A non-invasive method to produce pressure ulcers of varying severity in a spinal cord-injured rat model.
Experimental study. The objective of this study was to establish a non-invasive model to produce pressure ulcers of varying severity in animals with spinal cord injury (SCI). The study was conducted at the Johns Hopkins Hospital in Baltimore, Maryland, USA. A mid-thoracic (T7-T9) left hemisection was performed on Sprague-Dawley rats. At 7 days post SCI, rats received varying degrees of pressure on the left posterior thigh region. Laser Doppler Flowmetry was used to record blood flow. Animals were killed 12 days after SCI. A cardiac puncture was performed for blood chemistry, and full-thickness tissue was harvested for histology. Doppler blood flow after SCI prior to pressure application was 237.808±16.175 PFUs at day 7. Following pressure application, there was a statistically significant decrease in blood flow in all pressure-applied groups in comparison with controls with a mean perfusion of 118.361±18.223 (P<0.001). White blood cell counts and creatine kinase for each group were statistically significant from the control group (P=0.0107 and P=0.0028, respectively). We have created a novel animal model of pressure ulcer formation in the setting of a SCI. Histological analysis revealed different stages of injury corresponding to the amount of pressure the animals were exposed to with decreased blood flow immediately after the insult along with a subsequent marked increase in blood flow the next day, conducive to an ischemia-reperfusion injury (IRI) and a possible inflammatory response following tissue injury. Following ischemia and hypoxia secondary to microcirculation impairment, free radicals generate lipid peroxidation, leading to ischemic tissue damage. Future studies should be aimed at measuring free radicals during this period of increased blood flow, following tissue ischemia.


Solvation dynamics monitored by combined X-ray spectroscopies and scattering: photoinduced spin transition in aqueous [Fe(bpy)3](2+).
We have studied the photoinduced low spin (LS) to high spin (HS) conversion of aqueous Fe(bpy)3 with pulse-limited time resolution. In a combined setup permitting simultaneous X-ray diffuse scattering (XDS) and spectroscopic measurements at a MHz repetition rate we have unraveled the interplay between intramolecular dynamics and the intermolecular caging solvent response with 100 ps time resolution. On this time scale the ultrafast spin transition including intramolecular geometric structure changes as well as the concomitant bulk solvent heating process due to energy dissipation from the excited HS molecule are long completed. The heating is nevertheless observed to further increase due to the excess energy between HS and LS states released on a subnanosecond time scale. The analysis of the spectroscopic data allows precise determination of the excited population which efficiently reduces the number of free parameters in the XDS analysis, and both combined permit extraction of information about the structural dynamics of the first solvation shell.


Association of RNASEL variants with prostate cancer risk in Hispanic Caucasians and African Americans.
The RNASEL gene at 1q25 has been identified as a hereditary prostate cancer susceptibility gene, but to date, no study has investigated the role of RNASEL variants in Hispanic Caucasian men with prostate cancer. Two RNASEL common variants, located at amino acids 462 and 541, were genotyped in non-Hispanic Caucasian, Hispanic Caucasian, and African American prostate cancer cases and controls. The RNASEL 462 AA genotype was found to increase prostate cancer risk over 4-fold in Hispanic Caucasians [odds ratio (OR), 4.43; 95% confidence interval (95% CI), 1.68-11.68; P = 0.003] and over 10-fold in African Americans (OR, 10.41; 95% CI, 2.62-41.40; P = 0.001) when compared with the GG genotype. Analysis of the RNASEL 541 variant showed that Hispanic Caucasian patients with the GG genotype had a statistically significant increase in their risk for developing prostate cancer when compared with the TT and GT genotypes (OR, 1.91; 95% CI, 1.16-3.14; P = 0.01). A common G-T haplotype for the combination of the RNASEL 462 and 541 variants was found to occur more frequently in controls compared with cases in African Americans (P = 0.04) but not in non-Hispanic Caucasians or Hispanic Caucasians. This is the first study that investigates the association of prostate cancer risk with RNASEL variants in Hispanic men. Our data support the role of RNASEL as a predisposition gene for prostate cancer and showed a significant association between the RNASEL 462 variant and prostate cancer risk in African Americans and Hispanic Caucasians.


Impact of tannic acid on blood pressure, oxidative stress and urinary parameters in L-NNA-induced hypertensive rats.
Hypertension is a major health problem with increasing prevalence around the world. Tannic acid is water-soluble polyphenol that is present in tea, green tea, coffee, red wine, nuts, fruits and many plant foods. It has been reported to serve as an antioxidant or a pro-oxidant depending on the type of cells and its concentration. The purpose of our study was to evaluate the effect of tannic acid on systolic blood pressure, oxidative stress and some urinary parameters in the rat model of essential hypertension. Blood pressures of all rats were measured using the tail-cuff method. The nitric oxide synthase inhibitor N (omega)-nitro-L-arginine was administered orally at a dose of 0.5 g/l/day for 15 days to rats in order to create an animal model of hypertension. Tannic acid was intraperitoneally injected at a dose of 50 mg/kg for 15 days. Superoxide dismutase, catalase activity and the concentration of malondialdehyde (MDA) were determined in blood plasma and homogenates of heart, liver and kidney. In order to evaluate renal functions, urine pH, urine volume, urine creatine, uric acid, and urea nitrogen values were measured. Compared with the hypertension group, a decrease in MDA concentrations of heart tissue (p < 0.01), urea nitrogen values (p < 0.01) and urine volumes (p < 0.001) were established in hypertension + tannic acid group. There was also a decrease in blood pressure values (20th and 30th days) of this group, but there was no a statistical difference according to hypertension group. The findings of our research show the effect of tannic acid in lowering blood pressure in hypertensive rats.


Neonatal functional echocardiography.
The role of echocardiography has dramatically changed over the past decade and use of functional echocardiography has become increasingly popular among neonatologists and pediatric intensivists in making clinical decisions in sick infants and children. The purpose of this review is to outline the current capabilities and limitations of functional echocardiography, best practices for its clinical application, and evidence for its utility. Functional echocardiography can provide direct assessment of hemodynamics at bedside and can be used as a modern hemodynamic monitoring tool in the neonatal intensive care unit. It is now being regarded as a useful extension to the clinical examination and other monitoring tools in the critically ill infant. The anatomic, physiological, and hemodynamic information functional echocardiography provides can be used in targeting specific interventions and evaluating response to treatment. This review article is focused on an overview of the most common applications of functional neonatal echocardiography also called targeted neonatal echocardiography or neonatologist performed echocardiography. It will review assessment of hemodynamics and cardiac function in neonatal hypotension and shock, suspected patent ductus arteriosus, suspected persistent pulmonary hypertension of the newborn with evaluation of pulmonary artery pressure and assessment of pericardial effusion. It will also emphasize the specific requirements for the practice and training of functional neonatal echocardiography.


Significantly higher serologic responses of Chlamydia trachomatis B group serovars versus C and I serogroups.
Chlamydia trachomatis serovars are divided into three serogroups, namely serogroup B, serogroup I (Intermediate) and serogroup C, and subsequently into 19 different serovars. Worldwide, serogroup B is the most prevalent followed by serogroup I. Clear differences have been observed in the duration of infection and growth kinetics between serovars from different serogroups in murine and cell culture models. Reasons for these observed differences are bacterial and host related, and are not well understood. The aim of this study was to determine the differences in immunoglobulin (Ig) G responses between the three serogroups in a group of patients infected with different serovars. Serovars were assessed from 235 C. trachomatispositive patients and quantitative IgG responses were determined. Analyses of variance were used to compare the IgG responses between the three serogroups. Of the serovars, 46% were B group (with serovar E the most prevalent: 35.3%), 39.6% were I group and 14.3% were C group. A highly significant difference in serologic response was shown when comparing the mean IgG concentrations (AU/mL) of patients having serovars in the most prevalent serogroup compared to the other serogroups: B = 135, C = 46 and I = 60 (B vs. C and B vs. I, P < 0.001). In conclusion, the most prevalent serovars generate the highest serologic responses.


How Does Cultivar, Maturation, and Pre-Treatment Affect Nutritional, Physicochemical, and Pasting Properties of Plantain Flours?
The effect of cultivar, ripening stage, and pre-treatment method were investigated on the nutritional, physicochemical, and pasting properties of plantain flours from two plantains and two plantain hybrids. There were significant variations (p < 0.05) in chemical composition and physical properties influenced by the interaction of cultivars, ripening stages, and pre-treatment methods. The highest levels of amylose, water-holding capacity (WHC), and oil-holding capacity (OHC) were observed in unripe flours and acid-treated flour recorded the highest content of resistant starch (RS). Flour after pre-blanching contained the highest level of total phenolic (TP), carotenoid contents, and browning index (BI) value. In contrast, acid-treated flours had the lowest BI value. As ripening progressed, peak viscosity and breakdown values increased but final viscosity, setback, and pasting temperature values were reduced. Untreated flour samples showed the highest peak viscosity. Higher breakdown values were found in acid-treated samples and higher setback values in pre-blanched samples.


