Regulation of the protein kinase PKR by the vaccinia virus pseudosubstrate inhibitor K3L is dependent on residues conserved between the K3L protein and the PKR substrate eIF2alpha.
The mammalian double-stranded RNA-activated protein kinase PKR is a component of the cellular antiviral defense mechanism and phosphorylates Ser-51 on the alpha subunit of the translation factor eIF2 to inhibit protein synthesis. To identify the molecular determinants that specify substrate recognition by PKR, we performed a mutational analysis on the vaccinia virus K3L protein, a pseudosubstrate inhibitor of PKR. High-level expression of PKR is lethal in the yeast Saccharomyces cerevisiae because PKR phosphorylates eIF2alpha and inhibits protein synthesis. We show that coexpression of vaccinia virus K3L can suppress the growth-inhibitory effects of PKR in yeast, and using this system, we identified both loss-of-function and hyperactivating mutations in K3L. Truncation of, or point mutations within, the C-terminal portion of the K3L protein, homologous to residues 79 to 83 in eIF2alpha, abolished PKR inhibitory activity, whereas the hyperactivating mutation, K3L-H47R, increased the homology between the K3L protein and eIF2alpha adjacent to the phosphorylation site at Ser-51. Biochemical and yeast two-hybrid analyses revealed that the suppressor phenotype of the K3L mutations correlated with the affinity of the K3L protein for PKR and was inversely related to the level of eIF2alpha phosphorylation in the cell. These results support the idea that residues conserved between the pseudosubstrate K3L protein and the authentic substrate eIF2alpha play an important role in substrate recognition, and they suggest that PKR utilizes sequences both near and over 30 residues from the site of phosphorylation for substrate recognition. Finally, by reconstituting part of the mammalian antiviral defense mechanism in yeast, we have established a genetically useful system to study viral regulators of PKR.


Parental rules, parent and peer attachment, and adolescent drinking behaviors.
Family factors have been widely implicated in the development of adolescent drinking behaviors. These include parental attachment and parental rules concerning drinking behaviors. Moreover, throughout adolescence attachment to parents gives way to attachment to peers, and parental rules about alcohol use become less strict. The present study examined the relationship between parental and peer attachment, parental rules on drinking and alcohol use in a large sample (n = 1,724) of adolescents in the United Kingdom. Controlling for school grade (proxy for age), sex and the non-independence of respondents (clustering at school level) results showed that scores on a parental rules on drinking questionnaire were a significant statistical predictor when comparing moderate drinkers and abstainers, as well as moderate drinkers and problematic drinkers. Scores on both attachment scales were also significant, but only in the comparison between moderate and problematic drinkers, with lower attachment to parents and higher attachment to peers associated with problematic drinking.


Evaluation of the sustainability of contrasted pig farming systems: the procedure, the evaluated systems and the evaluation tools.
Although a few studies consider the sustainability of animal farming systems along the three classical main pillars (economy, environment and society), most studies on pig farming systems address only one of these pillars. The present paper is the introduction to a series of companion papers presenting the results of a study undertaken within the EU-supported project Q-PorkChains, aiming at building a comprehensive tool for the evaluation of pig farming systems, which is robust to accommodate the large variability of systems existing in Europe. The tool is mostly based on questions to farmers and comprises a total of 37 dimensions distributed along eight themes: Animal Welfare, Animal Health, Breeding Programmes, Environmental Sustainability, Meat Safety, Market Conformity, Economy and Working Conditions. The paper describes the procedure that was used for building the tool, using it on 15 contrasted pig farming systems and analysing the results. The evaluated systems are briefly described and a short overview of the dimensions is provided. Detailed descriptions of the theme-wise tools and results, as well as the results of an integrated evaluation, are available in the companion papers.


Enhanced disease resistance and hypersensitivity to BTH by introduction of an NH1/OsNPR1 paralog.
Non-expresser of pathogenesis-related genes 1 (NPR1) is the master regulator of salicylic acid-mediated systemic acquired resistance. Over-expression of Arabidopsis NPR1 and rice NH1 (NPR1 homolog1)/OsNPR1 in rice results in enhanced resistance. While there are four rice NPR1 paralogs in the rice genome, none have been demonstrated to function in disease resistance. To study rice NPR1 paralog 3, we introduced constructs into rice and tested for effects on resistance to infection by Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight. While over-expression of NH3 using the maize ubiquitin-1 promoter failed to enhance resistance, introduction of an extra copy of NH3 driven by its own promoter (nNT-NH3) resulted in clear, enhanced resistance. Progeny analysis confirms that the enhanced resistance phenotype, measured by Xoo-induced lesion length, is associated with the NH3 transgene. Bacterial growth curve analysis indicates that bacterial population levels are reduced 10-fold in nNT-NH3 lines compared to control rice lines. The transgenic plants exhibit higher sensitivity to benzothiadiazole (BTH) and 2,6-dichloroisonicotinic acid (INA) treatment as measured by increased cell death. Expression analysis of pathogenesis-related (PR) genes showed that nNT-NH3 plants display greatly enhanced induction of PR genes only after treatment with BTH. Our study demonstrates an alternative method to employ a regulatory protein to enhance plant defence. This approach avoids using undesirable constitutive, high-level expression and may prove to be more practical for engineering resistance.


Localization of alkaline phosphatase on basolateral plasma membrane of normal and regenerating retinal pigment epithelium. A cytochemical study in rabbits.
Ultrastructural cytochemistry was used to analyze the polarized distribution of alkaline phosphatase (AP) on the plasma membranes of normal and regenerating retinal pigment epithelium (RPE) and the ciliary body epithelium in rabbits. The AP activity was concentrated on the basolateral plasma membrane in normal RPE. In regenerating RPE (after intravenous administration of sodium iodate to damage the RPE), there was a differential expression of AP activity according to the site on the regenerating epithelial sheet. At the edge of the sheet, where cells were undifferentiated and immature (ie, without the polarized distribution of basolateral and apical plasma membrane specializations seen in normal RPE), no plasma membrane AP activity was observed. The AP activity was reexpressed more proximal in the regenerating sheet. It was first evident where contiguous cells formed junctional complexes and cytologic polarization again became apparent. New AP activity was restricted to the basolateral plasma membrane. Eventually, the polarized distribution of AP activity seen in normal RPE was reestablished. In the ciliary body, AP activity was localized to the basolateral plasma membranes of the outer, nonpigmented epithelial cells. It was concluded (1) that cytochemical activity for nonspecific AP is concentrated on the basolateral plasma membrane domain of normal RPE and the normal pattern of AP activity is lost initially and then reexpressed.


Cophylogenetic signal is detectable in pollination interactions across ecological scales.
That evolutionary history can influence the way that species interact is a basic tenet of evolutionary ecology. However, when the role of evolution in determining ecological interactions is investigated, focus typically centers on just one side of the interaction. A cophylogenetic signal, the congruence of evolutionary history across both sides of an ecological interaction, extends these previous explorations and provides a more complete picture of how evolutionary patterns influence the way species interact. To date, cophylogenetic signal has most typically been studied in interactions that occur between fine taxonomic clades that show high intimacy. In this study, we took an alternative approach and made an exhaustive assessment of cophylogeny in pollination interactions. To do so, we assessed the strength of cophylogenetic signal at four distinct scales of pollination interaction: (1) across plant-pollinator associations globally, (2) in local pollination communities, (3) within the modular structure of those communities, and (4) in individual modules. We did so using a globally distributed dataset comprised of 54 pollination networks, over 4000 species, and over 12,000 interactions. Within these data, we detected cophylogenetic signal at all four scales. Cophylogenetic signal was found at the level of plant-pollinator interactions on a global scale and in the majority of pollination communities. At the scale defined by the modular structure within those communities, however, we observed a much weaker cophylogenetic signal. Cophylogenetic signal was detectable in a significant proportion of individual modules and most typically when within-module phylogenetic diversity was low. In sum, the detection of cophylogenetic signal in pollination interactions across scales provides a new dimension to the story of how past evolution shapes extant pollinator-angiosperm interactions.


Low SAMHD1 expression following T-cell activation and proliferation renders CD4+ T cells susceptible to HIV-1.
HIV-1 replication depends on the state of cell activation and division. It is established that SAMHD1 restricts HIV-1 infection of resting CD4 T cells. The modulation of SAMHD1 expression during T-cell activation and proliferation, however, remains unclear, as well as a role for SAMHD1 during HIV-1 pathogenesis. SAMHD1 expression was assessed in CD4 T cells after their activation and in-vitro HIV-1 infection. We performed phenotype analyzes using flow cytometry on CD4 T cells from peripheral blood and lymph nodes from cohorts of HIV-1-infected individuals under antiretroviral treatment or not, and controls. We show that SAMHD1 expression decreased during CD4 T-cell proliferation in association with an increased susceptibility to in-vitro HIV-1 infection. Additionally, circulating memory CD4 T cells are enriched in cells with low levels of SAMHD1. These SAMHD1 cells are highly differentiated, exhibit a large proportion of Ki67 cycling cells and are enriched in T-helper 17 cells. Importantly, memory SAMHD1 cells were depleted from peripheral blood of HIV-infected individuals. We also found that follicular helper T cells present in secondary lymphoid organs lacked the expression of SAMHD1, which was accompanied by a higher susceptibility to HIV-1 infection in vitro. We demonstrate that SAMHD1 expression is decreased during CD4 T-cell activation and proliferation. Also, CD4 T-cell subsets known to be more susceptible to HIV-1 infection, for example, T-helper 17 and follicular helper T cells, display lower levels of SAMHD1. These results pin point a role for SAMHD1 expression in HIV-1 infection and the concomitant depletion of CD4 T cells.


