpretation. By varying the external bias, we determine carrier mobilities for quantum-well-specific trajectories taken through the active layers of the devices. The results suggest that the largest quantum wells are primarily responsible for photocurrent production, whereas the smallest quantum wells trap charge carriers and are a major source of energy loss in photovoltaic cells.


Patterns and control of cell motility in the Xenopus gastrula.
By comparing cells with respect to several motility-related properties and the ability to migrate on fibronectin, three cell types can be distinguished in the Xenopus gastrula. These occur in a distinct spatial pattern, thus defining three motility domains which do not correspond to the prospective germ layers. Migratory behavior is confined to a region encompassing the anterior mesoderm and endoderm. When stationary animal cap cells are induced to migrate by treatment with activin, cells become adhesive at low concentrations of fibronectin, show polarized protrusive activity, and form lamellipodia. Adhesion and polarization, but not lamellipodia formation, are mimicked by the immediate early response gene Mix.1. Goosecoid, another immediate early gene, is without effect when expressed alone in animal cap cells, but it acts synergistically with Mix.1 in the control of adhesion, and antagonistically in the polarization of protrusive activity. bFGF also induces migration, lamellipodia formation and polarization in animal cap cells, but has no effect on adhesion. By the various treatments of animal cap cells, new combinations of motile properties can be generated, yielding cell types which are not found in the embryo.


Effect of the influenza virus rapid antigen test on a physician's decision to prescribe antibiotics and on patient length of stay in the emergency department.
Influenza virus infection is a common reason for visits to the emergency department (ED) during the influenza season. A rapid and accurate diagnosis of influenza virus infection is important to reduce unnecessary antibiotic prescription and to improve patient care. The aim of this study was to examine whether using the Influenza Virus Rapid Antigen Test (IVRAT) in the ED affects the decision to prescribe antibiotics or the length of hospital stay (LOS). Data from patients suffering from an influenza-like illness (ILI) and who were discharged after visiting the ED at Chungbuk National University Hospital were reviewed over two influenza seasons: 2010-2011, when IVRAT was not used in the ED, and 2011-2012, when it was. The numbers of antibiotic prescriptions issued and the ED LOS during these two seasons were then compared. The number of antibiotic prescriptions was significantly lower in 2011-2012 (54/216, 25.0%) than in 2010-2011 (97/221, 43.9%; P<0.01). However, the median ED LOS for patients in 2011-2012 was much longer than that of patients in 2010-2011 (213 minutes vs. 257 minutes; P<0.01). During the 2011-2012 influenza season, 73 ILI patients showed a positive IVRAT result whereas 123 showed a negative result. Upon discharge, antibiotics were given to 42/123 (34.1%) ILI patients with a negative IVRAT result, but to only 7/73 (9.6%) patients with a positive IVRAT result (P<0.01). Performing IVRAT in the ED reduced the prescription of antibiotics to ILI patients discharged after ED care. However, the ED LOS for patients who underwent IVRAT was longer than that for patients who did not. Thus, performing IVRAT in the ED reduces the unnecessary prescription of antibiotics to ILI patients during the influenza season.


A 30-day prospective audit of all inpatient complications following acute care surgery: How well do we really perform?
Acute care surgery (ACS) and emergency general surgery (EGS) services must provide timely care and intervention for patients who have some of the most challenging needs. Patients treated by ACS services are often critically ill and have both substantial comorbidities and poor physiologic reserve. Despite the widespread implemention of ACS/EGS services across North America, the true postoperative morbidity rates remain largely unknown. In this prospective study, inpatients at 8 high-volume ACS/EGS centres in geographically diverse locations in Canada who underwent operative interventions were followed for 30 days or until they were discharged. Readmissions during the 30-day window were also captured. Preoperative, intraoperative and postoperative variables were tracked. Standard statistical methodology was employed. A total of 601 ACS/EGS patients were followed for up to 30 inpatient or readmission days after their index emergent operation. Fifty-one percent of patients were female, and the median age was 51 years. They frequently had substantial medical comorbidities (42%) and morbid obesity (15%). The majority of procedures were minimally invasive (66% laparoscopic). Median length of stay was 3.3 days and the early readmission (< 30 d) rate was 6%. Six percent of patients were admitted to the critical care unit. The overall complication and mortality rates were 34% and 2%, respectively. Cholecystitis (31%), appendicitis (21%), bowel obstruction (18%), incarcerated hernia (12%), gastrointestinal hemorrhage (7%) and soft tissue infections (7%) were the most common diagnoses. The morbidity and mortality rates for open surgical procedures were 73% and 5%, respectively. Nontrauma ACS/EGS procedures are associated with a high postoperative morbidity rate. This study will serve as a prospective benchmark for postoperative complications among ACS/EGS patients and subsequent quality improvement across Canada.