Effect of deletion of genes involved in lipopolysaccharide core and O-antigen synthesis on virulence and immunogenicity of Salmonella enterica serovar typhimurium.
Lipopolysaccharide (LPS) is a major virulence factor of Salmonella enterica serovar Typhimurium and is composed of lipid A, core oligosaccharide (C-OS), and O-antigen polysaccharide (O-PS). While the functions of the gene products involved in synthesis of core and O-antigen have been elucidated, the effect of removing O-antigen and core sugars on the virulence and immunogenicity of Salmonella enterica serovar Typhimurium has not been systematically studied. We introduced nonpolar, defined deletion mutations in waaG (rfaG), waaI (rfaI), rfaH, waaJ (rfaJ), wbaP (rfbP), waaL (rfaL), or wzy (rfc) into wild-type S. Typhimurium. The LPS structure was confirmed, and a number of in vitro and in vivo properties of each mutant were analyzed. All mutants were significantly attenuated compared to the wild-type parent when administered orally to BALB/c mice and were less invasive in host tissues. Strains with ΔwaaG and ΔwaaI mutations, in particular, were deficient in colonization of Peyer's patches and liver. This deficiency could be partially overcome in the ΔwaaI mutant when it was administered intranasally. In the context of an attenuated vaccine strain delivering the pneumococcal antigen PspA, all of the mutations tested resulted in reduced immune responses against PspA and Salmonella antigens. Our results indicate that nonreversible truncation of the outer core is not a viable option for developing a live oral Salmonella vaccine, while a wzy mutant that retains one O-antigen unit is adequate for stimulating the optimal protective immunity to homologous or heterologous antigens by oral, intranasal, or intraperitoneal routes of administration.


Patterns of hemispheric specialization for a communicative gesture in different primate species.
We review four studies investigating hand preferences for grasping versus pointing to objects at several spatial positions in human infants and three species of nonhuman primates using the same experimental setup. We expected that human infants and nonhuman primates present a comparable difference in their pattern of laterality according to tasks. We tested 6 capuchins, 6 macaques, 12 baboons, and 10 human infants. Those studies are the first of their kind to examine both human infants and nonhuman primate species with the same communicative task. Our results show remarkable convergence in the distribution of hand biases of human infants, baboons and macaques on the two kinds of tasks and an interesting divergence between capuchins' and other species' hand preferences in the pointing task. They support the hypothesis that left-lateralized language may be derived from a gestural communication system that was present in the common ancestor of macaques, baboons and humans.


Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections.
Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1) infection is of critical importance for an understanding of early viral pathogenesis and prophylactic vaccine design. Here, we used sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV-1 (or, for comparison, hepatitis B virus [HBV]or hepatitis C virus [HCV]) to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. Plasma viremia was quantitated over time, and levels of 30 cytokines and chemokines were measured using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. The increase in plasma viremia in acute HIV-1 infection was found to be associated with elevations in plasma levels of multiple cytokines and chemokines, including rapid and transient elevations in alpha interferon (IFN-alpha) and interleukin-15 (IL-15) levels; a large increase in inducible protein 10 (IP-10) levels; rapid and more-sustained increases in tumor necrosis factor alpha and monocyte chemotactic protein 1 levels; more slowly initiated elevations in levels of additional proinflammatory factors including IL-6, IL-8, IL-18, and IFN-gamma; and a late-peaking increase in levels of the immunoregulatory cytokine IL-10. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection and a delayed response of more intermediate magnitude in acute HCV infection, indicating that the rapid activation of a striking systemic cytokine cascade is not a prerequisite for viral clearance (which occurs in a majority of HBV-infected individuals). The intense early cytokine storm in acute HIV-1 infection may have immunopathological consequences, promoting immune activation, viral replication, and CD4(+) T-cell loss.


Expression of hydroxamate and phenolate siderophores by Shigella flexneri.
Shigella flexneri strains were assayed for the ability to synthesize and utilize phenolate and hydroxamate siderophores. The hydroxamate aerobactin was synthesized by all isolates tested, whereas phenolates were only rarely produced. Expression of aerobactin was accompanied by production of a single iron-regulated outer membrane protein (Mr = 74,000). This protein was not produced by a mutant defective in aerobactin utilization and may serve as the aerobactin receptor. Phenolate (enterobactin)-producing strains synthesized three additional outer membrane proteins (Mr = 74,000, 81,000, and 83,000) in response to iron starvation. These proteins are the same apparent size as those produced by Escherichia coli K-12 strains. Ent sequences are apparently present in strains which do not synthesize this compound. Although normally silent, ent genes can be activated in Ent- strains to produce Ent+ variants. These laboratory variants are phenotypically indistinguishable from clinical Ent+ isolates.


Dynamics of an orthopaedic team: Insights to improve teamwork through a design thinking approach.
Supporting teamwork in healthcare is a way to foster both the quality and safety of care, and better working conditions for all the team members. Although increasing attention is paid to this topic on a general level, there is less knowledge about its unfolding in orthopaedic units and its translation to interventions. To identify concrete opportunities for teamwork intervention through a design thinking approach by analysing the teamwork dynamics of an orthopaedic team. An adaptation of the learning history method, comprising shadowing, observations and interviews involving 26 orthopaedic team members at a top clinical teaching hospital in the Netherlands, was applied. A thematic analysis was conducted to derive themes that describe team dynamics and to subsequently extrapolate opportunities for intervention. We identified five themes and translated them into four design opportunities for intervention, namely: a) Improve daily rounds by reducing cognitive overload and promoting confidence; b) Improve collaboration by building empathy; c) Connect the patient with the professional team; and d) Support changes by fostering learning. Suggestions for concrete actions are presented for each opportunity. Opportunities to improve teamwork among healthcare professionals, specifically those in orthopaedics, revolve around the creation of common knowledge, the fostering of mutual understanding, and the design of tools and activities that support these processes.


Core discrete event simulation model for the evaluation of health care technologies in major depressive disorder.
A review of existing economic models in major depressive disorder (MDD) highlighted the need for models with longer time horizons that also account for heterogeneity in treatment pathways between patients. A core discrete event simulation model was developed to estimate health and cost outcomes associated with alternative treatment strategies. This model simulated short- and long-term clinical events (partial response, remission, relapse, recovery, and recurrence), adverse events, and treatment changes (titration, switch, addition, and discontinuation) over up to 5 years. Several treatment pathways were defined on the basis of fictitious antidepressants with three levels of efficacy, tolerability, and price (low, medium, and high) from first line to third line. The model was populated with input data from the literature for the UK setting. Model outputs include time in different health states, quality-adjusted life-years (QALYs), and costs from National Health Service and societal perspectives. The codes are open source. Predicted costs and QALYs from this model are within the range of results from previous economic evaluations. The largest cost components from the payer perspective were physician visits and hospitalizations. Key parameters driving the predicted costs and QALYs were utility values, effectiveness, and frequency of physician visits. Differences in QALYs and costs between two strategies with different effectiveness increased approximately twofold when the time horizon increased from 1 to 5 years. The discrete event simulation model can provide a more comprehensive evaluation of different therapeutic options in MDD, compared with existing Markov models, and can be used to compare a wide range of health care technologies in various groups of patients with MDD.


5D whole-heart sparse MRI.
A 5D whole-heart sparse imaging framework is proposed for simultaneous assessment of myocardial function and high-resolution cardiac and respiratory motion-resolved whole-heart anatomy in a single continuous noncontrast MR scan. A non-electrocardiograph (ECG)-triggered 3D golden-angle radial balanced steady-state free precession sequence was used for data acquisition. The acquired 3D k-space data were sorted into a 5D dataset containing separated cardiac and respiratory dimensions using a self-extracted respiratory motion signal and a recorded ECG signal. Images were then reconstructed using XD-GRASP, a multidimensional compressed sensing technique exploiting correlations/sparsity along cardiac and respiratory dimensions. 5D whole-heart imaging was compared with respiratory motion-corrected 3D and 4D whole-heart imaging in nine volunteers for evaluation of the myocardium, great vessels, and coronary arteries. It was also compared with breath-held, ECG-gated 2D cardiac cine imaging for validation of cardiac function quantification. 5D whole-heart images received systematic higher quality scores in the myocardium, great vessels and coronary arteries. Quantitative coronary sharpness and length were always better for the 5D images. Good agreement was obtained for quantification of cardiac function compared with 2D cine imaging. 5D whole-heart sparse imaging represents a robust and promising framework for simplified comprehensive cardiac MRI without the need for breath-hold and motion correction. Magn Reson Med 79:826-838, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Unwinding the twister ribozyme: from structure to mechanism.
The twister ribozyme motif has been identified by bioinformatic means very recently. Currently, four crystal structures with ordered active sites together with a series of chemical and biochemical data provide insights into how this RNA accomplishes its efficient self-cleavage. Of particular interest for a mechanistic proposal are structural distinctions observed in the active sites that concern the conformation of the U-A cleavage site dinucleotide (in-line alignment of the attacking 2'-O nucleophile to the to-be-cleaved PO5' bond versus suboptimal alignments) as well as the presence/absence of Mg2+ ions at the scissile phosphate. All structures support the notion that an active site guanine and the conserved adenine at the cleavage site are important contributors to cleavage chemistry, likely being involved in general acid base catalysis. Evidence for innersphere coordination of a Mg2+ ion to the pro-S nonbridging oxygen of the scissile phosphate stems from two of the four crystal structures. Together with the finding of thio/rescue effects for phosphorothioate substrates, this suggests the participation of divalent ions in the overall catalytic strategy employed by twister ribozymes. In this context, it is notable that twister retains wild-type activity when the phylogenetically conserved stem P1 is deleted, able to cleave a single nucleotide only. WIREs RNA 2017, 8:e1402. doi: 10.1002/wrna.1402 For further resources related to this article, please visit the WIREs website.