Environmental regulation of glycosidase and peptidase production by Streptococcus gordonii FSS2.
The synthesis of cell-associated and secreted proteins by Streptococcus gordonii FSS2, an infective endocarditis (IE) isolate, was influenced by both environmental pH and carbon source. Controlling the pH at 7.5 in stirred batch cultures showed that cell-associated and secreted protein concentrations were increased during late exponential and stationary phase by 68% and 125%, respectively, compared with similar cultures without pH control. The expression of five glycosidase and eight peptidase activities were examined using fluorogen-labelled synthetic substrates. Enzyme activities were significantly down-regulated during exponential growth, increasing during stationary phase (P<0.01) whether the culture pH was controlled at pH 7.5 or allowed to fall naturally to pH 4.4. Culture-supernatant activities were significantly increased (P<0.05) when the pH was maintained at 6.0 or 7.5, indicating modulation of enzyme activity by pH. Growth under nitrogen-limitation/glucose-excess conditions resulted in a significant repression of cell-associated glycosidase activities (P<0.01), whilst in the supernatant, activities were generally reduced. The expression of peptidase activities in the culture supernatant did not significantly change. The results suggest a possible role for catabolite repression by glucose in regulating enzyme expression. When S. gordonii FSS2 was cultured with 50% (v/v) added heat-inactivated foetal bovine serum, several cell-associated enzyme activities increased initially but were then reduced as the culture time was extended to 116 h. Culture-supernatant enzyme activities (N-acetyl-beta-D-glucosaminidase, N-acetyl-beta-D-galactosaminidase, thrombin, Hageman factor, collagenase and chymotrypsin), however, were significantly increased (P<0.01) over the same time period. The findings indicated that most of the important glycosidases synthesized by S. gordonii FSS2 were down-regulated by acid growth conditions and may also be subject to catabolite repression by glucose but conversely may be up-regulated by growth in serum. These results may have implications for streptococcal growth in an IE vegetation and in the mouth between meals or during sleep.


Extraction of stationary components in biosignal discrimination.
Biosignal recordings are widely used in the medical environment to support the evaluation and the diagnosis of pathologies. Nevertheless, the main difficulty lies in the non-stationary behavior of the biosignals, difficulting the obtention of patterns characterizing the changes in physiological or pathological states. Thus, the obtention of the stationary and non-stationary components of a biosignal is still an open issue. This work proposes a methodology to detect time-homogeneities based on time-frequency analysis with aim to extract the non-stationary behavior of the biosignal. Results show an increase in the stationarity and in the distance between classes of the reconstructions from the enhanced time-frequency representations. The stationary components extracted with the proposed approach can be used to solve biosignal classification problems.


Prognostic value of exercise tolerance test for predicting cardiovascular disease in asymptomatic individuals with heterozygous familiar hypercholesterolemia.
Heterozygous familiar hypercholesterolemia (hFH) is an autosomal dominant inherited dyslipidemia, associated with premature cardiovascular disease (CVD). Aim of the study was to define prognostic factors for cardiovascular events (CVE) in asymptomatic individuals with hFH. All participants with recent diagnosis of hFH were recruited from the outpatient lipid clinic from 1987 to 2016, without any previous clinical evidence of CVD. A detailed clinical evaluation and laboratory investigation was obtained. Exercise tolerance test (ETT) was performed until maximum exercise capacity was achieved, without evidence of ischemia. Primary endpoint of the study was the first CVE. Four hundred fifty one participants were followed up for 10 ± 8 years, with 68 recorded cases of CVD (15%). Cumulative incidence of CVD was 15%, 24% and 32% for the 3 decades, respectively. In univariate analysis, male gender (p = 0.016), progression of age (p < 0.001), menopause (p = 0.030), waist-hip ratio (p = 0.043) and increased levels of Lp(α) (p = 0.014) were significantly associated with increased CVD incidence; whereas, exercise capacity (p = 0.025), low variation of heart rate (HR) during all stages of ETT compared to resting state (p = 0.020), maximum systolic (p = 0.014) and diastolic (p < 0.001) blood pressure were inversely associated with CVD. In multi-adjusted analysis, male gender (p < 0.001), duration of ETT (p = 0.023), estimated HR (p = 0.029), variation of HR during ETT compared to resting state (p < 0.05) and maximum diastolic pressure (p = 0.044) were significantly associated with CVD. Parameters of ETT in asymptomatic individuals with hFH, without any evidence of ischemia, may predict CVD in these high-risk patients after decades of observation.


First Encounters: Repair Sequences in Cross-Signing.
Most human communication is between people who speak or sign the same languages. Nevertheless, communication is to some extent possible where there is no language in common, as every tourist knows. How this works is of some theoretical interest (Levinson, ). A nice arena to explore this capacity is when deaf signers of different languages meet for the first time and are able to use the iconic affordances of sign to begin communication. Here we focus on other-initiated repair (OIR), that is, where one signer makes clear he or she does not understand, thus initiating repair of the prior conversational turn. OIR sequences are typically of a three-turn structure (Schegloff ), including the problem source turn (T-1), the initiation of repair (T0), and the turn offering a problem solution (T+1). These sequences seem to have a universal structure (Dingemanse et al. 2013). We find that in most cases where such OIR occur, the signer of the troublesome turn (T-1) foresees potential difficulty and marks the utterance with "try markers" (Moerman, ; Sacks & Schegloff, ) which pause to invite recognition. The signers use repetition, gestural holds, prosodic lengthening, and eyegaze at the addressee as such try-markers. Moreover, when T-1 is try-marked this allows for faster response times of T+1 with respect to T0. This finding suggests that signers in these "first encounter" situations actively anticipate potential trouble and, through try-marking, mobilize and facilitate OIRs. The suggestion is that heightened meta-linguistic awareness can be utilized to deal with these problems at the limits of our communicational ability.


A rural community's involvement in the design and usability testing of a computer-based informed consent process for the Personalized Medicine Research Project.
Many informed consent studies demonstrate that research subjects poorly retain and understand information in written consent documents. Previous research in multimedia consent is mixed in terms of success for improving participants' understanding, satisfaction, and retention. This failure may be due to a lack of a community-centered design approach to building the interventions. The goal of this study was to gather information from the community to determine the best way to undertake the consent process. Community perceptions regarding different computer-based consenting approaches were evaluated, and a computer-based consent was developed and tested. A second goal was to evaluate whether participants make truly informed decisions to participate in research. Simulations of an informed consent process were videotaped to document the process. Focus groups were conducted to determine community attitudes towards a computer-based informed consent process. Hybrid focus groups were conducted to determine the most acceptable hardware device. Usability testing was conducted on a computer-based consent prototype using a touch-screen kiosk. Based on feedback, a computer-based consent was developed. Representative study participants were able to easily complete the consent, and all were able to correctly answer the comprehension check questions. Community involvement in developing a computer-based consent proved valuable for a population-based genetic study. These findings may translate to other types of informed consents, including those for trials involving treatment of genetic disorders. A computer-based consent may serve to better communicate consistent, clear, accurate, and complete information regarding the risks and benefits of study participation. Additional analysis is necessary to measure the level of comprehension of the check-question answers by larger numbers of participants. The next step will involve contacting participants to measure whether understanding of what they consented to is retained over time.


Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades.
This study sought to define the effects of age and gender effects on the normal range of time domain heart rate variability (HRV) over nine decades in healthy subjects. Low HRV is considered an independent marker of mortality risk. However, the age-related decline in HRV may limit its predictive value, particularly in the elderly. Delineation of the range of HRV in healthy subjects over the life span is needed. Gender-related differences in HRV also need clarification. We determined, according to decade, 24-h heart rate (HR) and HRV of 260 healthy subjects (10 to 99 years old; 112 male, 148 female) by means of five standard time domain measures: standard deviation of all normal sinus RR intervals over 24 h (SDNN), standard deviation of the averaged normal sinus RR intervals for all 5-mm segments (SDANN), mean of the standard deviations of all normal sinus RR intervals for all 5-min segments (SDNN index), root-mean-square of successive normal sinus RR interval difference (rMSSD) and the percentage of successive normal sinus RR intervals >50 ms (pNN50). 1) HRV decreased with aging, the pattern of change being measure dependent. HRV (SDNN and SDANN) decreased only very gradually, reaching 60% of baseline (second-decade values) by the tenth decade. With the SDNN index, HRV decreased linearly with aging, reaching 46% of baseline by the tenth decade. Using pNN50 and rMSSD, HRV decreased most rapidly, reaching 24% and 47% of baseline, respectively, by the sixth decade and then stabilized. 2) Using the SDNN index, rMSSD and pNN50, HRV of subjects >65 years old fell below published cutpoints for increased risk of mortality in 25%, 12% and 4%, respectively. 3) At age <30 years, HRV for all measures was lower in female than male subjects. Gender differences decreased at age >30 years and disappeared at age >50 years. 4) HR also declined with aging but much more slowly. HR at age <50 years was faster in female than in male subjects. Gender differences disappeared thereafter. 1) Using all measures, HRV of healthy subjects declines with aging, with measure-dependent patterns. 2) Using the SDNN index, rMSSD and pNN50, HRV of healthy subjects, particularly those >65 years old, may decrease to below levels associated with increased risk of mortality. 3) Gender influences HRV. Gender differences in HRV are age and measure dependent. 4) Age and gender also affect heart rate.


[Use of ultrasonography methods in the diagnosis of neurogenic paraosteoarthropathy in spinal cord injury].
To assess the role of the ultrasonic imaging evaluation of articular lesions suspected to be the initial presentation of heterotopic ossifications (HO), 59 consecutive injured patients were studied. 32 out of 59 patients showed clinical signs of local inflammation in one of the articular sites of the upper or lower limbs, sonographic scans proved to be diagnostic of HO in 7 out of those 32 patients before their radiographic findings. Serial sonographic examinations were performed utilizing a 7.5 MegaHertz transducer probe for 2 months. The imaging abnormalities were correlated with biochemical levels of serum alkaline phosphatase, modifications of radiographic features and bone 99nTC scintigraphy. Scintigraphy revealed to have a high sensitivity but a low specificity for the diagnosis of HO. Also the serum levels of alkaline phosphatase were not a sensitive indicator of early HO in our group of patients. Moreover serial sonographic scans confidently excluded the HO in the 25 patients with no initial signs of the disease without any false negative results. Thus, early sonographic assessment of patients, with spinal cord injury in which local signs of inflammation suggest initial HO formation, revealed to be superior to the other utilized technique for the diagnosis of HO and may be considered a valuable alternative in particular to evaluate the evolutive pattern of this disease.