Investigating the specificity of the neurologic pain signature against breathlessness and finger opposition.
Brain biomarkers of pain, including pain-predictive "signatures" based on brain activity, can provide measures of neurophysiological processes and potential targets for interventions. A central issue relates to the specificity of such measures, and understanding their current limits will both advance their development and explore potentially generalizable properties of pain to other states. Here, we used 2 data sets to test the neurologic pain signature (NPS), an established pain neuromarker. In study 1, brain activity was measured using high-field functional magnetic resonance imaging (7T fMRI, N = 40) during 5 to 25 seconds of experimental breathlessness (induced by inspiratory resistive loading), conditioned breathlessness anticipation, and finger opposition. In study 2, we assessed anticipation and breathlessness perception (3T, N = 19) under blinded saline (placebo) and remifentanil administration. The NPS responded to breathlessness, anticipation, and finger opposition, although no direct comparisons with painful events were possible. Local NPS patterns in anterior or midinsula, S2, and dorsal anterior cingulate responded to breathlessness and finger opposition and were reduced by remifentanil. Local NPS responses in the dorsal posterior insula did not respond to any manipulations. Therefore, significant global NPS activity alone is not specific for pain, and we offer insight into the overlap between NPS responses, breathlessness, and somatomotor demand.


Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation.
Signal peptide peptidase (SPP) is an endoplasmic reticulum (ER)-resident aspartyl protease mediating intramembrane cleavage of type II transmembrane proteins. Increasing evidence has supported the role of SPP in ER-associated protein degradation. In the present study, we show that SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome. Stable depletion of SPP expression in lung and breast cancer cell lines significantly reduced cell growth and migration/invasion abilities. Quantitative analysis of the proteomic changes of microsomal proteins in lung cancer cells by the stable isotope labeling with amino acids in cell culture (SILAC) approach revealed that the level of FKBP8, an endogenous inhibitor of mTOR, was significantly increased following SPP depletion. Co-immunoprecipitation assay and confocal immunofluorescence demonstrated that SPP interacted and colocalized with FKBP8 in ER, supporting that FKBP8 is a protein substrate of SPP. Cycloheximide chase and proteasome inhibition experiments revealed that SPP-mediated proteolysis facilitated FKBP8 protein degradation in cytosol. Further experiment demonstrated that the levels of phosphorylation in mTOR and its downstream effectors, S6K and 4E-BP1, were significantly lower in SPP-depleted cells. The reduced mTOR signaling and decreases of growth and migration/invasion abilities induced by SPP depletion in cancer cells could be reversed by FKBP8 downregulation. The implication of FKBP8 in SPP-mediated tumorigenicity was also observed in the xenograft model. Together, these findings disclose that SPP promotes tumor progression, at least in part, via facilitating the degradation of FKBP8 to enhance mTOR signaling.