MicroRNA-122 modulates the rhythmic expression profile of the circadian deadenylase Nocturnin in mouse liver.
Nocturnin is a circadian clock-regulated deadenylase thought to control mRNA expression post-transcriptionally through poly(A) tail removal. The expression of Nocturnin is robustly rhythmic in liver at both the mRNA and protein levels, and mice lacking Nocturnin are resistant to diet-induced obesity and hepatic steatosis. Here we report that Nocturnin expression is regulated by microRNA-122 (miR-122), a liver specific miRNA. We found that the 3'-untranslated region (3'-UTR) of Nocturnin mRNA harbors one putative recognition site for miR-122, and this site is conserved among mammals. Using a luciferase reporter construct with wild-type or mutant Nocturnin 3'-UTR sequence, we demonstrated that overexpression of miR-122 can down-regulate luciferase activity levels and that this effect is dependent on the presence of the putative miR-122 recognition site. Additionally, the use of an antisense oligonucleotide to knock down miR-122 in vivo resulted in significant up-regulation of both Nocturnin mRNA and protein expression in mouse liver during the night, resulting in Nocturnin rhythms with increased amplitude. Together, these data demonstrate that the normal rhythmic profile of Nocturnin expression in liver is shaped in part by miR-122. Previous studies have implicated Nocturnin and miR-122 as important post-transcriptional regulators of both lipid metabolism and circadian clock controlled gene expression in the liver. Therefore, the demonstration that miR-122 plays a role in regulating Nocturnin expression suggests that this may be an important intersection between hepatic metabolic and circadian control.


Remote conformational control of a molecular switch via methylation and deprotonation.
Exacting control over conformation in response to an external stimulus is the central focus of molecular switching. Here we describe the synthesis of a series of diphenylacetylene-based molecular switches, and examine their response to covalent modification and deprotonation at remote phenolic positions. A complex interplay between multiple intramolecular hydrogen bond donors and acceptors determines the global conformation.


Cysteine 2.59(89) in the second transmembrane domain of human CB2 receptor is accessible within the ligand binding crevice: evidence for possible CB2 deviation from a rhodopsin template.
In this study, the sensitivity of the CB2 receptor to methanethiosulfonate (MTS) derivatives was tested, and a native cysteine residue conferring the sensitivity was identified. By incubating human embryonic kidney 293 cells stably transfected with CB2 receptors and MTS derivatives such as MTS ethylammonium (MTSEA), [(3)H]HU-243 binding was inhibited. Pretreatment of the CB2 receptor with cannabinoid ligands prevented this inhibition, suggesting that MTSEA modification occurred within the binding crevice. To identify the cysteine(s) responsible for the MTSEA sensitivity, 10 CB2 mutants were prepared in which the eight cysteines in transmembrane domains or extracellular loop 2 were mutated to serine or alanine, one at a time or in combination. Five mutants exhibited specific [(3)H]HU-243 binding, with K(d) and B(max) values similar to those of wild-type CB2. However, five other mutants had no detectable ligand binding and were not detected on cell membranes by Western blot analysis. Among the five mutants with normal binding, only the sensitivity to MTSEA of the C2.59(89)S mutant was reduced significantly. These data demonstrate that C2.59(89) is the residue that mainly confers the inhibitory effect of MTSEA on ligand binding. Furthermore, the magnitude of the second-order rate constant (1.14 +/- 0.28 M(-1)s(-1)) for the MTSEA reaction with wild-type CB2 suggests that C2.59(89) resides at the margin of the CB2 binding site crevice. The accessibility of C2.59(89) to MTSEA provides experimental evidence for a possible conformational difference between TMH2 of CB2 versus Rho. Modeling studies undertaken to explore the origin of such differences suggest it is possibly caused by the conformational influence of S2.54(84).


In silico assessment of potential druggable pockets on the surface of α1-antitrypsin conformers.
The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α(1)-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a K(d) in the µM-nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation.


Training with supplemental oxygen in patients with COPD and hypoxaemia at peak exercise.
Supplemental oxygen has acute beneficial effects on exercise performance in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to investigate whether oxygen-supplemented training enhances the effects of training while breathing room air in patients with severe COPD. A randomized controlled trial was performed in 24 patients with severe COPD who developed hypoxaemia during incremental cycle exercise (arterial oxygen saturation (Sa,O2) <90% at peak exercise). All patients participated in an in-patient pulmonary rehabilitation programme of 10 weeks duration. They were assigned either to general exercise training while breathing room air (GET/RA group: forced expiratory volume in one second (FEV1) 38% of predicted; arterial oxygen tension (Pa,O2) 10.5 kPa at rest; Pa,O2 7.3 kPa at peak exercise), or to GET while breathing supplemental oxygen (GET/O2 group: FEV1 29% pred; Pa,O2 10.2 kPa at rest; Pa,O2 7.2 kPa at peak exercise). Sa,O2 was not allowed to fall below 90% during the training. The effects on exercise performance while breathing air and oxygen, and on quality of life were compared. Maximum workload (Wmax) significantly increased in the GET/RA group (mean (SD) 17 (15) W, p<0.01), but not in the GET/O2 group (7 (25) W). Six minute walking distance (6MWD), stair-climbing, weight-lifting exercise (all while breathing room air) and quality of life significantly increased in both groups. Acute administration of oxygen improved exercise performance before and after training. Training significantly increased Wmax, peak carbon dioxide production (V'CO2) and 6MWD while breathing oxygen in both groups. Differences between groups were not significant. Pulmonary rehabilitation improved exercise performance and quality of life in both groups. Supplementation of oxygen during the training did not add to the effects of training on room air.


To court or not to court - a multimodal sensory decision in Drosophila males.
When Drosophila males encounter another fly, they have to make a rapid assessment to ensure the appropriate response: should they court, fight or pursue a different action entirely? Previous work has focused on the significance of sensory cues detected by the male during these encounters; however, recent evidence highlights the importance of the male's own internal state in shaping his responses. Additionally, once triggered, courtship is not a rigid sequence of motor actions, but rather a finely tuned behavioural display that must continually update in response to sensory feedback. Here, we review recent findings highlighting how sensory information and internal states are integrated ensuring appropriate action selection, and how they sustain and fine-tune motor output. We further discuss recent advances in our understanding of species differences in sensory processing that may contribute to reproductive isolation.


Models-of-self and models-of-others as related to facial muscle reactions at different levels of cognitive control.
The hypotheses of this investigation were based on attachment theory and Bowlby's conception of "internal working models", supposed to consist of one mainly emotional (model-of-self) and one more conscious cognitive structure (model-of-others), which are assumed to operate at different temporal stages of information processing. Facial muscle reactions in individuals with positive versus negative internal working models were compared at different stages of information processing. The Relationship Scale Questionnaire (RSQ) was used to categorize subjects into positive or negative model-of-self and model-of-others and the State-Trait Anxiety Inventory was used to measure trait anxiety (STAI-T). Pictures of happy and angry faces followed by backward masking stimuli were exposed to 61 subjects at three different exposure times (17 ms, 56 ms, 2,350 ms) in order to elicit reactions first at an automatic level and then consecutively at more cognitively elaborated levels. Facial muscle reactions were recorded by electromyography (EMG), a higher corrugator activity representing more negative emotions and a higher zygomaticus activity more positive emotions. In line with the hypothesis, subjects with a negative model-of-self scored significantly higher on STAI-T than subjects with a positive model-of-self. They also showed an overall stronger corrugator than zygomatic activity, giving further evidence of a negative tonic affective state. At the longest exposure time (2,350 ms), representing emotionally regulated responses, negative model-of-self subjects showed a significantly stronger corrugator response and reported more negative feelings than subjects with a positive model-of-self. These results supported the hypothesis that subjects with a negative model-of-self would show difficulties in self-regulation of negative affect. In line with expectations, model-of-others, assumed to represent mainly knowledge structures, did not interact with the physiological emotional measures employed, facial muscle reactions or tonic affective state.


Fabrication of microinjection-molded miniature freeform Alvarez lenses.
Microinjection molding is a mass production method to fabricate affordable optical components. However, the intense nature of this process often results in part deformation and uneven refractive index distribution. These two factors limit the precision of replicated optics. In order to understand the influences of injection molding on freeform optical devices, in this study, finite element method (FEM) was employed to investigate the miniature microinjection-molded Alvarez lenses. In addition, an innovative metrology setup was proposed to evaluate the optical wavefront patterns in the molded lenses using an interferometer-based wavefront measurement system. This measurement setup utilized an optical matching liquid to reduce or eliminate the lenses' surface power such that the wavefront pattern with large deviation from the freeform lenses can be measured by a regular wavefront setup. The FEM simulation results were also used to explain the differences between the nominal and experimentally measured wavefront patterns of the microinjection-molded Alvarez lenses. In summary, the proposed method combining simulation and wavefront measurements is shown to be an effective approach for studying injection molding of freeform optics.


Do calcium channel blockers increase the diagnosis of heart failure in patients with hypertension?
Calcium channel blockers (CCBs) are widely used to control hypertension. Previous work suggested that their use could increase heart failure (HF), which is 1 of the consequences of uncontrolled hypertension. Information about the effect of CCBs on incident HF in patients with hypertension is scarce. A systematic review was conducted to evaluate patients with hypertension treated with CCBs and incident HF. An electronic search of publications was conducted using 8 major databases. Studies were eligible if they (1) were randomized clinical trials, (2) performed comparisons of CCBs versus active control, (3) randomized >200 patients, (4) had follow-up periods >6 months, and (5) provided data regarding incident HF. Trials of renal transplantation patients, placebo-controlled trials, and HF trials were excluded. A total of 156,766 patients were randomized to CCBs or control, with a total of 5,049 events. The analysis indicated a significant increase in the diagnosis of HF in patients allocated to CCBs (odds ratio 1.18, 95% confidence interval 1.07 to 1.31). The effect observed was independent of incident myocardial infarction. Subgroup analyses indicated that patients with diabetes were at higher risk for developing HF (odds ratio 1.71, 95% confidence interval 1.21 to 2.41). In conclusion, the results suggest that patients with hypertension treated with CCBs have increased incident HF.