Development of a Lethal Intranasal Exposure Model of Ebola Virus in the Cynomolgus Macaque.
Ebola virus (EBOV) is a filovirus that can cause Ebola virus disease (EVD). No approved vaccines or therapies exist for filovirus infections, despite an urgent need. The development and testing of effective countermeasures against EBOV requires use of animal models and a thorough understanding of how the model aligns with EVD in humans. The majority of published studies report outcomes of parenteral exposures for emulating needle stick transmission. However, based on data from EVD outbreaks, close contact exposures to infected bodily fluid seems to be one of the primary routes of EBOV transmission. Thus, further work is needed to develop models that represent mucosal exposure. To characterize the outcome of mucosal exposure to EBOV, cynomolgus macaques were exposed to EBOV via intranasal (IN) route using the LMA® mucosal atomization device (LMA® MAD). For comparison, four non-human primates (NHPs) were exposed to EBOV via intramuscular (IM) route. This IN exposure model was uniformly lethal and correlated with a statistically significant delay in time to death when compared to exposure via the IM route. This more closely reflects the timeframes observed in human infections. An IN model of exposure offers an attractive alternative to other models as it can offer insight into the consequences of exposure via a mucosal surface and allows for screening countermeasures via a different exposure route.


Unexpected tolerance of glycosylation by UDP-GalNAc:polypeptide alpha-N-acetylgalactosaminyltransferase revealed by electron capture dissociation mass spectrometry: carbohydrate as potential protective groups.
UDP-GalNAc:polypeptide alpha-N-acetylgalactosaminyltransferases (ppGalNAcTs, EC 188.8.131.52), a family of key enzymes that initiate posttranslational modification with O-glycans in mucin synthesis by introduction of alpha-GalNAc residues, are structurally composed of a catalytic domain and a lectin domain. It has been known that multiple Ser/Thr residues are assigned in common mucin glycoproteins as potential O-glycosylation sites and more than 20 distinct isoforms of this enzyme family contribute to produce densely O-glycosylated mucin glycoproteins. However, it seems that the functional role of the lectin domain of ppGalNAcTs remains unclear. We considered that electron capture dissociation mass spectrometry (ECD-MS), a promising method for highly selective fragmentation at peptide linkages of glycopeptides to generate unique c and z series of ions, should allow for precise structural characterization to uncover the mechanism in O-glycosylation of mucin peptides by ppGalNAcTs. In the present study, it was demonstrated that a system composed of an electrospray source, a linear RFQ ion trap that isolates precursor ions, the ECD device, and a TOF mass spectrometer is a nice tool to identify the preferential O-glycosylation sites without any decomposition of the carbohydrate moiety. It should be noted that electrons used for ECD are accelerated within a range from 1.75 to 9.75 eV depending on the structures of glycopeptides of interest. We revealed for the first time that additional installation of a alpha-GalNAc residue at potential glycosylation sites by ppGalNAcT2 proceeds smoothly in various unnatural glycopeptides having alpha-Man, alpha-Fuc, and beta-Gal residues as well as alpha-GalNAc residues. The results may suggest that ppGalNAcT2 did not differentiate totally presubstituted sugar residues in terms of configuration of functional groups, d-, l-configuration, and even alpha-, beta-stereochemistry at an anomeric carbon atom when relatively short synthetic peptides were employed for the acceptor substrates. Unexpected characteristics of ppGalNAcT2 motivated us to challenge site-directed installation of alpha-GalNAc residues at desired position(s) by protecting some hydroxyl groups of Thr/Ser residues with selectively removable sugars, notably a novel concept as "carbohydrate as protective groups", toward a goal of the systematic chemical and enzymatic synthesis of biologically important mucin glycopeptides.


Cl- channel is required for CXCL10-induced neuronal activation and itch response in a murine model of allergic contact dermatitis.
Persistent itch often accompanies allergic contact dermatitis (ACD), but the underlying mechanisms remain largely unexplored. We previously demonstrated that CXCL10/CXCR3 signaling activated a subpopulation of cutaneous primary sensory neurons and mediated itch response after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. The purpose of this study was to determine the ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch. In whole cell recordings, CXCL10 triggered a current in dorsal root ganglion (DRG) neurons innervating the area of CHS. This current was modulated by intracellular Cl- and blocked by the general Cl- channel inhibitors. Moreover, increasing Ca2+ buffering capacity reduced this current. In addition, blockade of Cl- channels significantly suppressed CXCL10-induced Ca2+ response. In behavioral tests, injection of CXCL10 into CHS site exacerbated itch-related scratching behaviors. Moreover, the potentiating behavioral effects of CXCL10 were attenuated by either of two Cl- channel blockers. Thus we suggest that the Cl- channel acts as a downstream target mediating the excitatory and pruritic behavioral effects of CXCL10. Cl- channels may provide a promising therapeutic target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.NEW & NOTEWORTHY The ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch are largely unexplored. This study revealed that CXCL10 evoked an ionic current mainly carried by Cl- channels. We suggest that Cl- channels are likely key molecular candidates responsible for the CXCL10-evoked neuronal activation and itch-like behaviors in a murine model of allergic contact dermatitis induced by the antigen squaric acid dibutylester. Cl- channels may emerge as a promising drug target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.


Anopheles gambiae: historical population decline associated with regional distribution of insecticide-treated bed nets in western Nyanza Province, Kenya.
High coverage of insecticide-treated bed nets in Asembo and low coverage in Seme, two adjacent communities in western Nyanza Province, Kenya; followed by expanded coverage of bed nets in Seme, as the Kenya national malaria programme rolled out; provided a natural experiment for quantification of changes in relative abundance of two primary malaria vectors in this holoendemic region. Both belong to the Anopheles gambiae sensu lato (s.l.) species complex, namely A. gambiae sensu stricto (s.s.) and Anopheles arabiensis. Historically, the former species was proportionately dominant in indoor resting collections of females. Data of the relative abundance of adult A. gambiae s.s. and A. arabiensis sampled from inside houses were obtained from the literature from 1970 to 2002 for sites west of Kisumu, Kenya, to the region of Asembo ca. 50 km from the city. A sampling transect was established from Asembo (where bed net use was high due to presence of a managed bed net distribution programme) eastward to Seme, where no bed net programme was in place. Adults of A. gambiae s.l. were sampled from inside houses along the transect from 2003 to 2009, as were larvae from nearby aquatic habitats, providing data over a nearly 40 year period of the relative abundance of the two species. Relative proportions of A. gambiae s.s. and A. arabiensis were determined for each stage by identifying species by the polymerase chain reaction method. Household bed net ownership was measured with surveys during mosquito collections. Data of blood host choice, parity rate, and infection rate for Plasmodium falciparum in A. gambiae s.s. and A. arabiensis were obtained for a sample from Asembo and Seme from 2005. Anopheles gambiae s.s. adult females from indoor collections predominated from 1970 to 1998 (ca. 85%). Beginning in 1999, A. gambiae s.s decreased proportionately relative to A. arabiensis, then precipitously declined to rarity coincident with increased bed net ownership as national bed net distribution programmes commenced in 2004 and 2006. By 2009, A. gambiae s.s. comprised proportionately ca. 1% of indoor collections and A. arabiensis 99%. In Seme compared to Asembo in 2003, proportionately more larvae were A. gambiae s.s., larval density was higher, and more larval habitats were occupied. As bed net use rose in Seme, the proportion of A. gambiae larvae declined as well. These trends continued to 2009. Parity and malaria infection rates were lower in both species in Asembo (high bed net use) compared to Seme (low bed net use), but host choice did not vary within species in both communities (predominantly cattle for A. arabiensis, humans for A. gambiae s.s.). A marked decline of the A. gambiae s.s. population occurred as household ownership of bed nets rose in a region of western Kenya over a 10 year period. The increased bed net coverage likely caused a mass effect on the composition of the A. gambiae s.l. species complex, resulting in the observed proportionate increase in A. arabiensis compared to its closely related sibling species, A. gambiae s.s. These observations are important in evaluating the process of regional malaria elimination, which requires sustained vector control as a primary intervention.


Phototoxic target lipid model of single polycyclic aromatic hydrocarbons.
A phototoxic target lipid model (PTLM) is developed to predict phototoxicity of individual polycyclic aromatic hydrocarbons (PAHs) measured either as median lethal concentration (LC50) or median lethal time (LT50) for a 50% toxic response. The model is able to account for the differences in the physical/chemical properties of PAHs, test species sensitivities, and variations in light source characteristics, intensity, and length of exposure. The PTLM is based on the narcotic target lipid model (NTLM) of PAHs. Both models rely on the assumption that mortality occurs when the toxicant concentration in the target lipid of the organism reaches a threshold concentration. The PTLM is applied to observed LC50s and LT50s for 20 individual PAHs, 15 test species-including arthropods, fishes, amphibians, annelids, mollusks, and algae-exposed to simulated solar and various UV light sources, for exposure times varying from less than 1 h to 100 h, a total of 333 observations. The LC50 concentrations range from less than 0.1 µg/L to greater that 104 µg/L. The model has 2 fitting parameters that are constant and apply to all PAHs and organisms. The root mean square errors of prediction for log(LC50) and log(LT50) are 0.473 and 0.382, respectively. The results indicate that the PTLM can predict the phototoxicity of single PAHs over a wide range of exposure conditions and to organisms with a wide range of sensitivities. Environ Toxicol Chem 2017;36:926-937. © 2016 SETAC.