Influence of Dietary Acid Load on Exercise Performance.
Diet composition can affect systemic pH and acid-base regulation, which may in turn influence exercise performance. An acidic environment in the muscle impairs performance and contributes to fatigue; therefore, current trends in sports nutrition place importance on maximizing the alkalinity of the body with ergogenic aids and dietary strategies. This review examines the evidence on the effects of dietary manipulations on acid load and exercise performance. Ten studies that investigated the effect of high versus low dietary acid loads on athletic performance generally identified that low dietary acid loads increased plasma pH, but did not consistently improve exercise performance at maximal or submaximal exercise intensities. In addition, the few studies conducted have several limitations including lack of female subjects and use of exercise tests exclusive to cycling or treadmill running. Although the research does not strongly support a performance benefit from low dietary acid loads, a more alkaline dietary pattern may be beneficial for overall health, as dietary induced acidosis has been associated with greater risk of cardiovascular disease and bone disease. The review includes dietary recommendations for athletes to reduce dietary acid load while still meeting sports nutrition recommendations.


Direct processing and presentation of antigen from malaria sporozoites by professional antigen-presenting cells in the induction of CD8 T-cell responses.
Irradiated malaria sporozoites induce better protection than viable untreated sporozoites. We observed early differences between irradiated and viable untreated sporozoites in priming responses in vivo to a protective CD8 T-cell epitope, pb9, of the circumsporozoite protein of Plasmodium berghei. Sporozoites were processed for MHC class I presentation by dendritic cells (DC) to prime pb9-specific IFN-gamma-producing CD8 T cells. DC pulsed with untreated and irradiated sporozoites were similarly capable of priming central memory T-cell responses, detectable by the IFN-gamma cultured ELISPOT assay. However, irradiation significantly enhanced sporozoites' ability to prime effector T-cell responses detectable by the IFN-gammaex vivo ELISPOT assay. Irradiation also enhanced the ability of splenic APC to process and present sporozoites in order to re-stimulate pb9-specific polyclonal and clonal T-cell responses. Sporozoites did not stimulate T cells in the absence of APC. Over-irradiation decreased the sporozoites' T-cell stimulating capacity in vitro at high parasite doses, which may indicate that an optimal irradiation dose is necessary to induce protective immunity by sporozoite inoculation. The induction of sporozoite-specific CD8 T-cell responses without the need for liver stage infection identifies a potentially important mechanism in the development of pre-erythrocytic immunity.


Fluorescence imaging of flowing cells using a temporally coded excitation.
Imaging fluorescence in moving cells is fundamentally challenging because the exposure time is constrained by motion-blur, which limits the available signal. We report a method to image fluorescently labeled leukemia cells in fluid flow that has an effective exposure time of up to 50 times the motion-blur limit. Flowing cells are illuminated with a pseudo-random excitation pulse sequence, resulting in a motion-blur that can be computationally removed to produce near diffraction-limited images. This method enables observation of cellular organelles and their behavior in a fluid environment that resembles the vasculature.


Quantification and significance of diffuse myocardial fibrosis and diastolic dysfunction in childhood hypertrophic cardiomyopathy.
The purpose of this study was to evaluate the presence of diffuse myocardial fibrosis in children and adolescents with hypertrophic cardiomyopathy (HCM) and to assess associations with echocardiographic and clinical parameters of disease. While a common end point in adults with HCM, it is unclear whether diffuse myocardial fibrosis occurs early in the disease. Cardiac magnetic resonance (CMR) estimation of myocardial post-contrast longitudinal relaxation time (T1) is an increasingly used method to estimate diffuse fibrosis. T1 measurements were taken using standard multi-breath-hold spoiled gradient echo phase-sensitive inversion-recovery CMR before and 15 min after the injection of gadolinium. The tissue-blood partition coefficient was calculated as a function of the ratio of T1 change of myocardium compared with blood. An echocardiogram and blood brain natriuretic peptide (BNP) levels were obtained on the day of the CMR. Twelve controls (mean age 12.8 years; 7 male) and 28 patients with HCM (mean age 12.8 years; 21 male) participated. The partition coefficient for both septal (0.27 ± 0.17 vs. 0.13 ± 0.09; p = 0.03) and lateral walls (0.22 ± 0.09 vs. 0.07 ± 0.10; p < 0.001) was increased in patients compared with controls. Eight patients had overt areas of late gadolinium enhancement (LGE). These patients did not show increased partition coefficient compared with those without LGE (0.27 ± 0.15 vs. 0.27 ± 0.19 and 0.22 ± 0.09 vs. 0.22 ± 0.09; p = 0.95 and 0.98, respectively). However, patients who were symptomatic (dyspnea, arrhythmia and/or chest pain) had higher lateral wall partition coefficient than asymptomatic HCM patients (0.27 ± 0.08 vs. 0.17 ± 0.08; p = 0.006). Similarly, patients with raised BNP (>100 pg/ml) had raised lateral wall coefficients (0.27 ± 0.07 vs. 0.20 ± 0.07; p = 0.03), as did those with traditional risk factors for sudden death (0.27 ± 0.06 vs. 0.18 ± 0.08; p = 0.007). Diffuse fibrosis, measured by the partition coefficient technique, is demonstrable in children and adolescents with HCM. Markers of fibrosis show an association with symptoms and raised serum BNP. Further study of the prognostic implication of this technique in young patients with HCM is warranted.


