Immunosuppressive treatment for focal segmental glomerulosclerosis in adults.
Corticosteroids remain the mainstay of treatment in idiopathic nephrotic syndrome, including focal and segmental glomerulosclerosis (FSGS). However, only about 20% of patients with FSGS experience a partial or complete remission of nephrotic syndrome despite treatment. To assess the effects of different immunomodulatory and immunosuppressive regimes in adults with FSGS. We searched MEDLINE, EMBASE and CENTRAL and handsearched congress reports of the American Society of Nephrology and the European Dialysis and Transplantation Association. Date of search: 31 January 2007. Randomised controlled trials (RCTs) and quasi-RCTs which examined the effects of different doses, dose strategies and duration of treatment of steroids, alkylating agents, cyclosporin A and antimetabolites in the treatment of FSGS in adults, where included. At least two authors independently assessed abstracts and/or full text articles to determine which studies satisfied the inclusion criteria. Information was entered onto a separate data sheet for each identified study. Data relevant to outcomes (complete or partial remission of nephrotic syndrome, doubling of serum creatinine, adverse effects) from identified studies were included. Results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Four studies (108 participants) were included. Three studies investigated cyclosporin A (CSA) with or without prednisone versus prednisone or no treatment and one compared chlorambucil plus prednisone versus no treatment. Outcome data was only available for complete or partial remission and doubling of serum creatinine. There was a significant increase in the number of participants who obtained complete or partial remission with CSA plus low dose prednisone versus prednisone alone (one study, 49 participants: RR 8.85, 95% CI 1.22 to 63.92). Pooled analyses were not performed due to the heterogeneity of the data. Adult patients treated with CSA at an initial dose of 3.5-5 mg/kg/d in two divided doses perhaps in combination with oral prednisolone 0.15 mg/kg/d are more likely to achieve a partial remission of the nephrotic syndrome compared with symptomatic treatment or prednisolone alone. However, there is a probability of deterioration of kidney function due to the nephrotoxic effect of CSA in the long term. For CSA, a larger controlled trial with longer follow-up should be performed to prove the benefit of this regimen not only on proteinuria but also on the preservation of kidney function. Present available data do not support the general use of alkylating substances for the treatment of FSGS in adults.


RNA polymerase I-driven reverse genetics system for enterovirus 71 and its implications for vaccine production.
Enterovirus 71 (EV71) is a virus that causes from mild hand, foot and mouth disease (HFMD) to severe neurological complications and deaths in infants and young children. Effective antiviral agents and vaccines against EV71 are not available. However, Vero cell-based chemically inactivated EV71 vaccines could be developed soon based on the success of inactivated polio vaccine. Like poliovirus, EV71 has a positive single-stranded RNA genome of about 7400 nucleotides which contains a single open reading frame (ORF) flanked by conserved and untranslated regions at both the 5' and 3' ends. The universal amplification of the full length genome of EV71 regardless of its genetic diversity, and the subsequent construction of a human RNA polymerase I-driven reverse genetics (RG) system to produce pure virus stocks in Vero cell within 10 days were described. The rescued viruses were characterized by DNA sequencing, cytopathic effect (CPE) and indirect fluorescent assay (IFA) in comparison with the wild-type viruses. Moreover, the rescued viruses grew to high titers and retained the same immunogenicity as the wild-type viruses. We have established a simplified method to rescue RG EV71 virus from diverse clinical isolates with detailed genetic information and to prepare virus stocks in only 10 days. This method could accelerate EV71 vaccine development.