Detection of cation-specific conformational changes in ribosomal RNA by gel electrophoresis.
Electrophoresis of ribosomal RNA in polyacrylamide-agrose composite gels separates 16S and 23S species into multiple bands. These bands of RNA represent multiple conformational forms of the molecules as judged by oligonucleotide analysis of the 16S RNA. Gel elctrophoresis was used to test for cation-specific conformational changes in ribosomal RNA. Relative to magnesium-equilibrated RNA, barium ion and putrescine induced alterations in the electrophoretic behavior of ribosomal RNA while calcium ion produced no change. Exchange of a critical level of bound magnesium ion for barium or putrescine was necessary for these changes to take place. The alterations in electrophoretic behavior were unaffected by simply restoring magnesium ion, but in addition required heating for reversal. We suggest that these conformational changes are a result of interaction at a specific class of cation binding sites previously observed with intact ribosomes.


A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.
Genetic differences in immune responses may affect susceptibility to mycobacterial infection, but no specific genes have been implicated in humans. We studied four children who had an unexplained genetic susceptibility to mycobacterial infection and who appeared to have inherited the same recessive mutation from a common ancestor. We used microsatellite analysis, immunofluorescence studies, and sequence analysis to study the affected patients, unaffected family members, and normal controls. A genome search using microsatellite markers identified a region on chromosome 6q in which the affected children were all homozygous for eight markers. The gene for interferon-gamma receptor 1 maps to this region. Immunofluorescence studies showed that the receptor was absent on leukocytes from the affected children. Sequence analysis of complementary DNA for the gene for interferon-gamma receptor 1 revealed a point mutation at nucleotide 395 that introduces a stop codon and results in a truncated protein that lacks the transmembrane and cytoplasmic domains. Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferon-gamma. The interferon-gamma pathway is important in the response to intracellular pathogens such as mycobacteria.


Development of a Novel Multi-Channel Thermocouple Array Sensor for In-Situ Monitoring of Ice Accretion.
A test was performed to determine the efficacy of a novel multi-channel thermocouple temperature sensor employing "N+1" array architecture for the in-situ detection of icing in cold climates. T-type thermoelements were used to fabricate a sensor with six independent temperature sensing points, capable of two-dimensional temperature mapping. The sensor was intended to detect the high latent heat of fusion of water (334 J/g) which is released to the environment during ice formation. The sensor was embedded on a plywood board and an aluminium plate, respectively by an epoxy resin. Three different ice accretion cases were considered. Ice accretion for all cases was achieved on the surface of the resin layer. In order to analyse the temperature variation for all three cases, the first 20 s response for each case was averaged between three cases. A temperature increase of (1.0 ± 0.1) °C and (0.9 ± 0.1) °C was detected by the sensors 20 s after the onset of icing, attributed to the latent heat of fusion of water. The results indicate that the sensor design is well-suited to cold temperature applications and that detection of the latent heat of fusion could provide a rapid and robust means of icing detection.


Secretory component and immunoglobulin in human gastric carcinoma: an immunohistochemical study.
The occurrence of secretory component (SC), IgA, IgG and IgM within tumor cells was immunohistochemically examined in a total of 101 gastric carcinomas comprising 50 early cancers and 51 advanced cancers. In advanced cancers, the frequency of SC was significantly higher in well-differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. The frequency of IgA did not differ with stage of cancer, but the frequencies of IgG and IgM were significantly higher in advanced cancer than in early cancer. The immunoglobulin-producing plasma cells in the stroma of advanced cancer were chiefly IgG, followed by IgA and IgM producers. The intensity of IgA plasma cell infiltration correlated with presence of IgA in tumor cells. No correlation was noted between serum immunoglobulin value and immunoglobulin in tumor cells. The survival rate indicated a tendency for IgG-containing advanced cancers which were infiltrated with many IgG plasma cells to have a better prognosis.


Knockdown of the histone di-methyltransferase G9a in nucleus accumbens shell decreases cocaine self-administration, stress-induced reinstatement, and anxiety.
Comorbid neuropsychiatric disorders such as addiction and anxiety could involve common underlying mechanisms. One potential mechanism involves epigenetic regulation of histone 3 dimethylation at lysine 9 residues (H3K9me2) by the histone dimethyltransferase G9a. Here we provide evidence that local AAV-RNAi-mediated knockdown of G9a expression in nucleus accumbens shell (NAcSh) of male rats reduces both addictive-related and anxiety-related behaviors. Specifically, G9a knockdown reduces sensitivity to low dose cocaine reinforcement when cocaine is freely available (fixed ratio schedule). Similarly, G9a knockdown reduces motivation for cocaine under higher effort demands (progressive ratio schedule). Following several weeks of forced abstinence, G9a knockdown attenuates extinction responding and reinstatement triggered by either cocaine-priming injections or footshock stress. This decrease in addictive behavior is associated with a long-term reduction in anxiety-like behavior as measured by the elevated plus maze (EPM). G9a knockdown also reduces basal anxiety-like behavior in EPM and marble burying tests in drug-naïve rats. These results complement our previous work showing that increased G9a expression in NAcSh enhances addictive-related and anxiety-related behaviors, indicating that G9a bi-directionally controls these responses. These results also suggest that regulation of G9a-influenced gene expression could be a common epigenetic mechanism for co-morbid anxiety and psychostimulant addiction.


Isostasy in australia and the evolution of the compensation mechanism.
A linear transfer function analysis has been applied to gravity and topographic data from Australia to calculate the isostatic response function of Dorman and Lewis. The Australian response function is considerably different from that calculated for the United States. The differences can be explained on the basis of an apparent evolution of the isostatic compensation mechanism in which viscoelastic creep occurs in the lithosphere and relaxes the initial long-wavelength elastic stresses.


VDAC Genes Expression and Regulation in Mammals.
VDACs are pore-forming proteins, coating the mitochondrial outer membrane, and playing the role of main regulators for metabolites exchange between cytosol and mitochondria. In mammals, three isoforms have evolutionary originated, VDAC1, VDAC2, and VDAC3. Despite similarity in sequence and structure, evidence suggests different biological roles in normal and pathological conditions for each isoform. We compared Homo sapiens and Mus musculus VDAC genes and their regulatory elements. RNA-seq transcriptome analysis shows that VDAC isoforms are expressed in human and mouse tissues at different levels with a predominance of VDAC1 and VDAC2 over VDAC3, with the exception of reproductive system. Numerous transcript variants for each isoform suggest specific context-dependent regulatory mechanisms. Analysis of VDAC core promoters has highlighted that, both in a human and a mouse, VDAC genes show features of TATA-less ones. The level of CG methylation of the human VDAC genes revealed that VDAC1 promoter is less methylated than other two isoforms. We found that expression of VDAC genes is mainly regulated by transcription factors involved in controlling cell growth, proliferation and differentiation, apoptosis, and bioenergetic metabolism. A non-canonical initiation site termed "the TCT/TOP motif," the target for translation regulation by the mTOR pathway, was identified in human VDAC2 and VDAC3 and in every murine VDACs promoter. In addition, specific TFBSs have been identified in each VDAC promoter, supporting the hypothesis that there is a partial functional divergence. These data corroborate our experimental results and reinforce the idea that gene regulation could be the key to understanding the evolutionary specialization of VDAC isoforms.


Product inhibition slow down the moving velocity of processive chitinase and sliding-intermediate state blocks re-binding of product.
Processive movement is the key reaction for crystalline polymer degradation by enzyme. Product release is an important phenomenon in resetting the moving cycle, but how it affects chitinase kinetics was unknown. Therefore, we investigated the effect of diacetyl chitobiose (C2) on the biochemical activity and movement of chitinase A from Serratia marcescens (SmChiA). The apparent inhibition constant of C2 on crystalline chitin degradation of SmChiA was 159 μM. The binding position of C2 obtained by X-ray crystallography was at subsite +1, +2 and Trp275 interact with C2 at subsite +1. This binding state is consistent with the competitive inhibition obtained by biochemical analysis. The apparent inhibition constant of C2 on the moving velocity of high-speed (HS) AFM observations was 330 μM, which is close to the biochemical results, indicating that the main factor in crystalline chitin degradation is also the decrease in degradation activity due to inhibition of processive movement. The Trp275 is a key residue for making a sliding intermediate complex. SmChiA W275A showed weaker activity and affinity than WT against crystalline chitin because it is less processive than WT. In addition, biochemical apparent inhibition constant for C2 of SmChiA W275A was 45.6 μM. W275A mutant showed stronger C2 inhibition than WT even though the C2 binding affinity is weaker than WT. This result indicated that Trp275 is important for the interaction at subsite +1, but also important for making sliding intermediate complex and physically block the rebinding of C2 on the catalytic site for crystalline chitin degradation.


Fusion of intracellular rod outer segment disk membranes with the surrounding plasma membrane.
The series of experiments described were undertaken to evaluate the use of a cell-free lysis model to measure membrane fusion events in photoreceptor rod outer segments (ROS). The experiments measure fusion initiated with the osmotic disruption of fluorescenty-labeled ROS and correlate these findings with previously described disc-plasma membrane fusion. The influence of calcium and disc membrane cholesterol content on fusion between ROS membrane species was evaluated. Membrane fusion was followed by measuring the dilution of a membrane-associated fluorophore (R18) from labeled plasma membrane to an unlabeled membrane species; discs. Free calcium in the ROS preparations was measured using the calcium-sensitive fluorophore Quin-2. The affects of cholesterol content on fusion were investigated by increasing and decreasing disc membrane cholesterol content using well established lipid exchange techniques. There is an increase in R18 fluorescence on hypotonic lysis of ROS whose plasma membrane is labeled with R18. This increase in fluorescence is inhibited by EGTA and requires nanomolar levels of calcium. The initial rates of fusion between R18-labeled plasma membrane and discs were virtually identical in discs with increased and decreased levels of membrane cholesterol. The increase in R18 fluorescence on lysis of R18-labeled ROS is consistent with fusion between disc membranes and the surrounding plasma membrane. This fusion is dependent on nanomolar levels of calcium, is inhibited by EGTA, and is independent of the cholesterol content of these membranes.