Monocyte Distribution Width, Neutrophil-to-Lymphocyte Ratio, and Platelet-to-Lymphocyte Ratio Improves Early Prediction for Sepsis at the Emergency.
(1) Background: Sepsis is a life-threatening condition, and most patients with sepsis first present to the emergency department (ED) where early identification of sepsis is challenging due to the unavailability of an effective diagnostic model. (2) Methods: In this retrospective study, patients aged ≥20 years who presented to the ED of an academic hospital with systemic inflammatory response syndrome (SIRS) were included. The SIRS, sequential organ failure assessment (SOFA), and quick SOFA (qSOFA) scores were obtained for all patients. Routine complete blood cell testing in conjugation with the examination of new inflammatory biomarkers, namely monocyte distribution width (MDW), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), was performed at the ED. Propensity score matching was performed between patients with and without sepsis. Logistic regression was used for constructing models for early sepsis prediction. (3) Results: We included 296 patients with sepsis and 1184 without sepsis. A SIRS score of >2, a SOFA score of >2, and a qSOFA score of >1 showed low sensitivity, moderate specificity, and limited diagnostic accuracy for predicting early sepsis infection (c-statistics of 0.660, 0.576, and 0.536, respectively). MDW > 20, PLR > 9, and PLR > 210 showed higher sensitivity and moderate specificity. When we combined these biomarkers and scoring systems, we observed a significant improvement in diagnostic performance (c-statistics of 0.796 for a SIRS score of >2, 0.761 for a SOFA score of >2, and 0.757 for a qSOFA score of >1); (4) Conclusions: The new biomarkers MDW, NLR, and PLR can be used for the early detection of sepsis in the current sepsis scoring systems.


Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer.
Non-muscle invasive (NMI) bladder cancer is characterised by increased expression and activating mutations of FGFR3. We have previously investigated the role of microRNAs in bladder cancer and have shown that FGFR3 is a target of miR-100. In this study, we investigated the effects of hypoxia on miR-100 and FGFR3 expression, and the link between miR-100 and FGFR3 in hypoxia. Bladder cancer cell lines were exposed to normoxic or hypoxic conditions and examined for the expression of FGFR3 by quantitative PCR (qPCR) and western blotting, and miR-100 by qPCR. The effect of FGFR3 and miR-100 on cell viability in two-dimensional (2-D) and three-dimensional (3-D) was examined by transfecting siRNA or mimic-100, respectively. In NMI bladder cancer cell lines, FGFR3 expression was induced by hypoxia in a transcriptional and HIF-1α-dependent manner. Increased FGFR3 was also in part dependent on miR-100 levels, which decreased in hypoxia. Knockdown of FGFR3 led to a decrease in phosphorylation of the downstream kinases mitogen-activated protein kinase (MAPK) and protein kinase B (PKB), which was more pronounced under hypoxic conditions. Furthermore, transfection of mimic-100 also decreased phosphorylation of MAPK and PKB. Finally, knocking down FGFR3 profoundly decreased 2-D and 3-D cell growth, whereas introduction of mimic-100 decreased 3-D growth of cells. Hypoxia, in part via suppression of miR-100, induces FGFR3 expression in bladder cancer, both of which have an important role in maintaining cell viability under conditions of stress.