Lysosomotropic agents: impact on lysosomal membrane permeabilization and cell death.
Lysosomes are acidic organelles essential for degradation, signalling and cell homoeostasis. In addition, they play a key role in cell death. Permeabilization of the lysosomal membrane and release of hydrolytic enzymes to the cytosol accompanies apoptosis signalling in several systems. The regulatory mechanism of lysosomal stability is, however, poorly understood. Lipophilic or amphiphilic compounds with a basic moiety will become protonated and trapped within lysosomes, and such lysosomotropic behaviour is also found in many pharmacological drugs. The natural sphingolipid sphingosine exhibits lysosomotropic detergent ability and is an endogenous candidate for controlling lysosomal membrane permeabilization. The lysosomotropic properties of certain detergents might be of use in lysosome-targeting anticancer drugs and drug delivery system in the future. The present review summarizes the current knowledge on the targeting and permeabilizing properties of lysosomotropic detergents from a cellular and physicochemical perspective.


Ureteral Avulsion Associated with Ureteroscopy: Insights from the MAUDE Database.
Flexible and semirigid ureteroscopy (URS) are widely performed for the treatment of upper tract calculi and tumors. Ureteral avulsion is a rare, but devastating complication of endoscopic stone removal having multiple possible etiologies. Awareness and avoidance of this rare complication depend on identifying responsible mechanisms. This study examines the situations in which ureteral avulsion occurs as described anonymously in the Manufacturer and User facility Device Experience (MAUDE) database. The MAUDE database was systematically reviewed to account for all reported complications of flexible and semirigid URS. Keywords "ureteroscopy, injury, death, malfunction and other" were entered in the database and medical device reports were reviewed to capture any cases resulting in ureteral avulsion. Attention was paid to the type of ureteroscope involved and the mechanism for avulsion. A total of 104 entries were found detailing the reported complications of flexible and semirigid URS. Ureteral avulsion was clearly noted in six reports with flexible (2) and semirigid ureteroscopes (4). Potential mechanisms included locked deflection of a flexible ureteroscope (1), bunching of the distal bending rubber in a flexible ureteroscope (1), scabbard avulsion (3), and stone basketing (1). Although the incidence of ureteral avulsion cannot truly be determined from this study, some potentially novel mechanisms for this rare complication are observed. This may target future educational efforts to maximize awareness and avoidance of this complication.


Antagonism by antidepressant drugs of the inhibitory effect of trifluoromethylphenylpiperazine (TFMPP) on [3H]acetylcholine release in rat or guinea-pig hippocampal synaptosomes.
The effects of antidepressant drugs on the m-trifluoromethylphenylpiperazine (TFMPP)-induced inhibition of K(+)-evoked [3H]acetylcholine (3H-ACh) release were studied in rat or guinea-pig hippocampal synaptosomes. The serotonergic agonist TFMPP dose-dependently inhibited the K(+)-evoked release of 3H-ACh in rat hippocampus (IC50 = 53 microM). Chlorimipramine (5-500 nM), a typical tricyclic antidepressant, and minaprine (1-100 nM), an atypical antidepressant drug, partially antagonized the effect of TFMPP on 3H-ACh release in a dose-dependent manner. Other antidepressants (imipramine, citalopram, indalpine, fluoxetine, fluvoxamine, oxaprotiline, mianserine, nomifensine), at concentrations ranging from 10 to 500 nM, produced similar effects. Drugs with no antidepressant effect, such as chlorpromazine, clobazam, and cocaine (50, 100 and 500 nM), were without significant influence on the TFMPP effect. In guinea-pig hippocampal synaptosomes, minaprine (50 nM) also reduced the TFMPP-induced inhibition of 3H-ACh release, whilst clobazam (50 nM) was inactive. These results suggest that antidepressant drugs interact in vitro with heterologous serotonergic presynaptic receptors on cholinergic nerve terminals in rat and guinea-pig hippocampus.


Novel β-ketoiminato complexes of zirconium: synthesis, characterization and evaluation for solution based processing of ZrO2 thin films.
Treatment of tetrakis(diethylamido)zirconium(IV); [Zr(NEt2)4] with a series of β-ketoimines ({[RHN]C(CH3)=C(H)C(CH3)=O} where R is a functionalized side-chain; 4-(2-methoxyethylamino)pent-3-en-2-one, Hmeap; 4-(3-methoxypropylamino)pent-3-en-2-one, Hmpap; 4-(2-(dimethylamino)ethylamino)pent-3-en-2-one, Hdeap; 4-(3-(dimethylamino)propylamino)pent-3-en-2-one, Hdpap) leads to an amine substitution reaction that yielded novel monomeric heteroleptic mixed amido-ketoiminato complexes of the type bis(4-(2-methoxyethylamino)pent-3-en-2-onato)bis(diethylamido)zirconium(IV) (1), bis(4-(3-methoxypropylamino)pent-3-en-2-onato)bis(diethylamido)zirconium(IV) (2), and bis(4-(3-(dimethylamino)propylamino)pent-3-en-2-onato)bis(diethylamido)zirconium(IV) (3), and eight-coordinated homoleptic complexes tetrakis(4-(2-methoxyethylamino)pent-3-en-2-onato)zirconium(IV) (4) and tetrakis(4-(2-(dimethylamino)ethylamino)pent-3-en-2-onato)zirconium(IV) (5), depending on the ratio of the ligand to zirconium. Adopting a similar strategy with zirconium alkoxide, namely [Zr(O(i)Pr)4·(i)PrOH], with β-ketoimine Hmeap, leads to the formation of a dimer, bis(μ2-isopropoxo)bis(4-(2-methoxyethylamino)pent-3-en-2-onato)tetrakis(isopropoxo)dizirconium(IV) (6). The newly synthesised complexes were characterized by NMR spectroscopy, mass spectrometry, single crystal X-ray diffraction, elemental analysis and thermal analysis. The low decomposition temperature facilitated by the stepwise elimination of the ketominate ligand from the complex and the stability of the complexes obtained in air as well as in solution makes them highly suitable for solution based processing of ZrO2 thin films, which is demonstrated using compound 5 on Si(100) substrates. High quality ZrO2 films were obtained and were investigated for their structure, morphology, composition and optical properties. Low temperature crystallisation of ZrO2 is achieved by a simple chemical deposition process using the new class of Zr precursors and the films exhibit an optical transmittance above 90%.


Are our 'UHC systems' learning systems? Piloting an assessment tool and process in six African countries.
If there is one universal recommendation to countries wanting to make progress towards Universal Health Coverage (UHC), it is to develop the learning capacities that will enable them to 'find their own way' - this is especially true for countries struggling with fragmented health financing systems. This paper explores results from a multi-country study whose main aim was to assess the extent to which UHC systems and processes at country level operate as 'learning systems'. This study is part of a multi-year action-research project implemented by two communities of practice active in Africa. For this specific investigation, we adapted the concept of the learning organisation to so-called 'UHC systems'. Our framework organises the assessment around 92 questions divided into blocks, sub-blocks and levels of learning, with a seven scale score in a standardised questionnaire developed during a protocol and methodology workshop attended by all the research teams. The study was implemented in six francophone African countries by national research teams involving researchers and cadres of the ministries involved in the UHC policy. Across the six countries, the questionnaire was administrated to 239 UHC actors. Data were analysed per country, per blocks and sub-blocks, by levels of learning and per question. The study confirms the feasibility and relevance of adapting the learning organisation framework to UHC systems. All countries scored between 4 and 5 for all the sub-blocks of the learning system. The study and the validation workshops organised in the six countries indicate that the tool is particularly powerful to assess weaknesses within a specific country. However, some remarkable patterns also emerge from the cross-country analysis. Our respondents recognise the leadership developed at governmental level for UHC, but they also report some major weaknesses in the UHC system, especially the absence of a learning agenda and the limited use of data. Countries will not progress towards UHC without strong learning systems. Our tool has allowed us to document the situation in six countries, create some awareness at country level and initiate a participatory action-oriented process.


Loratadine versus levocetirizine in chronic idiopathic urticaria: A comparative study of efficacy and safety.
Treatment of chronic idiopathic urticaria (CIU) is challenging because of its unpredictable course and negative influence on the quality of life. New treatments are being developed, but antihistaminics remain the cornerstone of the therapeutic approach. Newer generation antihistaminics such as loratadine and levocetirizine have already proved to be safe and efficacious for CIU. To choose the better drug between loratadine and levocetirizine for CIU, by comparing their efficacy and safety. A randomized, open, outdoor-based clinical study was conducted on 60 patients of CIU, to compare the two drugs. After initial clinical assessment and baseline investigations, loratadine was prescribed to 30 patients and levocetirizine to another 30 patients for four weeks. At follow-up, the patients were re-evaluated and then compared using different statistical tools. The comparative study showed that the changes in differential eosinophil count (P = 0.006) and absolute eosinophil count (P = 0.003) in the levocetirizine group was statistically significant. The results of the Total Symptom Score showed better symptomatic improvement of CIU with levocetirizine as compared to loratadine. The overall incidence of adverse drug reactions was also found to be less in the levocetirizine group. An analysis of the results of all the parameters of safety and efficacy proves the superiority of levocetirizine over loratadine for CIU.