(D)-Amino acid chemical reporters reveal peptidoglycan dynamics of an intracellular pathogen.
Peptidoglycan (PG) is an essential component of the bacterial cell wall. Although experiments with organisms in vitro have yielded a wealth of information on PG synthesis and maturation, it is unclear how these studies translate to bacteria replicating within host cells. We report a chemical approach for probing PG in vivo via metabolic labeling and bioorthogonal chemistry. A wide variety of bacterial species incorporated azide and alkyne-functionalized d-alanine into their cell walls, which we visualized by covalent reaction with click chemistry probes. The d-alanine analogues were specifically incorporated into nascent PG of the intracellular pathogen Listeria monocytogenes both in vitro and during macrophage infection. Metabolic incorporation of d-alanine derivatives and click chemistry detection constitute a facile, modular platform that facilitates unprecedented spatial and temporal resolution of PG dynamics in vivo.


Effects of DL-2-bromopalmitoyl-CoA and bromoacetyl-CoA in rat liver and heart mitochondria. Inhibition of carnitine palmitoyltransferase and displacement of [14C]malonyl-CoA from mitochondrial binding sites.
The overt form of carnitine palmitoyltransferase (CPT1) in rat liver and heart mitochondria was inhibited by DL-2-bromopalmitoyl-CoA and bromoacetyl-CoA. S-Methanesulphonyl-CoA inhibited liver CPT1. The inhibitory potency of DL-2-bromopalmitoyl-CoA was 17 times greater with liver than with heart CPT1. Inhibition of CPT1 by DL-2-bromopalmitoyl-CoA was unaffected by 5,5'-dithiobis-(2-nitrobenzoic acid) or (in liver) by starvation. In experiments in which DL-2-bromopalmitoyl-CoA displaced [14C]malonyl-CoA bound to liver mitochondria, the KD (competing) was 25 times the IC50 for inhibition of CPT1 providing evidence that the malonyl-CoA-binding site is unlikely to be the same as the acyl-CoA substrate site. Bromoacetyl-CoA inhibition of CPT1 was more potent in heart than in liver mitochondria and was diminished by 5,5'-dithiobis-(2-nitrobenzoic acid) or (in liver) by starvation. Bromoacetyl-CoA displaced bound [14C]malonyl-CoA from heart and liver mitochondria. In heart mitochondria this displacement was competitive with malonyl-CoA and was considerably facilitated by L-carnitine. In liver mitochondria this synergism between carnitine and bromoacetyl-CoA was not observed. It is suggested that bromoacetyl-CoA interacts with the malonyl-CoA-binding site of CPT1. L-Carnitine also facilitated the displacement by DL-2-bromopalmitoyl-CoA of [14C]malonyl-CoA from heart, but not from liver, mitochondria. DL-2-Bromopalmitoyl-CoA and bromoacetyl-CoA also inhibited overt carnitine octanoyl-transferase in liver and heart mitochondria. These findings are discussed in relation to inter-tissue differences in (a) the response of CPT1 activity to various inhibitors and (b) the relationship between high-affinity malonyl-CoA-binding sites and those sites for binding of L-carnitine and acyl-CoA substrates.


[Issues in oncologic radiation physics and the establishing of a nuclear medicine service in Russia].
The creation of a framework of federal and regional medico-physical agencies at key medical, research and educational establishments will help solve many problems of development of oncological radiation physics. The setting-up of a medico-physical service in Russia will be instrumental in providing effective radiation treatment to cancer patients and will prevent huge losses in resources.


Fluorescence technique for comparative studies of substrate-binding subsites in serine proteinases. Application to subtilisins.
A fluorescence technique for comparative studies of substrate-binding subsites in serine proteinases is described. It consists of: selective labelling of the corresponding subsites with a fluorescent group by using N alpha-dansyl(5-dimethylaminonaphthalene-1-sulphonyl)ated peptide chloromethanes containing different numbers of amino acid residues, and probing the immediate environment of the subsites by quenching experiments using ionic and neutral quenchers. Intramolecular distances between the subsites and particular chromophores can be also determined. The technique is of general applicability to all serine proteinases. The above mentioned approach was applied to two proteinases: subtilisin Novo and mesentericopeptidase. It was concluded that the substrate-binding site of mesentericopeptidase is considerably more polar than that of subtilisin Novo. Intramolecular distances between the labelled subsites and tryptophan residues in the two proteinases were determined.


[Therapeutic use of carminomycin in soft tissue sarcomas].
A total of 39 patients with sarcoma of the soft tissues were treated with carminomycin administered intravenously in doses of 10-15 mg twice a week, the total dose being 60-70 mg. The intervals between the courses were 1 month. The objective effect was observed in 17 out of 39 patients, i. e. 43.6%. The tumor decrease was registered in 6 out of 15 patients with leuomyosarcoma, in 3 out of 6 patients with synovial sarcoma, in 2 out of 4 patients with robdomyosarcoma, in 1 out of 4 patients with angiosarcoma, in 1 out of 3 patients with fibrosarcoma, in 1 patient with liposarcoma and in 3 out of 5 patients with stromal sarcoma of the uterus. A necessity for repeated treatment courses in spite of a positive effect or absence of the disease progress is underlined.


Nobiletin protects PC12 cells from ERS-induced apoptosis in OGD/R injury via activation of the PI3K/AKT pathway.
Nobiletin (NOB) possesses multiple pharmacological effects, but its anti-apoptotic property has acquired a great deal of attention. Endoplasmic reticulum (ER) stress (ERS)-induced apoptosis acts as the pivotal aetiology in neuronal oxygen-glucose deprivation and reoxygenation (OGD/R) injury. The aim of this study focused on whether NOB exerts neuro-protective effects on OGD/R injury by repressing ERS-induced apoptosis. The PC12 neuronal cell line was subjected to 4 h OGD and 24 h reoxygenation following NOB treatment. A PI3K/AKT inhibitor (LY294002) was added during the mechanistic experiments. Cell viability, lactate dehydrogenase (LDH) release and apoptosis were determined. Western blotting was used to measure protein expression levels. The results showed that OGD/R caused neuronal damageas exhibited by the increase in LDH release and the reduction of cellular viability. Moreover, ERS-induced apoptosis was markedly stimulated by OGD/R in PC12 cells, as evidenced by the elevation in the apoptotic rate and protein levels of C/EBP homologous protein/glucose-regulated protein-78. However, NOB administration significantly reversed neuronal damage and the ERS-induced apoptosis in response to OGD/R injury. Mechanistic detections showed that the neuron-favorable and ERS-repressing contributions of NOB were, in part, a result of the activation of the PI3K/AKT pathway, which was validated by a specific PI3K/AKT inhibitor (LY294002). Therefore, NOB protects PC12 cells from ERS-induced apoptosis in OGD/R injury mainly through enhancement of the PI3K/AKT pathway, which may provide a novel therapeutic avenue for the prevention of cerebral ischemia/reperfusion injury.


Breaking the silence: Determining Prevalence and Understanding Stillbirth Stigma.
The 2011 and 2016 Stillbirth Lancet series made a call to action to identify mechanisms to reduce stillbirth stigma. This research answers that call, investigating the extent and dimensions of stillbirth stigma experienced by an international sample of mothers bereaved by stillbirth. To determine the prevalence and type as well as explore explanatory variables associated with higher levels of stillbirth stigma with bereaved mothers in high-income countries (Australia, United Kingdom, The United States of America and New Zealand). An international survey of 889 bereaved mothers was conducted utilising the recently developed Stillbirth Stigma Scale to explore the extent and types of stigma experienced, as well as the association between stigma and self-esteem (Rosenberg Self- Esteem Scales), perinatal grief (Perinatal Grief Scale), and perceived social support (Perceived Social Support Scale). Demographic information (e.g. age, education, stillbirth history, sexual orientation and mental health) were collected to determine the association between individual demographic factors and stillbirth stigma. Results of the Stillbirth Stigma Scale indicated that a majority (54%) of bereaved mothers experienced stigma. Self-stigma was the predominant type of stigma experienced (80%), followed by perceived devaluation (64.9%). Bereaved mothers also experienced discrimination (29.1%) and issues with disclosing their stillbirth to their community (36.7%). Stillbirth stigma scores were higher in bereaved mothers who had experienced the loss of their first child. High scores were associated with the mother's mental health status (diagnoses prior to stillbirth, and/or after stillbirth (p<.05)).The other scales used indicated that higher stillbirth stigma scores were also associated with lower self-esteem (r (877) =-.304, p<.001), lower perceived social support (r (871) =-.448, p<.001) and higher levels of grief (r (829) =.609, p<.001). The current research was the first to identify that 54% of bereaved mothers experienced stigma, with self-stigma being the most prominent. Bereaved mothers endured discriminating experiences and had trouble disclosing their stillbirth to others within their community. The first-time mother with a self- reported history of mental illnesses appears to be the most at-risk of higher levels of stigma. Future longitudinal research needs to be conducted to determine the direction of the explanatory variables i.e. mental health, self-esteem and social support and develop interventions, which support the bereaved mother and reduce stillbirth stigma. This study is the first to demonstrate the prevalence, extent, type and explanatory variables of stigma reported by bereaved mothers and the association between this and poorer outcomes including increased grief and decreased self-esteem. This study begins a dialogue about prevalence and explanatory variables of stillbirth stigma and its impact, to inform future prevention and support potential stigma reduction programs for community and bereaved mothers.