Relationship Between Quality of Comorbid Condition Care and Costs for Cancer Survivors.
To estimate the association between cancer survivors' comorbid condition care quality and costs; to determine whether the association differs between cancer survivors and other patients. Using the SEER-Medicare-linked database, we identified survivors of breast, prostate, and colorectal cancers who were diagnosed in 2004, enrolled in Medicare fee-for-service for at least 12 months before diagnosis, and survived ≥ 3 years. Quality of care was assessed using nine process indicators for chronic conditions, and a composite indicator representing seven avoidable outcomes. Total costs on the basis of Medicare amount paid were grouped as inpatient and outpatient. We examined the association between care quality and costs for cancer survivors, and compared this association among 2:1 frequency-matched noncancer controls, using comparisons of means and generalized linear regressions. Our sample included 8,661 cancer survivors and 17,332 matched noncancer controls. Receipt of recommended care was associated with higher outpatient costs for eight indicators, and higher inpatient and total costs for five indicators. For three measures (visit every 6 months for patients with chronic obstructive pulmonary disease or diabetes, and glycosylated hemoglobin or fructosamine every 6 months for patients with diabetes), costs for cancer survivors who received recommended care increased less than for noncancer controls. The absence of avoidable events was associated with lower costs of each type. An annual eye examination for patients with diabetes was associated with lower inpatient costs. Higher-quality processes of care may not reduce short-term costs, but the prevention of avoidable outcomes reduces costs. The association between quality and cost was similar for cancer survivors and noncancer controls.


Understanding Nanoparticle Toxicity Mechanisms To Inform Redesign Strategies To Reduce Environmental Impact.
There has been a surge of consumer products that incorporate nanoparticles, which are used to improve or impart new functionalities to the products based on their unique physicochemical properties. With such an increase in products containing nanomaterials, there is a need to understand their potential impacts on the environment. This is often done using various biological models that are abundant in the different environmental compartments where the nanomaterials may end up after use. Beyond studying whether nanomaterials simply kill an organism, the molecular mechanisms by which nanoparticles exhibit toxicity have been extensively studied. Some of the main mechanisms include (1) direct nanoparticle association with an organism's cell surface, where the membrane can be damaged or initiate internal signaling pathways that damage the cell, (2) dissolution of the material, releasing toxic ions that impact the organism, generally through impairing important enzyme functions or through direct interaction with a cell's DNA, and (3) the generation of reactive oxygen species and subsequent oxidative stress on an organism, which can also damage important enzymes or an organism's genetic material. This Account reviews these toxicity mechanisms, presenting examples for each with different types of nanomaterials. Understanding the mechanism of nanoparticle toxicity will inform efforts to redesign nanoparticles with reduced environmental impact. The redesign strategies will need to be chosen based on the major mode of toxicity, but also considering what changes can be made to the nanomaterial without impacting its ability to perform in its intended application. To reduce interactions with the cell surface, nanomaterials can be designed to have a negative surface charge, use ligands such as polyethylene glycol that reduce protein binding, or have a morphology that discourages binding with a cell surface. To reduce the nanoparticle dissolution to toxic ions, the toxic species can be replaced with less toxic elements that have similar properties, the nanoparticle can be capped with a shell material, the morphology of the nanoparticle can be chosen to minimize surface area and thus minimize dissolution, or a chelating agent can be co-introduced or functionalized onto the nanomaterial's surface. To reduce the production of reactive oxygen species, the band gap of the material can be tuned either by using different elements or by doping, a shell layer can be added to inhibit direct contact with the core, or antioxidant molecules can be tethered to the nanoparticle surface. When redesigning nanoparticles, it will be important to test that the redesign strategy actually reduces toxicity to organisms from relevant environmental compartments. It is also necessary to confirm that the nanomaterial still demonstrates the critical physicochemical properties that inspired its inclusion in a product or device.