The use of bacterial spore formers as probiotics.
The field of probiosis has emerged as a new science with applications in farming and aqaculture as alternatives to antibiotics as well as prophylactics in humans. Probiotics are being developed commercially for both human use, primarily as novel foods or dietary supplements, and in animal feeds for the prevention of gastrointestinal infections, with extensive use in the poultry and aquaculture industries. The impending ban of antibiotics in animal feed, the current concern over the spread of antibiotic resistance genes, the failure to identify new antibiotics and the inherent problems with developing new vaccines make a compelling case for developing alternative prophylactics. Among the large number of probiotic products in use today are bacterial spore formers, mostly of the genus Bacillus. Used primarily in their spore form, these products have been shown to prevent gastrointestinal disorders and the diversity of species used and their applications are astonishing. Understanding the nature of this probiotic effect is complicated, not only because of the complexities of understanding the microbial interactions that occur within the gastrointestinal tract (GIT), but also because Bacillus species are considered allochthonous microorganisms. This review summarizes the commercial applications of Bacillus probiotics. A case will be made that many Bacillus species should not be considered allochthonous microorganisms but, instead, ones that have a bimodal life cycle of growth and sporulation in the environment as well as within the GIT. Specific mechanisms for how Bacillus species can inhibit gastrointestinal infections will be covered, including immunomodulation and the synthesis of antimicrobials. Finally, the safety and licensing issues that affect the use of Bacillus species for commercial development will be summarized, together with evidence showing the growing need to evaluate the safety of individual Bacillus strains as well as species on a case by case by basis.


Direct radioimmunoassay of androstenediol-3-sulfate in the serum of normal men.
A commercially available antidihydrotestosterone antiserum was used for the direct radioimmunoassay of androstenediol-3-sulfate (ADS) in human serum. Aliquots of 1 or 2 microliter male serum (mean age of 40 subjects, 38.2 +/- 5.0 years) were diluted and extracted with ethanol for assay. The tracer, [7-3H]ADS, was prepared by sodium borohydride reduction of [7-3H]dehydroepiandrosterone sulfate (DS). Significantly cross-reacting steroids were testosterone, DS, androsterone sulfate, and epiandrosterone sulfate, which combined to produce a mean overestimation of ADS of 4.3 micrograms/dl in male serum. Mean serum ADS was 23.6 +/- 10.0 micrograms/dl (SD) in 20 fresh-frozen sera versus 28.4 +/- 9.7 micrograms/dl (SD) in 20 long-term (24.4 +/- 1.2 years) frozen specimens, showing stability on long-term frozen storage. Androstenediol-3-sulfate also showed a strong correlation with serum DS (r = 0.75). The possible physiologic significance of ADS is discussed, particularly in terms of the known estrogenicity of unconjugated androstenediol.


[EBM: otitis media in children: how to formulate a PICO question].
This series of articles begins with a problem frequently encountered in children: acute otitis media. Under the insistence of parents, antibiotics are frequently prescribed. The physician knows that the value of that therapy is debatable, but what for a child of 6 years of age? The physician whishes to compare his/her opinion with what is published in the litterature or available on the web. How to start his/her research? In this first article the physician will find out how to translate his/her practical question into a question which leads to a practical answer, and then to a PICO question. This will allow the physician to find sources of directly usable and relevant data which will offer a rational and wellfounded answer to his/her clinical question.


Isoform-Level Gene Expression Profiles of Human Y Chromosome Azoospermia Factor Genes and Their X Chromosome Paralogs in the Testicular Tissue of Non-Obstructive Azoospermia Patients.
The human Y chromosome has an inevitable role in male fertility because it contains many genes critical for spermatogenesis and the development of the male gonads. Any genetic variation or epigenetic modification affecting the expression pattern of Y chromosome genes may thus lead to male infertility. In this study, we performed isoform-level gene expression profiling of Y chromosome genes within the azoospermia factor (AZF) regions, their X chromosome counterparts, and few autosomal paralogues in testicular biopsies of 12 men with preserved spermatogenesis and 68 men with nonobstructive azoospermia (NOA) (40 Sertoli-cell-only syndrome (SCOS) and 28 premiotic maturation arrest (MA)). This was undertaken using quantitative real-time PCR (qPCR) at the transcript level and Western blotting (WB) and immunohistochemistry (IHC) at the protein level. We profiled the expression of 41 alternative transcripts encoded by 14 AZFa, AZFb, and AZFc region genes (USP9Y, DDX3Y, XKRY, HSFY1, CYORF15A, CYORF15B, KDM5D, EIF1AY, RPS4Y2, RBMY1A1, PRY, BPY2, DAZ1, and CDY1) as well as their X chromosome homologue transcripts and a few autosomal homologues. Of the 41 transcripts, 18 were significantly down-regulated in men with NOA when compared with those of men with complete spermatogenesis. In contrast, the expression of five transcripts increased significantly in NOA patients. Furthermore, to confirm the qPCR results at the protein level, we performed immunoblotting and IHC experiments (based on 24 commercial and homemade antibodies) that detected 10 AZF-encoded proteins. In addition, their localization in testis cell types and organelles was determined. Interestingly, the two missing proteins, XKRY and CYORF15A, were detected for the first time. Finally, we focused on the expression patterns of the significantly altered genes in 12 MA patients with successful sperm retrieval compared to those of 12 MA patients with failed sperm retrieval to predict the success of sperm retrieval in azoospermic men. We showed that HSFY1-1, HSFY1-3, BPY2-1, KDM5C2, RBMX2, and DAZL1 transcripts could be used as potential molecular markers to predict the presence of spermatozoa in MA patients. In this study, we have identified isoform level signature that can be used to discriminate effectively between MA, SCOS, and normal testicular tissues and suggests the possibility of diagnosing the presence of mature sperm cell in azoospermic men to prevent additional testicular sperm extraction (TESE) surgery.