Sequencing robot-assisted extended pelvic lymph node dissection prior to radical prostatectomy: a step-by-step guide to exposure and efficiency.
To describe a novel, step-by-step approach to robot-assisted extended pelvic lymph node dissection (ePLND) at the time of robot-assisted radical prostatectomy (RARP) for intermediate-high risk prostate cancer. The sequence of ePLND is at the beginning of the operation to take advantage of greater visibility of the deeper hypogastric planes. The urachus is left intact for an exposure/retraction point. The anatomy is described in terms of lymph nodes (LNs) that are easily retrieved vs those that require additional manipulation of the anatomy, and a determined surgeon. A representative cohort of 167 RARPs was queried for representative metrics that distinguish the ePLND: 146 primary cases and 21 with neoadjuvant systemic therapy. The median (interquartile range, IQR) LN yield was 22 (16-28) for primary surgeries and 21 (16-23) for neoadjuvant cases. The percentage of cases with positive LNs (pN1) was 16.4% for primary and 29% for neoadjuvant. The hypogastric LNs were involved in 75% of pN1 primary cases and uniquely positive in 33%. Each side of ePLND took the attending surgeon a median (IQR) of 16 (13-20) min and trainees 25 (24-38) min. Robot-assisted ePLND before RARP provides an anatomical approach to surgical extirpation mimicking the open approach. We think this sequence offers efficiency and efficacy advantages in high-risk and select intermediate-risk patients with prostate cancer undergoing RARP.


Sibling transmission of vaccine-derived rotavirus (RotaTeq) associated with rotavirus gastroenteritis.
Although rotavirus vaccines are known to be shed in stools, transmission of vaccine-derived virus to unvaccinated contacts resulting in symptomatic rotavirus gastroenteritis has not been reported to our knowledge. We document here the occurrence of vaccine-derived rotavirus (RotaTeq [Merck and Co, Whitehouse Station, NJ]) transmission from a vaccinated infant to an older, unvaccinated sibling, resulting in symptomatic rotavirus gastroenteritis that required emergency department care. Results of our investigation suggest that reassortment between vaccine component strains of genotypes P7[5]G1 and P1A[8]G6 occurred during replication either in the vaccinated infant or in the older sibling, raising the possibility that this reassortment may have increased the virulence of the vaccine-derived virus. Both children remain healthy 11 months after this event and are without underlying medical conditions.


A case of intestinal Behçet's disease treated with infliximab monotherapy who successfully maintained clinical remission and complete mucosal healing for six years.
Behçet's disease is a chronic relapsing disease with multiple organ system involvement, including the gastrointestinal tract, which is known as intestinal Behçet's disease. Intestinal Behçet's disease is often resistant to empirical treatments such as 5-aminosalicylic acid, immunomodulators and steroids and often causes a perforation, requiring surgical resection. Therefore, intestinal lesions are considered to be a poor prognostic factor in Behçet's disease. Recently, several reports have demonstrated the efficacy of anti-TNFα monoclonal antibodies, such as infliximab, against intestinal Behçet's disease, however, it remains unknown whether anti-TNFα therapy can improve the prognosis of patients with intestinal Behçet's disease. We herein report the case of an adult female patient with intestinal Behçet's disease who responded well to the induction therapy with infliximab, and has been maintained in remission by scheduled administration of infliximab. Her C-reactive protein level has been sustained at a negative level, and endoscopic findings revealed complete mucosal healing. Therefore, infliximab may have the potential to induce "sustained deep remission" in patients with intestinal Behçet's disease.


Effects of diagnosis, demographic characteristics, and case management on rehospitalization.
A randomized controlled study was conducted to assess the effects of case management and patients' characteristics on the use of inpatient psychiatric services. Inpatients discharged from Harlem Hospital Center in 1984-1985 were randomly assigned to an outreach case management team or standard aftercare. Analysis of variance was used to assess the main effects and two- and three-way interaction effects of treatment status, gender, age, substance abuse, and diagnosis on the number of days of psychiatric rehospitalization in state and city community hospitals. In the follow-up period, 75 of the 146 patients in the case management group (51.4 percent) and 51 of the 143 patients in the control group (35.7 percent) were rehospitalized for psychiatric care. On average, patients spent 31.1 days in city hospitals and 26.6 days in state hospitals. Members of the case management team spent a mean total of 18.1 hours a month in direct and indirect care for each patient. They spent most time with substance-abusing older women. Significant three-way interaction effects were found between treatment status and diagnosis and gender, diagnosis and age, and diagnosis and substance abuse on the number of days patients spent rehospitalized for psychiatric care in city and state hospitals. It is unlikely that case management intervention will reduce rehospitalization rates unless appropriate and effective outpatient and community services are available. Effective surveillance of patient populations by case managers frequently results in rehospitalization as the only treatment alternative if other options for meeting the needs and resolving the crises of patients are not available.


Regulation of human histone gene expression: kinetics of accumulation and changes in the rate of synthesis and in the half-lives of individual histone mRNAs during the HeLa cell cycle.
We have analyzed the kinetics of accumulation of each of the individual core histone mRNAs throughout the HeLa cell cycle in cells synchronized by sequential thymidine and aphidicolin treatments. These analyses showed that during the S phase there was a 15-fold increase in the levels of histone mRNAs and that this resulted from both an increased rate of synthesis and a lengthening of the half-life of histone mRNAs. A comparison of the kinetics of accumulation of histone mRNA in the total cellular and nuclear RNA populations suggested an increased transcription rate through the S phase. Within 30 min after the inhibition of DNA synthesis in mid-S phase, the steady-state concentration and the rate of synthesis of histone mRNA each declined to their non-S-phase levels. Reactivation of histone mRNA accumulation could occur even after an extended mid-S-phase block in DNA synthesis. These results suggest that the mechanisms responsible for histone mRNA synthesis are not restricted to the G1/S boundary of the HeLa cell cycle, but can operate whenever DNA synthesis is occurring.


The impact of community mobilisation on HIV prevention in middle and low income countries: a systematic review and critique.
While community mobilisation (CM) is increasingly advocated for HIV prevention, its impact on measurable outcomes has not been established. We performed a systematic review of the impact of CM within HIV prevention interventions (N = 20), on biomedical, behavioural and social outcomes. Among most at risk groups (particularly sex workers), the evidence is somewhat consistent, indicating a tendency for positive impact, with stronger results for behavioural and social outcomes than for biomedical ones. Among youth and general communities, the evidence remains inconclusive. Success appears to be enhanced by engaging groups with a strong collective identity and by simultaneously addressing the socio-political context. We suggest that the inconclusiveness of the findings reflects problems with the evidence, rather than indicating that CM is ineffective. We discuss weaknesses in the operationalization of CM, neglect of social context, and incompatibility between context-specific CM processes and the aspiration of review methodologies to provide simple, context-transcending answers.


Methylphenidate extended release (OROS MPH) for the treatment of antidepressant-related sexual dysfunction in patients with treatment-resistant depression: results from a 4-week, double-blind, placebo-controlled trial.
There are limited data to indicate effective treatment strategies for antidepressant-related sexual dysfunction, in particular for patients with treatment-resistant major depression. We subanalyzed our published data whether augmentation with methylphenidate extended release (OROS MPH) improved sexual dysfunction associated with antidepressants in patients with treatment-resistant major depression. The primary efficacy measure was the change in Arizona Sexual Experiences Survey (ASEX) from baseline to end of treatment in an intent-to-treat analysis with last observation carried forward approach. There were no significant differences between the 2 groups in terms of changes in ASEX scores over time (F1,35 = 1.14; P = 0.32), although the numerical decrease in ASEX score was greater in OROS MPH (mean change, -4.5; 20.1% decrease) than in the placebo group (mean change, -0.6; 2.6% decrease). Augmentation with OROS MPH showed no statistically significant benefit in antidepressant-related sexual dysfunction, although addition of OROS MPH to antidepressants did not worsen preexisting sexual dysfunction. Adequately powered controlled trials are needed to fully evaluate the efficacy of OROS MPH in this area.


Planning for ex situ conservation in the face of uncertainty.
Ex situ conservation strategies for threatened species often require long-term commitment and financial investment to achieve management objectives. We present a framework that considers the decision to adopt ex situ management for a target species as the end point of several linked decisions. We used a decision tree to intuitively represent the logical sequence of decision making. The first decision is to identify the specific management actions most likely to achieve the fundamental objectives of the recovery plan, with or without the use of ex-situ populations. Once this decision has been made, one decides whether to establish an ex situ population, accounting for the probability of success in the initial phase of the recovery plan, for example, the probability of successful breeding in captivity. Approaching these decisions in the reverse order (attempting to establish an ex situ population before its purpose is clearly defined) can lead to a poor allocation of resources, because it may restrict the range of available decisions in the second stage. We applied our decision framework to the recovery program for the threatened spotted tree frog (Litoria spenceri) of southeastern Australia. Across a range of possible management actions, only those including ex situ management were expected to provide >50% probability of the species' persistence, but these actions cost more than use of in situ alternatives only. The expected benefits of ex situ actions were predicted to be offset by additional uncertainty and stochasticity associated with establishing and maintaining ex situ populations. Naïvely implementing ex situ conservation strategies can lead to inefficient management. Our framework may help managers explicitly evaluate objectives, management options, and the probability of success prior to establishing a captive colony of any given species.


Shaping a morphogen gradient for positional precision.
Morphogen gradients, which provide positional information to cells in a developing tissue, could in principle adopt any nonuniform profile. To our knowledge, how the profile of a morphogen gradient affects positional precision has not been well studied experimentally. Here, we compare the positional precision provided by the Drosophila morphogenetic protein Bicoid (Bcd) in wild-type (wt) embryos with embryos lacking an interacting cofactor. The Bcd gradient in the latter case exhibits decreased positional precision around mid-embryo compared with its wt counterpart. The domain boundary of Hunchback (Hb), a target activated by Bcd, becomes more variable in mutant embryos. By considering embryo-to-embryo, internal, and measurement fluctuations, we dissect mathematically the relevant sources of fluctuations that contribute to the error in positional information. Using this approach, we show that the defect in Hb boundary positioning in mutant embryos is directly reflective of an altered Bcd gradient profile with increasing flatness toward mid-embryo. Furthermore, we find that noise in the Bcd input signal is dominated by internal fluctuations but, due to time and spatial averaging, the spatial precision of the Hb boundary is primarily affected by embryo-to-embryo variations. Our results demonstrate that the positional information provided by the wt Bcd gradient profile is highly precise and necessary for patterning precision.


Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (KV3.1): contribution to the firing of action potentials.
Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the K(V)3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K(+) current (I(K(DR))) in a concentration-dependent manner with an IC(50) value of 37 microM. LEV (30 microM) shifted the steady-state activation of I(K(DR)) to a more positive potential by 10 mV, without shifting the steady-state inactivation of I(K(DR)). Neither Na(+), nor erg (ether-a-go-go-related)-mediated K(+) and ATP-sensitive K(+) currents were affected by LEV (100 microM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating I(K(DR)) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating I(K(DR)) (K(V)3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.


Automated particle correspondence and accurate tilt-axis detection in tilted-image pairs.
Tilted electron microscope images are routinely collected for an ab initio structure reconstruction as a part of the Random Conical Tilt (RCT) or Orthogonal Tilt Reconstruction (OTR) methods, as well as for various applications using the "free-hand" procedure. These procedures all require identification of particle pairs in two corresponding images as well as accurate estimation of the tilt-axis used to rotate the electron microscope (EM) grid. Here we present a computational approach, PCT (particle correspondence from tilted pairs), based on tilt-invariant context and projection matching that addresses both problems. The method benefits from treating the two problems as a single optimization task. It automatically finds corresponding particle pairs and accurately computes tilt-axis direction even in the cases when EM grid is not perfectly planar.


Effects of age and sex on aquaporin-4 autoimmunity.
To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56,464 patient samples. Observational analysis. Mayo Clinic Neuroimmunology Laboratory. Between October 1, 2005, and January 4, 2011, 56,464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive. Seropositivity for AQP4-IgG. Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P < .001). More females than males were tested (37,662 vs 16,810, respectively; P < .001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P < .001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female:male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P < .001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P < .001). The proportion of AQP4-IgG-seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years. Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.


Case Report: Altered with PRES.
In this case, we discuss a 51-year-old female with history of anxiety, depression, and alcohol abuse who presented for altered mental status, focal neurological deficits, and seizure. She was found to be significantly hypertensive. Non-contrast computed tomography (CT) scan imaging of the head revealed changes suggestive of posterior reversible encephalopathy syndrome (PRES), which was ultimately confirmed by MRI imaging. The patient was treated appropriately with anti-hypertensive therapy and seizure prophylaxis. Due to the prompt recognition of PRES and immediate management, the patient was able to make a favorable neurological recovery. This case highlights the importance of including PRES as part of a wide differential diagnosis for a patient with altered mental status, significantly elevated blood pressure, and focal neurological deficits. Early recognition and treatment of PRES can improve neurological outcomes and quality of life for patients. Altered mental status, seizure, hypertensive emergency, posterior reversible encephalopathy syndrome, PRES.


Oral zinc supplementation restores high molecular weight seminal zinc binding protein to normal value in Iraqi infertile men.
Zinc in human seminal plasma is divided into three types of ligands which are high (HMW), intermediate (IMW), and low molecular weight ligands (LMW). The present study was aimed to study the effect of Zn supplementation on the quantitative and qualitative characteristics of semen along with Zinc Binding Protein levels in the seminal plasma in asthenozoospermic patients. Semen samples were obtained from 37 fertile and 37 asthenozoospermic infertile men with matched age. The subfertile group was treated with zinc sulfate, every participant took two capsules per day for three months (each one 220 mg). Semen samples were obtained (before and after zinc sulfate supplementation). After liquefaction seminal fluid at room temperature, routine semen analyses were performed. For determination of the amount of zinc binding proteins, the gel filtration of seminal plasma on Sephadex G-75 was performed. All the fractions were investigated for protein and for zinc concentration by atomic absorption spectrophotometry. Evaluation of chromatograms was made directly from the zinc concentration in each fraction. A significant high molecular weight zinc binding ligands percentage (HMW-Zn %) was observed in seminal plasma of fertile males compared with subfertile males. However, seminal low molecular weight ligands (LMW-Zn) have opposite behavior. The mean value of semen volume, progressive sperm motility percentage and total normal sperm count were increased after zinc sulfate supplementation. Zinc supplementation restores HMW-Zn% in seminal plasma of asthenozoospermic subjects to normal value. Zinc supplementation elevates LMW-Zn% in seminal plasma of asthenozoospermic subjects to more than normal value. ClinicalTrials.gov identifier NCT01612403.


Single-pulse ultrafast laser imprinting of axial dot arrays in bulk glasses.
Ultrafast laser processing of bulk transparent materials can significantly gain flexibility when the number of machining spots is increased. We present a photoinscription regime in which an array of regular dots is generated before the region of main laser focus under single-pulse exposure in fused silica and borosilicate crown glass without any external spatial phase modulation. The specific position of the dots does not rely on nonlinear propagation effects but is mainly determined by beam truncation and is explained by a Fresnel propagation formalism taking into account beam apodization and linear wavefront distortions at the air/glass interface. The photoinscription regime is employed to generate a two-dimensional array of dots in fused silica. We show that an additional phase modulation renders flexible the pattern geometry.


Overexpression of transforming growth factor-beta 1 mRNA is associated with up-regulation of glomerular tenascin and laminin gene expression in nonobese diabetic mice.
Nonobese diabetic (NOD) mice spontaneously develop immune-mediated insulin-dependent diabetes mellitus and nephropathy, providing an opportunity to study the early molecular events in a model of diabetic glomerulosclerosis. The expression of several genes coding for growth factors and extracellular matrix was examined in microdissected glomeruli, by the use of reverse transcription-competitive polymerase chain reaction, in diabetic NOD mice (mean duration of diabetes, 28.5 +/- 7 days) and age-matched nondiabetic NOD mice with normal glucose tolerance. The levels of mRNA coding for transforming growth factor-beta 1, tenascin, and laminin B1 increased 1.9-, 2.0-, and 1.7-fold, respectively, whereas platelet-derived growth factor (PDGF)-B, alpha 1(IV) collagen, 72-kd collagenase, alpha-smooth muscle actin, and beta-actin mRNA remained stable in the diabetic mice. The kidney advanced glycosylation end-products levels increased 2.1-fold in the diabetic mice, and the diabetic glomeruli showed an accumulation of tenascin and laminin but not of type IV collagen by immunofluorescence microscopy. There was no increase in cell number per glomerulus after the onset of diabetes, a finding consistent with stable PDGF-B and alpha-smooth muscle actin mRNA levels. These findings provide evidence that increased glomerular transforming growth factor-beta 1, but not PDGF-B, mRNA is associated with the up-regulation of tenascin and laminin expression after advanced glycosylation endproduct accumulation, early after the onset of diabetes.


Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice.
Pretargeting with phosphorodiamidate morpholino oligomers (MORFs) involves administration of a MORF-conjugated anti-tumor antibody such as MN14 as a pretargeting agent before that of the radiolabeled complementary MORF (cMORF) as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are the four pretargeting variables. The goal of this study was to develop a semiempirical description capable of predicting the biodistribution of the radiolabeled effector in pretargeted mice and then to compare predictions with experimental results from pretargeting studies in tumored animals in which the pretargeting interval and the detection time were both fixed but the dosages of both the effector and the pretargeting agent were separately varied. Pretargeting studies in LS174T tumored mice were performed using the anti-CEA antibody MN14 conjugated with MORF and the cMORF radiolabeled with (99m)Tc. A description was developed based on our previous observations in the same mouse model of the blood and tumor levels of MORF-MN14, accessibility of MORF-MN14 to labeled cMORF, the tumor accumulation of labeled cMORF relative to MORF-MN14 levels therein, and the kidney accumulation of labeled cMORF. The predicted values were then compared with the experimental values. The predicted biodistribution of the radiolabeled effector and the experimental data were in gratifying agreement in normal organs, suggesting that the description of the pretargeting process was reliable. The tumor accumulations occasionally fell outside two standard deviations of that predicted, but after tumor size correction, good agreement between predicted and experimental values was observed here as well. A semiempirical description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. We believe that the approach described herein may be applied to any of the alternative pretargeting approaches and animal tumor models currently under investigation. Furthermore, appreciation of the concepts may provide a rationale for selecting dosages and timings in human pretargeting studies as an alternative to pure empirical means.


Wheat alleles introgress into selfing wild relatives: empirical estimates from approximate Bayesian computation in Aegilops triuncialis.
Extensive gene flow between wheat (Triticum sp.) and several wild relatives of the genus Aegilops has recently been detected despite notoriously high levels of selfing in these species. Here, we assess and model the spread of wheat alleles into natural populations of the barbed goatgrass (Aegilops triuncialis), a wild wheat relative prevailing in the Mediterranean flora. Our sampling, based on an extensive survey of 31 Ae. triuncialis populations collected along a 60 km × 20 km area in southern Spain (Grazalema Mountain chain, Andalousia, totalling 458 specimens), is completed with 33 wheat cultivars representative of the European domesticated pool. All specimens were genotyped with amplified fragment length polymorphism with the aim of estimating wheat admixture levels in Ae. triuncialis populations. This survey first confirmed extensive hybridization and backcrossing of wheat into the wild species. We then used explicit modelling of populations and approximate Bayesian computation to estimate the selfing rate of Ae. triuncialis along with the magnitude, the tempo and the geographical distance over which wheat alleles introgress into Ae. triuncialis populations. These simulations confirmed that extensive introgression of wheat alleles (2.7 × 10(-4) wheat immigrants for each Ae. triuncialis resident, at each generation) into Ae. triuncialis occurs despite a high selfing rate (Fis ≈ 1 and selfing rate = 97%). These results are discussed in the light of risks associated with the release of genetically modified wheat cultivars in Mediterranean agrosystems.