Cerebro-renal interaction and stroke.
Stroke is an event causing a disturbance in cerebral function leading to death and disability worldwide. Both acute kidney injury and chronic kidney disease (CKD) are associated with an increased risk of stroke and cerebrovascular events. The underlying mechanistic approach between impaired renal function and stroke is limitedly explored and has attracted researchers to learn more for developing therapeutic intervention. Common risk factors such as hypertension, hyperphosphatemia, atrial fibrillation, arteriosclerosis, hyperhomocysteinemia, blood-brain barrier disruption, inflammation, etc. are observed in the general population, but are high in renal failure patients. Also, risk factors like bone mineral metabolism, uremic toxins, and anemia, along with the process of dialysis in CKD patients, eventually increases the risk of stroke. Therefore, early detection of risks associated with stroke in CKD is imperative, which may decrease the mortality associated with it. This review highlights mechanisms by which kidney dysfunction can lead to cerebrovascular events and increase the risk of stroke in renal impairment.


A survey of public attitudes towards barking dogs in New Zealand.
To investigate public attitudes towards barking dogs in New Zealand in order to quantify the extent to which people perceive barking dogs to be a problem, to compare tolerance of barking with that of other common suburban noises, to assess the level of public understanding about the function of barking, to determine risk factors for intolerance of barking and to assess knowledge of possible strategies for the investigation and management of problem barking. A 12-page questionnaire was sent to 2,000 people throughout New Zealand randomly selected from the electoral roll. Risk factors for being bothered by barking were examined using logistic regression analysis. A total of 1,750 questionnaires were successfully delivered; of these, 727 (42%) were returned. Among respondents, 356/727 (49.0%) indicated that frequent barking during the day would bother them while 545/727 (75.0%) would be bothered by barking at night. Barking and howling were ranked above other suburban noises as a cause of annoyance. Risk factors for being bothered by daytime barking were not being home during the day, not owning a dog, and considering a dog bite to be a serious health risk. Risk factors for being bothered by night-time barking were not being home during the day, marital status, considering dog bites to pose a serious health risk, and having been frightened by a dog. Overall, 510/699 (73%) respondents understood that barking was a form of communication. Action likely to be taken by 666 respondents hearing frequent barking included notifying and offering to help the owner (119; 17.8%), complaining to the owner (127; 19.1%) or the authorities (121; 18.2%), or doing nothing (299; 48%). Possible responses by 211 dog owners if they had a barking dog included seeking help from dog trainers (59; 28%) or behaviourists (54; 26%), buying an anti-barking device (33; 15%) or getting rid of the dog (20; 10%). Barking was considered to be potentially disturbing by respondents to this survey. Attitudes towards barking were most influenced by age, dog ownership, past experience with dogs and attitude towards dog bites. Public understanding of the possible reasons for barking and appropriate methods of managing the behaviour when it becomes a problem could be improved by better education and the provision of information through veterinary clinics and social media.


N,N-Bis(4-nitro-phen-yl)acetamide.
In the title compound, C14H11N3O5, the dihedral angles between the amide group (r.m.s. deviation = 0.0429 Å) and the two benzene rings are 39.66 (6) and 63.04 (7)°. The dihedral angle between the benzene rings is 86.04 (7)°. The benzene rings form dihedral angles of 4.42 (5) and 8.91 (5)° with the adjacent nitro groups. In the crystal, mol-ecules are linked via a pair of C-H⋯O hydrogen bonds, forming inversion dimers, which are linked via a second pair of C-H⋯O hydrogen bonds, forming chains propagating along [100].


A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis.
Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies. Plasma concentrations of cytokines [interleukin 1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1beta), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration < or = 12 months; > or = 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis. Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1beta), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1beta), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group. Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients.


Photochemical reaction dynamics in SO(2)-acetylene complexes.
The dynamics of photoinduced reactions between electronically excited SO(2) molecule (A (1)A(2)<--X (1)A(1)) and acetylene molecule (X (1)Sigma(g) (+)) in the SO(2)-acetylene van der Waals (vdW) complexes (clusters) was studied. The SO(2) molecule was excited by frequency-doubled radiation of a tunable dye laser, and resonance enhancement multiphoton photoionization of the produced photofragments was induced by ArF (193 nm) laser radiation or by frequency-doubled radiation of a second tunable dye laser to observe the C(2)H radical. The HOSO radical was detected by its IR emission. We found that the main photodecomposition channel of the vdW complexes (clusters) involves the SO(2) ( *)+C(2)H(2)-->HOSO+C(2)H reaction. Indeed, the analysis of the action spectra of the excitation laser radiation showed that the photofragments emerging in our experimental conditions (SO(2), 5%; C(2)H(2), 5%; and Xe; P(0)=2 atm) originate from the SO(2)...C(2)H(2) vdW complex (cluster). We analyzed the structure of this vdW complex theoretically, obtaining C(s) symmetry, with the acetylene molecule located above the OSO plane. The resonance-enhanced multiphoton photoionization action spectra of the C(2)H (A<--X) photofragmentation and the IR emission spectra of the HOSO radical allowed the authors to probe the energy distribution between the photofragments formed. The reaction that involves transition of the acetylene H atom to the SO(2) oxygen should be the primary step of the process considered, followed by nonstatistic dissociation of the vdW complex (cluster), with the C(2)H radical formed in its vibrationless state and excited both rotationally and translationally, and the HOSO radical excited vibrationally, rotationally and translationally. The proposed reaction mechanism was discussed, employing transition-state and Rice-Ramsperger-Kassel-Marcus (RRKM) approaches. The kinetics of photofragment formation was investigated, yielding characteristic radical build-up time of 0.64 micros.


A comparative study of hydroxide adsorption on the (111), (110), and (100) faces of silver with cyclic voltammetry, ex situ electron diffraction, and in situ second harmonic generation.
Hydroxide adsorption on the (111), (110), and (100) faces of silver electrodes from mixed NaOH/NaF solution is studied using cyclic voltammetry and in situ second harmonic generation (SHG). Cyclic voltammograms for the three low index silver planes in alkaline electrolytes are for the first time compared. They show two pairs of anodic and cathodic peaks in the potential interval below the equilibrium Ag/Ag(2)O potential. These are attributed to the specific adsorption of hydroxide ions followed by submonolayer oxide formation. The differences in the cyclic voltammograms for the (111), (110), and (100) planes are attributed to different (i) work functions, (ii) surface atomic densities, and (iii) corrugation potentials for these surfaces. Ex situ low energy electron diffraction (LEED) and reflection high energy electron diffraction (RHEED) show that disordered adlayers are formed on Ag(111) and Ag(100), in contrast to Ag(110), where ordered structures are produced in the region of the first pair of current peaks. In the region of the second pair of peaks, LEED indicates disordered oxide phases on each crystal plane and RHEED shows the presence of small islands of c(2 x 2) structure at some potentials on (110) and (100). SHG measurements were performed (i) in the potential scan mode at constant rotational angle and (ii) at constant potential as a function of the rotational angle. The isotropic (for the (111), (110), and (100) planes) and anisotropic (for the (110) and (111) planes) contributions to the SHG intensity were calculated by fitting the experimental data and are discussed in terms of their dependence on the charge density at the interface, on hydroxide adsorption, and on submonolayer oxide formation.


Underreporting of cancer in medical surveys: a source of systematic error in cancer research.
Systematic errors occur in the reports of disease frequency derived from health surveys based on questionnaire interviews. Five hundred and thirty-three persons with clinically and histologically confirmed disease in a case-control study of cancer were interviewed in their homes by carefully trained interviewers using a standardized questionnaire interview schedule. Comparisons of the information obtained by interview about past history of cancer with cancer registry and hospital medical record information about the same people revealed serious underestimates of correct frequency and wide variation in the rates of correct reporting. The findings reported here and elsewhere add support to an essential requirement in medical survey research: the completeness and accuracy of responses in health interview surveys must be verified and the methods of verification must be reported before the results can be interpreted with confidence.


The conundrum of recurrent low-grade tumours: to treat or to observe?
To describe the importance of risk stratification and the role of more conservative management like office fulguration, office laser ablation and active surveillance in recurrent low-grade Ta tumours. Updated models have been designed for risk stratification of intermediate-risk tumours. Conservative forms of management like office fulguration or laser ablation and even active surveillance seem well tolerated; however, randomized, controlled trials are lacking. In patients who have been tumour free for 5 years, late recurrences have been described. Recurrent low-grade Ta tumours are classified in the intermediate risk group, which is a heterogeneous group. Therefore, risk stratification should be done by updated models or patients should be stratified in a risk group sub-classification. Recurrent low-grade Ta patients have a favourable prognosis and consequently are prone to overtreatment. Office fulguration or laser ablation or even active surveillance could be implemented in strictly selected patients. For active surveillance, Miyake et al. proposed a helpful flowchart with criteria for patient selection and for intervention. Follow up using cystoscopy and cytology is essential, but an optimal scheme has not been identified. As late recurrences are not infrequent and recurrent low-grade Ta patients can even die from bladder cancer, long term follow-up should be performed yearly, by cystoscopy and cytology.


A benchmark of gene expression tissue-specificity metrics.
One of the major properties of genes is their expression pattern. Notably, genes are often classified as tissue specific or housekeeping. This property is of interest to molecular evolution as an explanatory factor of, e.g. evolutionary rate, as well as a functional feature which may in itself evolve. While many different methods of measuring tissue specificity have been proposed and used for such studies, there has been no comparison or benchmarking of these methods to our knowledge, and little justification of their use. In this study, we compare nine measures of tissue specificity. Most methods were established for ESTs and microarrays, and several were later adapted to RNA-seq. We analyse their capacity to distinguish gene categories, their robustness to the choice and number of tissues used and their capture of evolutionary conservation signal.