Genes, psychological traits and civic engagement.
Civic engagement is a classic example of a collective action problem: while civic participation improves life in the community as a whole, it is individually costly and thus there is an incentive to free ride on the actions of others. Yet, we observe significant inter-individual variation in the degree to which people are in fact civically engaged. Early accounts reconciling the theoretical prediction with empirical reality focused either on variation in individuals' material resources or their attitudes, but recent work has turned to genetic differences between individuals. We show an underlying genetic contribution to an index of civic engagement (0.41), as well as for the individual acts of engagement of volunteering for community or public service activities (0.33), regularly contributing to charitable causes (0.28) and voting in elections (0.27). There are closer genetic relationships between donating and the other two activities; volunteering and voting are not genetically correlated. Further, we show that most of the correlation between civic engagement and both positive emotionality and verbal IQ can be attributed to genes that affect both traits. These results enrich our understanding of the way in which genetic variation may influence the wide range of collective action problems that individuals face in modern community life.


Correlation between the degree of left subclavian artery stenosis and the left vertebral artery waveform by pulse Doppler ultrasonography.
Development of retrograde blood flow may be observed in the vertebral artery and is associated with progressive ipsilateral proximal subclavian or innominate artery stenosis. The subclavian steal phenomenon is more prevalent in the left subclavian artery (LSA). The purpose of this study was to analyze the correlation between the degree of LSA stenosis and pulse Doppler waveforms of the left vertebral artery (LVA). A retrospective analysis of LVA waveforms was performed in 22 cases with LSA proximal stenosis before the origin of the LVA in conventional angiograms. The degree of LSA stenosis was classified into 5 groups (<50, 50-59, 60-69, 70-89, 90-100%). Pulse Doppler waveforms of the LVA were also classified into 5 subtypes depending on the depth of the mid-systolic notch representing retrograde blood flow (normal, mid-systolic notch, retrograde flow smaller than antegrade flow, retrograde flow larger than antegrade flow, retrograde flow without antegrade flow). A statistically significant correlation (R(2) = 0.646, p < 0.0001) was found between the degree of LSA stenosis and the LVA waveform. The pattern analysis of LVA pulse Doppler waveforms seems to be useful in determining the degree of LSA stenosis.


Vaccine administration by paramedics: a model for bioterrorism and disaster response preparation.
The events of 11 September 2001 have had a profound effect on disaster planning efforts in the United States. This is true especially in the area of bioterrorism. One of the major tenets of bioterrorism response is the vaccination of at-risk populations. This paper investigates the efficacy of training emergency medical services paramedics to administer vaccines in public health settings as preparation for and response to bioterrorism events and other disaster events. The concept of vaccination administration by specially trained paramedics is not new. Various programs to provide immunizations for emergency services personnel and at-risk civilian populations have been reported. Vaccination programs by paramedics should follow the guidelines of the National Vaccine Advisory Committee of the Centers for Disease Control and Prevention (CDC). This paper compares the seven standards of the CDC guidelines to routine paramedic practice and education. It is concluded that paramedics are adequately trained to administer vaccines. However, specific training and protocols are needed in the areas of administrative paperwork and patient education. A proposed outline for a paramedic-training program is presented.