[Impact of music therapy on anxiety and depression for patients with Alzheimer's disease and on the burden felt by the main caregiver (feasibility study)].
The impact of music therapy on dementia care for patients with Alzheimer's disease (AD) is well-recognized. Music alters the different components of the disease through sensory, cognitive, emotional, behavioral and social impacts. The academic aspect of music therapy in this area was based on the fact that music can alter the various components of the overall evolution of this disease. We found around 10 case studies presenting various results from receptive music therapy sessions on patients with Alzheimer's disease. The results of these studies point out the interest of music therapy in the multidisciplinary care of Alzheimer's disease and its related syndromes. It has been deemed useful for significantly reducing the medication given to AD patients. A music therapy protocol, specifically tailored to the patient's needs has been shown to significantly reduce anxiety, depression and aggressiveness in patients suffering from Alzheimer's disease. This technique has also demonstrated its impact on helping AD patients recall their previous life experience. To demonstrate the feasibility and to evaluate the impact of music therapy on anxiety and depression at the early to moderate stage of Alzheimer's disease and on the main caregiver burden. Five outpatients suffering from early stage of Alzheimer's disease (MMS: 18-26) were prospectively included. They were living in Montpellier with a reliable caregiver. A weekly receptive music therapy session was delivered to patients over a 10-week period, according to the U method standardized protocol. This technique was based on the recommendations made by Gardner and Good relating to the importance given to an individualized choice of music. Instrumental tracks were selected from various music styles (classic, jazz, world music...) and were tailored to the patient's requirements. This individual session was always followed by an interview with the music therapist in order to allow the patient to express the emotions felt during the session and to stimulate the patient's cognitive functions by recalling memories and images from his past life experience. The main evaluation criterion was regular session attendance at the hospital. Secondary criteria were: anxiety score (Hamilton scale), depression score (Cornell scale) and the burden score felt by the main caregiver (Zarit scale). Evaluations took place at W1, W4 and W10. The score evolution on the Hamilton, Cornell and Zarit scales were tested using the Wilcoxon test on paired data. The significance threshold has conventionally been set at 5% for all tests used. The statistical analysis was done using the SAS software (8th version) (SAS Institute, Cary, N.C.; proc npar1way, proc univariate, proc freq). Alzheimer's disease is a recognized indication for music therapy. A simple oral consent was collected prior to the study inclusion. Five patients were included for a total of 44 sessions. The patients' regular attendance at the music therapy sessions showed its feasibility. Thanks to oral feedback, we were able to see that music therapy was very well-accepted both by patients and caregivers. After the sessions, all patients expressed a sensation of well-being and pleasure, such as: "Music made me feel better, I feel more relaxed", "I feel better", "I didn't know that music could have such an impact on me"... Other verbal comments were collected regarding the patients' previous life experience: "This music reminds me of my childhood", "I imagined myself dancing just like I used to in the old days", "This reminds me of my trip to Italy with my children"... The level of anxiety (Hamilton scale) dropped significantly from 9.4 (+/-2.2) to 3.4 (+/-2.6) between the first session and the fourth session (P<0.004). The differences observed between W4-W10 and W1-W10 were close to the threshold of significance due to a major drop in the anxiety level starting at W4 (P=NS). On the Cornell scale, the depression level dropped significantly from 10.8 (+/-5.3) to 2.2 (+/-1.9) between the first session and the fourth session (P<0.01). The differences observed between W4-W10 and W1-W10 were not significant (P=NS). The weight of the physical and emotional burden experienced by the main caregiver (Zarit scale) fell significantly from 30.2 (+/-11.7) to 15.6 (+/-10.4) between W1-W4 (P<0.002). The differences observed between W4-W10 and W1-W10 were not significant (P=NS). This preliminary study demonstrates the feasibility as well as the initial efficacy of music therapy in terms of its impact on the overall care for patients suffering from Alzheimer's disease. This easily applicable technique can be useful in treating anxiety and depression in a patient with Alzheimer's disease and also in relieving the emotional and physical burden experienced by the main caregiver.


Assessment of the environmental health of an ecologically sensitive, semi-enclosed, basin - A water quality modelling approach.
Semi-enclosed basins are environmentally dynamic and some of the most anthropogenically affected components of the coastal realm. They can reflect various environmental impacts, thus qualifying as natural laboratories to study these impacts. The Gulf of Khambhat (GoK) is such a system where analysis of in situ parameters indicated polluted conditions. The sources of various contaminants were deciphered. Though there are considerable inputs of pollutants, the assimilative capacity of the GoK holds good with high Dissolved Oxygen (DO) (6-9.3 mg/L) content as revealed in situ and in silico. High Biochemical Oxygen Demand (BOD) and marginal ammonia contamination prevail in the region. Simulations revealed that the rivers bring in a considerable amount of nitrate, organic material and phosphate into the Gulf. Considering the prevailing environmental condition, the current study posits to have regular water quality monitoring; and the carrying capacity of the Gulf should be assessed before the authorization of anthropogenic activities.


Importance of household-level risk factors in explaining micro-epidemiology of asymptomatic malaria infections in Ratanakiri Province, Cambodia.
Heterogeneity in malaria risk is considered a challenge for malaria elimination. A cross-sectional study was conducted to describe and explain micro-epidemiological variation in Plasmodium infection prevalence at household and village level in three villages in Ratanakiri Province, Cambodia. A two-level logistic regression model with a random intercept fitted for each household was used to model the odds of Plasmodium infection, with sequential adjustment for individual-level then household-level risk factors. Individual-level risk factors for Plasmodium infection included hammock net use and frequency of evening outdoor farm gatherings in adults, and older age in children. Household-level risk factors included house wall material, crop types, and satellite dish and farm machine ownership. Individual-level risk factors did not explain differences in odds of Plasmodium infection between households or between villages. In contrast, once household-level risk factors were taken into account, there was no significant difference in odds of Plasmodium infection between households and between villages. This study shows the importance of ongoing indoor and peridomestic transmission in a region where forest workers and mobile populations have previously been the focus of attention. Interventions targeting malaria risk at household level should be further explored.


Control of plant defense mechanisms and fire blight pathogenesis through the regulation of 6-thioguanine biosynthesis in Erwinia amylovora.
Fire blight is a devastating disease of Rosaceae plants, such as apple and pear trees. It is characterized by necrosis of plant tissue, caused by the phytopathogenic bacterium Erwinia amylovora. The plant pathogen produces the well-known antimetabolite 6-thioguanine (6TG), which plays a key role in fire blight pathogenesis. Here we report that YcfR, a member of the LTTR family, is a major regulator of 6TG biosynthesis in E. amylovora. Inactivation of the regulator gene (ycfR) led to dramatically decreased 6TG production. Infection assays with apple plants (Malus domestica cultivar Holsteiner Cox) and cell cultures of Sorbus aucuparia (mountain ash, rowan) revealed abortive fire blight pathogenesis and reduced plant response (biphenyl and dibenzofuran phytoalexin production). In the presence of the ΔycfR mutant, apple trees were capable of activating the abscission machinery to remove infected tissue. In addition to unveiling the regulation of 6TG biosynthesis in a major plant pathogen, we demonstrate for the first time that this antimetabolite plays a pivotal role in dysregulating the plant response to infection.


OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms.
The bHLH transcription factor, OLIG2, is universally expressed in adult human gliomas and, as a major factor in the development of oligodendrocytes, is expressed at the highest levels in low-grade oligodendroglial tumors. In addition, it is functionally required for the formation of high-grade astrocytomas in a genetically relevant murine model. The pediatric gliomas have genomic profiles that are different from the corresponding adult tumors and accordingly, the expression of OLIG2 in non-oligodendroglial pediatric gliomas is not well documented within specific tumor types. In the current study, the pattern of OLIG2 expression in a spectrum of 90 non-oligodendroglial pediatric gliomas varied from very low levels in the ependymomas (cellular and tanycytic) to high levels in pilocytic astrocytoma, and in the diffuse-type astrocytic tumors (WHO grades II-IV). With dual-labeling, glioblastoma had the highest percentage of OLIG2 expressing cells that were also Ki-67 positive (mean = 16.3%) whereas pilocytic astrocytoma WHO grade I and astrocytoma WHO grade II had the lowest (0.9 and 1%, respectively); most of the Ki-67 positive cells in the diffuse-type astrocytomas (WHO grade II-III) were also OLIG2 positive (92-94%). In contrast to the various types of pediatric astrocytic tumors, all ependymomas WHO grade II, regardless of site of origin, showed at most minimal OLIG2 expression, suggesting that OLIG2 function in pediatric gliomas is cell lineage dependent.


Quantitative proteomic analysis of ibuprofen-degrading Patulibacter sp. strain I11.
Ibuprofen is the third most consumed pharmaceutical drug in the world. Several isolates have been shown to degrade ibuprofen, but very little is known about the biochemistry of this process. This study investigates the degradation of ibuprofen by Patulibacter sp. strain I11 by quantitative proteomics using a metabolic labelling strategy. The whole-genome of Patulibacter sp. strain I11 was sequenced to provide a species-specific protein platform for optimal protein identification. The bacterial proteomes of actively ibuprofen-degrading cells and cells grown in the absence of ibuprofen was identified and quantified by gel based shotgun-proteomics. In total 251 unique proteins were quantitated using this approach. Biological process and pathway analysis indicated a number of proteins that were up-regulated in response to active degradation of ibuprofen, some of them are known to be involved in the degradation of aromatic compounds. Data analysis revealed that several of these proteins are likely involved in ibuprofen degradation by Patulibacter sp. strain I11.