The Need for Understanding and Addressing Microaggressions in the Workplace.
The special issue on microaggressions highlighted how subtle interpersonal bias is complex, harms its targets, and reinforces established systems of inequity. The aim of this commentary is to contribute an organizational science perspective to this insightful and important dialogue. Given that the workplace is a microcosm of the broader society where adults spend most of their waking hours, studying microaggressions in this context can shed light on their unique manifestations and consequences, as well as methods to address this unique source of workplace adversity. Unlike other social contexts, many employees do not have complete autonomy over whom they interact with (e.g., choosing one's supervisor, officemates, or clients) and what they are able to convey authentically and safely in those interactions (i.e., choices about how one responds to microaggressions). As a result, people from minoritized backgrounds must often maintain professional relationships with colleagues or supervisors who harbor bias and (un)consciously convey it via microinvalidations, microassaults, and microinsults. Further, reward systems in the world of work (e.g., wages, promotions) may not only reflect but also reinforce systems of disadvantage (e.g., who experiences social mobility). In addition to understanding microaggressions in the workplace, there is a need to actively address them. We engage with Ong et al., Johnson et al., and Spanierman et al. to suggest that organizational understanding and remediation of microaggressions offers a viable avenue for challenging systems of oppression and fostering employee and organizational resilience to adversity.


Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells.
Ex vivo selection of transduced hematopoietic stem cells (HSC) with drug-resistance genes offers the possibility to enrich transduced cells prior to engraftment, toward increased reconstitution in transplant recipients. We evaluated the potential of highly methotrexate (MTX)-resistant variants of human dihydrofolate reductase (hDHFR) for this application. Two subsets of hDHFR variants with reduced affinity for MTX that had been previously identified in a bacterial system were considered: those with substitutions at positions 31, 34, and/or 35, and those with substitutions at position 115. The variants were characterized for their resistance to pemetrexed (PMTX), an antifolate that is related to MTX. We observed a strong correlation between decreased binding to both antifolates, although the identity of specific sequence variations modulated the correlation. We chose a subset of hDHFR variants for tests of ex vivo MTX resistance, taking into consideration their residual specific activity and their decrease in affinity for the related antifolates. Murine myeloid progenitors and other differentiated hematopoietic cells were transduced and exposed to MTX in a nucleotide-free medium. Bone marrow (BM) cells including 15% cells infected with F31R/Q35E were enriched to 98% transduced cells within 6 days of ex vivo selection. hDHFR variant F31R/Q35E allowed a strong ex vivo enrichment upon a short exposure to MTX relative to a less resistant variant of hDHFR, L22Y. We have thus demonstrated that bacterial selection of highly antifolate-resistant hDHFR variants can provide selectable markers for rapid ex vivo enrichment of hematopoietic cells.


A locally modified phantom model for assessing the worst-case heating configuration of orthopedic implants under MRI.
This paper proposes a locally modified phantom model to numerically assess the worst-case configuration of orthopedic implants under magnetic resonance imaging (MRI). The proposed model is developed based on the standard American Society for Testing and Materials (ASTM) phantom and bone models with cancellous or cortical materials. Three orthopedic implant families, metallic rods, a nail and screw system, and a plate and screw system, are studied. The worst-case configurations of orthopedic implants are identified inside the proposed model and ASTM phantom. These worst-case heating configurations are then implanted in a human body model to evaluate the RF-induced heating in terms of peak SAR1g. For the orthopedic implants fully inside the bone, like the rod and the nail and screw systems, the peak SAR1g values of worst-case configurations obtained from the proposed phantom model are higher than those obtained inside the ASTM phantom. For the orthopedic implants that are mainly outside the bone, such as the plate and screw system, similar worst-case configurations lead to a negligible variation of peak SAR1g inside the human body model.Clinical Relevance- The new phantom model leads to more accurate predictions of the worst-case configuration of orthopedic implants for MR conditional labeling.


Comparison of in-house IgM and IgG ELISAs for the serodiagnosis of melioidosis in Malaysia.
Melioidosis is an endemic infectious disease in Southeast Asia and northern Australia, caused by Burkholderia pseudomallei. However, the incidence rate in Malaysia is not well documented. The high mortality rate and broad range of clinical presentations require rapid and accurate diagnosis for appropriate treatment. This study compared the efficacy of in-house IgM and IgG ELISA methods using a local B. pseudomallei strain. The diagnostic accuracy of the in-house IgG ELISA was better than that of the IgM ELISA: sensitivity (IgG: 84.71 %, IgM: 76.14 %) and specificity (IgG: 93.64 %, IgM: 90.17 %); positive predictive value (IgG: 86.75 %, IgM: 79.76 %) and negative predictive value (IgG: 92.57 %, IgM: 89.66 %); likelihood ratio (LR) [IgG: 13.32, IgM: 7.75 (LR+); IgG: 0.16, IgM: 0.26 (LR-)], and was supported by the observation of the absorbance value in comparisons between culture and serology sampling. In-house IgG ELISA was shown to be useful as an early diagnostic tool for melioidosis.


Susceptibility weighted imaging (SWI) of the kidney at 3T--initial results.
Susceptibility weighted imaging provides diagnostic information in strokes, hemorrhages, and cerebral tumors and has proven to be a valuable tool in imaging venous vessels in the cerebrum. The SWI principle is based on the weighting of T(2)* weighted magnitude images with a phase mask, therewith improving image contrast of veins or neighbouring structures of different susceptibility, in general. T(2)* weighted MRI is already used for assessment of kidney function. In this paper, the feasibility of SWI on kidneys was investigated. Translation of SWI from the brain to the kidneys comes along with two main challenges: (i) organ motion due to breathing and (ii) a higher oxygenation level of renal veins compared to the brain. To handle these problems, the acquisition time has been cut down to allow for breath-hold examinations, and different post-processing methods including a new phase mask were investigated to visualize renal veins. Results showed that by a new post-processing strategy SWI contrast was enhanced on average by a factor of 1.33 compared to the standard phase mask. In summary, initial experiences of SWI on the kidneys demonstrated the feasibility. However, further technical developments have to be performed to make this technology applicable in clinical abdominal MRI.


Performance of biological magnetic powdered activated carbon for drinking water purification.
Combining the high adsorption capacity of powdered activated carbon (PAC) with magnetic properties of iron oxide nanoparticles (NPs) leads to a promising composite material, magnetic PAC or MPAC, which can be separated from water using magnetic separators. We propose MPAC as an alternative adsorbent in the biological hybrid membrane process and demonstrate that PAC covered with magnetic NPs is suitable as growth support for heterotrophic and nitrifying bacteria. MPAC with mass fractions of 0; 23; 38 and 54% maghemite was colonized in small bioreactors for over 90 days. Although the bacterial community composition (16s rRNA analysis) was different on MPAC compared to PAC, NPs neither inhibited dissolved organic carbon and ammonia biological removals nor contributed to significant adsorption of these compounds. The same amount of active heterotrophic biomass (48 μg C/cm(3)) developed on MPAC with a mass fraction of 54% NPs as on the non-magnetic PAC control. While X-ray diffraction confirmed that size and type of iron oxides did not change over the study period, a loss in magnetization between 10% and 34% was recorded.


Combining organic and mineral fertilizers as a climate-smart integrated soil fertility management practice in sub-Saharan Africa: A meta-analysis.
Low productivity and climate change require climate-smart agriculture (CSA) for sub-Saharan Africa (SSA), through (i) sustainably increasing crop productivity, (ii) enhancing the resilience of agricultural systems, and (iii) offsetting greenhouse gas emissions. We conducted a meta-analysis on experimental data to evaluate the contributions of combining organic and mineral nitrogen (N) applications to the three pillars of CSA for maize (Zea mays). Linear mixed effect modeling was carried out for; (i) grain productivity and agronomic efficiency of N (AE) inputs, (ii) inter-seasonal yield variability, and (iii) changes in soil organic carbon (SOC) content, while accounting for the quality of organic amendments and total N rates. Results showed that combined application of mineral and organic fertilizers leads to greater responses in productivity and AE as compared to sole applications when more than 100 kg N ha-1 is used with high-quality organic matter. For yield variability and SOC, no significant interactions were found when combining mineral and organic fertilizers. The variability of maize yields in soils amended with high-quality organic matter, except manure, was equal or smaller than for sole mineral fertilizer. Increases of SOC were only significant for organic inputs, and more pronounced for high-quality resources. For example, at a total N rate of 150 kg N ha-1 season-1, combining mineral fertilizer with the highest quality organic resources (50:50) increased AE by 20% and reduced SOC losses by 18% over 7 growing seasons as compared to sole mineral fertilizer. We conclude that combining organic and mineral N fertilizers can have significant positive effects on productivity and AE, but only improves the other two CSA pillars yield variability and SOC depending on organic resource input and quality. The findings of our meta-analysis help to tailor a climate smart integrated soil fertility management in SSA.


Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments.
Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.