Neural substrate of modified and unmodified pathways for learning in monkey vestibuloocular reflex.
To understand how the brain learns, we need to identify the full neural circuit for a behavior; characterize how neural responses in the circuit change during behavioral learning; and understand the nature, location, and control of the cellular changes that are responsible for learning. This goal seems attainable for the vestibuloocular reflex (VOR), where the neural circuit basis for learning is already partially understood. The current hypothesis for VOR learning postulates cellular changes in the cerebellar cortex and the vestibular nucleus. It suggests that the brain stem contains two parallel pathways that have been modeled on the basis of extensive biological data as unmodified and modified VOR pathways with frequency-dependent internal gains and different time delays. We now show a correspondence between the responses of different groups of neurons in the vestibular nucleus and the signals emanating from the two pathways in the model. Floccular target neurons (FTNs) and position-vestibular-pause neurons (PVPs) were identified by their discharge during eye movements and by the presence or absence of inhibition by floccular stimulation. FTNs had response gains and phases that coincided with predictions for pathways that are modified in association with learning, whereas PVPs had responses in agreement with predictions for the unmodified pathways. The quantitative agreement of prior model predictions and new data supports the identity of FTNs and PVPs as brain stem interneurons in the modified and unmodified VOR pathways. Other aspects of the data make predictions about how vestibular inputs are transformed as they pass through the two pathways.


Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation.
The initial differential treatment of the two X chromosomes during X-chromosome inactivation is controlled by the X-inactivation centre (Xic). This locus determines how many X chromosomes are present in a cell ('counting') and which X chromosome will be inactivated in female cells ('choice'). Critical control sequences in the Xic include the non-coding RNAs Xist and Tsix, and long-range chromatin elements. However, little is known about the process that ensures that X inactivation is triggered appropriately when more than one Xic is present in a cell. Using three-dimensional fluorescence in situ hybridization (FISH) analysis, we showed that the two Xics transiently colocalize, just before X inactivation, in differentiating female embryonic stem cells. Using Xic transgenes capable of imprinted but not random X inactivation, and Xic deletions that disrupt random X inactivation, we demonstrated that Xic colocalization is linked to Xic function in random X inactivation. Both long-range sequences and the Tsix element, which generates the antisense transcript to Xist, are required for the transient interaction of Xics. We propose that transient colocalization of Xics may be necessary for a cell to determine Xic number and to ensure the correct initiation of X inactivation.


Compartmentalization and Ca2+ buffering are essential for prevention of light-induced retinal degeneration.
Fly photoreceptors are polarized cells, each of which has an extended interface between its cell body and the light-signaling compartment, the rhabdomere. Upon intense illumination, rhabdomeric calcium concentration reaches millimolar levels that would be toxic if Ca(2+) diffusion between the rhabdomere and cell body was not robustly attenuated. Yet, it is not clear how such effective attenuation is obtained. Here we show that Ca(2+) homeostasis in the photoreceptor cell relies on the protein calphotin. This unique protein functions as an immobile Ca(2+) buffer localized along the base of the rhabdomere, separating the signaling compartment from the cell body. Generation and analyses of transgenic Drosophila strains, in which calphotin-expression levels were reduced in a graded manner, showed that moderately reduced calphotin expression impaired Ca(2+) homeostasis while calphotin elimination resulted in severe light-dependent photoreceptor degeneration. Electron microscopy, electrophysiology, and optical methods revealed that the degeneration was rescued by prevention of Ca(2+) overload via overexpression of CalX, the Na(+)-Ca(2+) exchanger. In addition, Ca(2+)-imaging experiments showed that reduced calphotin levels resulted in abnormally fast kinetics of Ca(2+) elevation in photoreceptor cells. Together, the data suggest that calphotin functions as a Ca(2+) buffer; a possibility that we directly demonstrate by expressing calphotin in a heterologous expression system. We propose that calphotin-mediated compartmentalization and Ca(2+) buffering constitute an effective strategy to protect cells from Ca(2+) overload and light-induced degeneration.


Outpatient myelography with fine-needle technique: an appraisal.
Postmyelography headaches are produced mostly by CSF leakage at the dural puncture site and are therefore largely dependent on the size of the needle used. Our study of 300 consecutive outpatients who had lumbar myelograms performed with 25- and 26-gauge spinal needles shows that the procedure has become virtually innocuous. We recommend that 26-gauge spinal needles be widely adopted as the standard for fluoroscopically controlled intrathecal injections of contrast material.