The economic impact of non-melanoma skin cancer: a review.
Non-melanoma skin cancer (NMSC) is the most common cancer in the United States. Cost of NMSC care primarily depends on 2 factors: care settings and treatment modalities. However, the cost efficacy of NMSC care has been insufficiently addressed in previous literature. Therefore, this article evaluates available research on the cost implications to compare the costs associated with treatment within different care settings and specialties involved, and to assess the costs of different treatment modalities with respect to procedure type, tumor size, and tumor location. This evaluation showed that physician-office settings provided the lowest cost per episode of care ($492) and were the dominant setting for NMSC care; dermatologists managed most NMSC episodes and used a wider range of treatment options than other specialists. Regarding treatment modalities, Mohs micrographic surgery was shown to be similar in cost to traditional surgical excision with permanent sections and was less costly than excision with frozen sections. Electrodessication and curettage and imiquimod were also reported to be inexpensive treatments. Furthermore, a positive correlation was seen between cost and tumor size for any particular treatment modality. Given these comparisons, and the rising incidence of NMSC and potential legislative measures to regulate office-based procedures, it is important to preserve the low-cost management of this disease.


The Jack Wills crowd: towards a sociology of an elite subculture.
British sociologists have long been interested in youth sub-cultures. However British sociologists have tended to focus on working class subcultures and avoided engagement with exclusive sub-cultures of elite social groups. This article seeks to attend to this gap by examining the subculture of a British elite: ex-public school students at select universities in the UK in the twenty-first century. This group consists of a relatively small group of young adults, aged between 18 and 23, who attended public schools, especially one of the nine Clarendon schools (Eton, Winchester, Westminster, St. Paul's, Merchant Taylor's, Shrewsbury, Rugby, Harrow and Charterhouse), and were students at a selective group of British universities, primarily Oxford and Cambridge, Durham, Bristol, Exeter, Bath, Manchester, St Andrews and Edinburgh. The article examines the way in which this group has reconfigured and re-constituted itself in the face of globalizing challenges. Specifically, it examines the way in which participation of ex-public school students in events run by and under the patronage of the high street retailing company, Jack Wills, has played a galvanising role for this group in the last decade. The Jack Wills crowd is an example of how some young adults form exclusive social networks and reproduce prevailing forms of privilege. The social networks built around the Jack Wills subculture is likely to provide them with advantages in the job market through a prodigious network of connections and patrons. The Jack Wills subculture potentially contributions to the socio-economic reproduction of the higher professional middle classes.


Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.
Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages. In vivo, IVIg modified the polarization of tumor-associated myeloid cells in a Fcεr1γ chain-dependent manner, modulated cytokine blood levels in tumor-bearing animals, and impaired tumor progression via FcγRIII (CD16), FcγRIV, and FcRγ engagement, the latter two effects being macrophage mediated. Therefore, IVIg immunomodulatory activity is dependent on the polarization state of the responding macrophages, and its ability to trigger a M2-to-M1 macrophage polarization switch might be therapeutically useful in cancer, in which proinflammatory or immunogenic functions should be promoted.


Cost-effectiveness of Maintenance Treatment with a Barrier-strengthening Moisturizing Cream in Patients with Atopic Dermatitis in Finland, Norway and Sweden.
Atopic dermatitis is a chronic skin disorder with high prevalence, especially in the Nordic countries. Effective maintenance therapy during symptom-free episodes may prolong the time to eczema relapse according to a previously published clinical trial. The present study evaluates the cost-effectiveness of a barrier-strengthening moisturizer containing 5% urea, compared with a moisturizer with no active ingredients during eczema-free periods. A health economic microsimulation model, based on efficacy data from the randomized clinical trial, analysed the cost-effectiveness of the barrier-strengthening treatment in Finland, Norway and Sweden. The barrier-strengthening moisturizer was cost-saving compared with the moisturizer with no active ingredients in all 3 countries. The result was confirmed in all but one sensitivity analysis. In conclusion, the barrier-strengthening moisturizer is cost-effective as maintenance therapy for patients with atopic dermatitis compared with a moisturizer with no active ingredients.


How to assess gay, bisexual and other men who have sex with men for chemsex.
Sexualised substance use, 'chemsex', is being increasingly reported by gay, bisexual and other men who have sex with men (GBMSM) in sexual health clinics. We aim to describe the evidence base and practical ways in which clinicians can assess and advise patients disclosing chemsex. We review published literature on chemsex, discuss vulnerability to substance use, highlight the importance of clinical communication and discuss a management approach. GBMSM are vulnerable to substance use problems, which interplay with mental, physical and sexual health. Knowledge on sexualised drug use and related communication skills are essential to facilitating disclosure. Identifying sexual health and other consequences of harmful drug use may motivate patients to seek change. Sexual health clinicians are well placed to make more holistic assessments of GBMSM accessing their services to promote broader sexual health and well-being beyond the management of HIV and sexually transmitted infections (STIs) alone.


Monetary costs of dementia in the United States.
Dementia affects a large and growing number of older adults in the United States. The monetary costs attributable to dementia are likely to be similarly large and to continue to increase. In a subsample (856 persons) of the population in the Health and Retirement Study (HRS), a nationally representative longitudinal study of older adults, the diagnosis of dementia was determined with the use of a detailed in-home cognitive assessment that was 3 to 4 hours in duration and a review by an expert panel. We then imputed cognitive status to the full HRS sample (10,903 persons, 31,936 person-years) on the basis of measures of cognitive and functional status available for all HRS respondents, thereby identifying persons in the larger sample with a high probability of dementia. The market costs associated with care for persons with dementia were determined on the basis of self-reported out-of-pocket spending and the utilization of nursing home care; Medicare claims data were used to identify costs paid by Medicare. Hours of informal (unpaid) care were valued either as the cost of equivalent formal (paid) care or as the estimated wages forgone by informal caregivers. The estimated prevalence of dementia among persons older than 70 years of age in the United States in 2010 was 14.7%. The yearly monetary cost per person that was attributable to dementia was either $56,290 (95% confidence interval [CI], $42,746 to $69,834) or $41,689 (95% CI, $31,017 to $52,362), depending on the method used to value informal care. These individual costs suggest that the total monetary cost of dementia in 2010 was between $157 billion and $215 billion. Medicare paid approximately $11 billion of this cost. Dementia represents a substantial financial burden on society, one that is similar to the financial burden of heart disease and cancer. (Funded by the National Institute on Aging.).


A novel role for the centrosomal protein, pericentrin, in regulation of insulin secretory vesicle docking in mouse pancreatic beta-cells.
The centrosome is important for microtubule organization and cell cycle progression in animal cells. Recently, mutations in the centrosomal protein, pericentrin, have been linked to human microcephalic osteodysplastic primordial dwarfism (MOPD II), a rare genetic disease characterized by severe growth retardation and early onset of type 2 diabetes among other clinical manifestations. While the link between centrosomal and cell cycle defects may account for growth deficiencies, the mechanism linking pericentrin mutations with dysregulated glucose homeostasis and pre-pubertal onset of diabetes is unknown. In this report we observed abundant expression of pericentrin in quiescent pancreatic beta-cells of normal animals which led us to hypothesize that pericentrin may have a critical function in beta-cells distinct from its known role in regulating cell cycle progression. In addition to the typical centrosome localization, pericentrin was also enriched with secretory vesicles in the cytoplasm. Pericentrin overexpression in beta-cells resulted in aggregation of insulin-containing secretory vesicles with cytoplasmic, but not centrosomal, pericentriolar material and an increase in total levels of intracellular insulin. RNAi- mediated silencing of pericentrin in secretory beta-cells caused dysregulated secretory vesicle hypersecretion of insulin into the media. Together, these data suggest that pericentrin may regulate the intracellular distribution and secretion of insulin. Mice transplanted with pericentrin-depleted islets exhibited abnormal fasting hypoglycemia and inability to regulate blood glucose normally during a glucose challenge, which is consistent with our in vitro data. This previously unrecognized function for a centrosomal protein to mediate vesicle docking in secretory endocrine cells emphasizes the adaptability of these scaffolding proteins to regulate diverse cellular processes and identifies a novel target for modulating regulated protein secretion in disorders such as diabetes.


Mannose-6-phosphate regulates destruction of lipid-linked oligosaccharides.
Mannose-6-phosphate (M6P) is an essential precursor for mannosyl glycoconjugates, including lipid-linked oligosaccharides (LLO; glucose(3)mannose(9)GlcNAc(2)-P-P-dolichol) used for protein N-glycosylation. In permeabilized mammalian cells, M6P also causes specific LLO cleavage. However, the context and purpose of this paradoxical reaction are unknown. In this study, we used intact mouse embryonic fibroblasts to show that endoplasmic reticulum (ER) stress elevates M6P concentrations, leading to cleavage of the LLO pyrophosphate linkage with recovery of its lipid and lumenal glycan components. We demonstrate that this M6P originates from glycogen, with glycogenolysis activated by the kinase domain of the stress sensor IRE1-α. The apparent futility of M6P causing destruction of its LLO product was resolved by experiments with another stress sensor, PKR-like ER kinase (PERK), which attenuates translation. PERK's reduction of N-glycoprotein synthesis (which consumes LLOs) stabilized steady-state LLO levels despite continuous LLO destruction. However, infection with herpes simplex virus 1, an N-glycoprotein-bearing pathogen that impairs PERK signaling, not only caused LLO destruction but depleted LLO levels as well. In conclusion, the common metabolite M6P is also part of a novel mammalian stress-signaling pathway, responding to viral stress by depleting host LLOs required for N-glycosylation of virus-associated polypeptides. Apparently conserved throughout evolution, LLO destruction may be a response to a variety of environmental stresses.