Unexpectedly Higher Morbidity and Mortality of Hospitalized Elderly Patients Associated with Rhinovirus Compared with Influenza Virus Respiratory Tract Infection.
Rhinovirus is a common cause of upper and lower respiratory tract infections in adults, especially among the elderly and immunocompromised. Nevertheless, its clinical characteristics and mortality risks have not been well described. A retrospective analysis on a prospective cohort was conducted in a single teaching hospital center over a one-year period. We compared adult patients hospitalized for pneumonia caused by rhinovirus infection with those hospitalized for influenza infection during the same period. All recruited patients were followed up for at least 3 months up to 15 months. Independent risk factors associated with mortality for rhinovirus infection were identified. Between 1 March 2014 and 28 February 2015, a total of 1946 patients were consecutively included for analysis. Of these, 728 patients were hospitalized for rhinovirus infection and 1218 patients were hospitalized for influenza infection. Significantly more rhinovirus patients were elderly home residents and had chronic lung diseases (p < 0.001), whereas more influenza patients had previous stroke (p = 0.02); otherwise, there were no differences in the Charlson comorbidity indexes between the two groups. More patients in the rhinovirus group developed pneumonia complications (p = 0.03), required oxygen therapy, and had a longer hospitalization period (p < 0.001), whereas more patients in the influenza virus group presented with fever (p < 0.001) and upper respiratory tract symptoms of cough and sore throat (p < 0.001), and developed cardiovascular complications (p < 0.001). The 30-day (p < 0.05), 90-day (p < 0.01), and 1-year (p < 0.01) mortality rate was significantly higher in the rhinovirus group than the influenza virus group. Intensive care unit admission (odds ratio (OR): 9.56; 95% confidence interval (C.I.) 2.17-42.18), elderly home residents (OR: 2.60; 95% C.I. 1.56-4.33), requirement of oxygen therapy during hospitalization (OR: 2.62; 95% C.I. 1.62-4.24), and hemoglobin level <13.3 g/dL upon admission (OR: 2.43; 95% C.I. 1.16-5.12) were independent risk factors associated with 1-year mortality in patients hospitalized for rhinovirus infection. Rhinovirus infection in the adults was associated with significantly higher mortality and longer hospitalization when compared with influenza virus infection. Institutionalized older adults were particularly at risk. More stringent infection control among health care workers in elderly homes could lower the infection rate before an effective vaccine and antiviral become available.


Enoxaparin dosing and associated risk of in-hospital bleeding and death in patients with non ST-segment elevation acute coronary syndromes.
The efficacy of enoxaparin sodium in non-ST-segment elevation acute coronary syndromes is well established; however, concerns remain regarding bleeding risk. The extent to which bleeding risk is attributable to excess dosing of enoxaparin is unclear. Using data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative, we determined the frequency of administration of excess (>10 mg above the recommended dose), lower-than-recommended (>10 mg below the recommended dose), and recommended doses of enoxaparin. We also determined unadjusted and adjusted risks of in-hospital major bleeding and death associated with excess and lower-than-recommended doses of enoxaparin. Of 10 687 patients, 2002 (18.7%) received an excess dose and 3116 (29.2%) received a lower-than-recommended dose of enoxaparin. Patients receiving excess doses were older (median age, 78 vs 66 years), smaller (median body mass index [calculated as weight in kilograms divided by height in meters squared], 26.2 vs 27.8), and more likely to be female (59.5% vs 38.2%) than patients receiving recommended doses (P < .001 for all). After adjustment for baseline characteristics, an excess dose was significantly associated with major bleeding (odds ratio, 1.43; 95% confidence interval [CI], 1.18-1.75) and death (odds ratio, 1.35; 95% CI, 1.03-1.77) compared with a recommended dose. A lower-than-recommended dose was not associated with major bleeding (odds ratio, 1.01; 95% CI, 0.84-1.21), but there was a trend toward higher mortality (odds ratio, 1.25; 95% CI, 0.93-1.68). Almost half the patients treated with enoxaparin did not receive a recommended dose and had worse outcomes, especially those receiving an excess dose. Improved adherence to the recommended dose could substantially improve the safety profile of enoxaparin.


Incidence of potentially avoidable urgent readmissions and their relation to all-cause urgent readmissions.
Urgent, unplanned hospital readmissions are increasingly being used to gauge the quality of care. We reviewed urgent readmissions to determine which were potentially avoidable and compared rates of all-cause and avoidable readmissions. In a multicentre, prospective cohort study, we reviewed all urgent readmissions that occurred within six months among patients discharged to the community from 11 teaching and community hospitals between October 2002 and July 2006. Summaries of the readmissions were reviewed by at least four practising physicians using standardized methods to judge whether the readmission was an adverse event (poor clinical outcome due to medical care) and whether the adverse event could have been avoided. We used a latent class model to determine whether the probability that each readmission was truly avoidable exceeded 50%. Of the 4812 patients included in the study, 649 (13.5%, 95% confidence interval [CI] 12.5%-14.5%) had an urgent readmission within six months after discharge. We considered 104 of them (16.0% of those readmitted, 95% CI 13.3%-19.1%; 2.2% of those discharged, 95% CI 1.8%-2.6%) to have had a potentially avoidable readmission. The proportion of patients who had an urgent readmission varied significantly by hospital (range 7.5%-22.5%; χ(2) = 92.9, p < 0.001); the proportion of readmissions deemed avoidable did not show significant variation by hospital (range 1.2%-3.7%; χ(2) = 12.5, p < 0.25). We found no association between the proportion of patients who had an urgent readmission and the proportion of patients who had an avoidable readmission (Pearson correlation 0.294; p = 0.38). In addition, we found no association between hospital rankings by proportion of patients readmitted and rankings by proportion of patients with an avoidable readmission (Spearman correlation coefficient 0.28, p = 0.41). Urgent readmissions deemed potentially avoidable were relatively uncommon, comprising less than 20% of all urgent readmissions following hospital discharge. Hospital-specific proportions of patients who were readmitted were not related to proportions with a potentially avoidable readmission.


Development and validation of the Ryerson Social Anxiety Scales (RSAS).
Background: Extant self-report measures of social anxiety primarily assess the breadth of social situations in which respondents feel anxious, rather than assessing severity in terms of the distress and impairment that individuals experience due to their social anxiety symptoms. This paper describes the development and validation of the Ryerson Social Anxiety Scales (RSAS; Rogojanski et al., 2019; see Appendix), a new measure for assessing both the breadth of situations that trigger social anxiety and the severity (i.e., distress and impairment) associated with social anxiety, across two studies. Method/Design: Two samples of university students (N = 501 total) completed demographic and self-report symptom measures. In Study 1, participants completed the RSAS and several other measures of psychological symptoms. In Study 2, participants completed the same measures and were also assessed for the presence of Social Anxiety Disorder (SAD) using a semistructured clinical interview. Results: Across both samples, the RSAS demonstrated excellent internal consistency and incremental validity. It consistently emerged as a unique predictor of psychosocial impairment. In Study 2, increases in RSAS scores were associated with increased odds of having SAD. Conclusions: The RSAS has robust psychometric properties and fills an important gap among available measures for assessing SAD severity.


Dermatofibrosarcoma protuberans: a case report.
We present a typical case of dermatofibrosarcoma protuberans with local recurrence 2 months after surgery and, motivated by this patient, make a review of the most important aspects. This is a rare tumor and we call special attention to the fact that its recurrence is extremely frequent, so there is absolute need to observe these patients periodically after surgery.


[Evidence in support of Florence Nightingale's theories. 100 years after her death].
This article has been written to pay homage to Florence Nightingale as a pioneer and beacon for scientific curiosity which should serve as the nursing professional's guide for fine praxis. For this purpose, the author studied the evidence regarding Ms Nightingale's supposed theories; these have been arranged into four large groups in order to make those findings which support her theories easier to understand.


Similarities Between Alcohol and Tobacco Advertising Exposure and Adolescent Use of Each of These Substances.
Underage alcohol use is a major public health problem and substantial corporate money supports alcohol advertising across multiple venues. A diverse research literature demonstrates that adolescent exposure to such advertising is associated with drinking attitudes and behavior, but no scientific body has determined these associations to be causal. The objective of this study was to assess the association between alcohol advertising and teen drinking in the context of the "Analogy" criterion of the Bradford Hill criteria and consider a determination that the association between exposure to alcohol advertising and alcohol use is causal. This study was a narrative review on the association between adolescent exposure to alcohol advertising and subsequent alcohol use in the context of domains utilized in the Surgeon General's 2012 Report, Preventing Tobacco Use Among Youth and Young Adults, which concluded, "Advertising and promotional activities by tobacco companies have been shown to cause the onset and continuation of smoking among adolescents and young adults." In every aspect compared (i.e., adolescent knowledge; attitudes toward; initiation of use; continuation of use; mediums of advertisement; the use of mascots, celebrities, and themes; and frequency and density of advertisements and retailers), the findings for both tobacco and alcohol and their association with exposure to advertising are analogous. Application of the Analogy criterion of the Bradford Hill criteria comparing alcohol and tobacco supports a judgment that the association between exposure to alcohol advertising and increased adolescent knowledge, attitudes toward, initiation, and continuation of alcohol use are causal in nature.


Orienting periodic organic-inorganic nanoscale domains through one-step electrodeposition.
One of the challenges in the synthesis of hybrid materials with nanoscale structure is to precisely control morphology across length scales. Using a one-step electrodeposition process on indium tin oxide (ITO) substrates followed by annealing, we report here the preparation of materials with preferentially oriented lamellar domains of electron donor surfactants and the semiconductor ZnO. We found that either increasing the concentration of surfactant or the water to dimethyl sulfoxide ratio of solutions used resulted in the suppression of bloomlike morphologies and enhanced the density of periodic domains on ITO substrates. Furthermore, by modifying the surface of the ITO substrate with the conductive polymer blend poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), we were able to alter the orientation of these electrodeposited lamellar domains to be perpendicular to the substrate. The long-range orientation achieved was characterized by 2D grazing incidence small-angle X-ray scattering. This high degree of orientation in electronically active hybrids with alternating nanoscale p-type and n-type domains is of potential interest in photovoltaics or thermoelectric materials.


[Acute confusional state in hospitalized patients].
Delirium or acute confusional status (ACS) is a common mental disorder found in hospitalized patients. A total of 278 patients were evaluated. Of these, 30 (10.8%) developed ACS. The patients who developed ACS were 70 years of age or older, had history of stroke or dementia, as well as impairment in activities of daily living, and required enteral feeding more frequently. The infections and hip fracture were the most frequent reasons for hospitalization. The mortality in patients with ACS was significantly higher than in patients without ACS.