Cooperative Electronic and Structural Regulation in a Bioinspired Allosteric Photoredox Catalyst.
Herein, we report the first allosteric photoredox catalyst regulated via constructively coupled structural and electronic control. While often synergistically exploited in nature, these two types of control mechanisms have only been applied independently in the vast majority of allosteric enzyme mimics and receptors in the literature. By embedding a model of photosystem II in a supramolecular coordination complex that responds to chloride as an allosteric effector, we show that distance and electronic control of light harvesting can be married to maximize allosteric regulation of catalytic activity. This biomimetic system is composed of a Bodipy photoantenna, which is capable of transferring excited-state energy to a photoredox pair, wherein the excitation energy is used to generate a catalytically active charge-separated state. The structural aspect of allosteric regulation is achieved by toggling the coordination chemistry of an antenna-functionalized hemilabile ligand via partial displacement from a Rh(I) structual node using chloride. In doing so, the distance between the antenna and the central photoredox catalyst is increased, lowering the inherent efficiency of through-space energy transfer. At the same time, coordination of chloride lowers both the charge of the Rh(I) node and the reduction potential of the Rh(II/I) couple, to the extent that electronic quenching of the antenna excited state is possible via photoinduced electron transfer from the metal center. Compared to a previously developed system that operates solely via electronic regulation, the present system demonstrates that coupling electronic and structural approaches to allosteric regulation gives rise to improved switching ratios between catalytically active and inactive states. Contributions from both structural and electronic control mechanisms are probed via nuclear magnetic resonance, X-ray diffraction, electrochemical, spectroelectrochemical, and transient absorption studies. Overall, this work establishes that intertwined electronic and structural regulatory mechanisms can be borrowed from nature to build stimuli-responsive inorganic materials with potential applications in sensing, catalysis, and photonic devices.


Trypanosoma cruzi and virological studies in idiopathic cardiomyopathy in Cali, Colombia.
During a 10-year period a series of 114 patients was studied to determine if Trypanosoma cruzi and arboviruses could be the etiologic agents of idiopathic cardiomyopathy (ICM) in Cali, Colombia. In this area, ICM (together with rheumatic and artherosclerotic cardiopathy) represents the second most frequent cause (determined by necropsy) among adult patients with cardiopathies, hypertension being the first. No association was observed between ICM and any of the arboviruses assessed by hemagglutination tests. Only 10 of 114 cases (8.7%) showed positive seroparasitological tests for T. cruzi. Autopsy was performed in 4 of these 10 cases; 1 had Chagas myocarditis and the other 3 were patients with non-inflammatory ICM. In all 9 T. cruzi-negative cases the autopsies showed non-inflammatory ICM lesions. In contrast to typical Chagas cases, the most frequent EKG change in ICM is left bundle branch block rather than right. Since the EKG varies within either group, this distinction may not be valid in individual cases. Because of the similarities in clinical characteristics and variations in EKG between Chagas myocarditis and ICM, it is suggested that autopsies should be done in populations in endemic areas of T. cruzi to assess the frequency of ICM and its importance in the differential diagnosis of Chagas myocarditis.


Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation.
Patients with autism have been often reported to have a smaller corpus callosum (CC) than control subjects. We conducted a meta-analysis of the literature, analyzed the CC in 694 subjects of the Autism Brain Imaging Data Exchange project, and performed computer simulations to study the effect of different analysis strategies. Our meta-analysis suggested a group difference in CC size; however, the studies were heavily underpowered (20% power to detect Cohen's d = .3). In contrast, we did not observe significant differences in the Autism Brain Imaging Data Exchange cohort, despite having achieved 99% power. However, we observed that CC scaled nonlinearly with brain volume (BV): large brains had a proportionally smaller CC. Our simulations showed that because of this nonlinearity, CC normalization could not control for eventual BV differences, but using BV as a covariate in a linear model would. We also observed a weaker correlation of IQ and BV in cases compared with control subjects. Our simulations showed that matching populations by IQ could then induce artifactual BV differences. The lack of statistical power in the previous literature prevents us from establishing the reality of the claims of a smaller CC in autism, and our own analyses did not find any. However, the nonlinear relationship between CC and BV and the different correlation between BV and IQ in cases and control subjects may induce artifactual differences. Overall, our results highlight the necessity for open data sharing to provide a more solid ground for the discovery of neuroimaging biomarkers within the context of the wide human neuroanatomical diversity.


Perception and the strongest sensory memory trace of multi-stable displays both form shortly after the stimulus onset.
We investigated the relation between perception and sensory memory of multi-stable structure-from-motion displays. The latter is an implicit visual memory that reflects a recent history of perceptual dominance and influences only the initial perception of multi-stable displays. First, we established the earliest time point when the direction of an illusory rotation can be reversed after the display onset (29-114 ms). Because our display manipulation did not bias perception towards a specific direction of illusory rotation but only signaled the change in motion, this means that the perceptual dominance was established no later than 29-114 ms after the stimulus onset. Second, we used orientation-selectivity of sensory memory to establish which display orientation produced the strongest memory trace and when this orientation was presented during the preceding prime interval (80-140 ms). Surprisingly, both estimates point towards the time interval immediately after the display onset, indicating that both perception and sensory memory form at approximately the same time. This suggests a tighter integration between perception and sensory memory than previously thought, warrants a reconsideration of its role in visual perception, and indicates that sensory memory could be a unique behavioral correlate of the earlier perceptual inference that can be studied post hoc.


Livebearing or egg-laying mammals: 27 decisive nucleotides of FAM168.
In the present study, we determine comprehensive molecular phylogenetic relationships of the novel myelin-associated neurite-outgrowth inhibitor (MANI) gene across the entire eukaryotic lineage. Combined computational genomic and proteomic sequence analyses revealed MANI as one of the two members of the novel family with sequence similarity 168 member (FAM168) genes, consisting of FAM168A and FAM168B, having distinct genetic differences that illustrate diversification in its biological function and genetic taxonomy across the phylogenetic tree. Phylogenetic analyses based on coding sequences of these FAM168 genes revealed that they are paralogs and that the earliest emergence of these genes occurred in jawed vertebrates such as Callorhinchus milii. Surprisingly, these two genes are absent in other chordates that have a notochord at some stage in their lives, such as branchiostoma and tunicates. In the context of phylogenetic relationships among eukaryotic species, our results demonstrate the presence of FAM168 orthologs in vertebrates ranging from Callorhinchus milii to Homo sapiens, displaying distinct taxonomic clusters, comprised of fish, amphibians, reptiles, birds, and mammals. Analyses of individual FAM168 exons in our sample provide new insights into the molecular relationships between FAM168A and FAM168B (MANI) on the one hand and livebearing and egg-laying mammals on the other hand, demonstrating that a distinctive intermediate exon 4, comprised of 27 nucleotides, appears suddenly only in FAM168A and there in the livebearing mammals only but is absent from all other species including the egg-laying mammals.


Why Do Phylogenomic Data Sets Yield Conflicting Trees? Data Type Influences the Avian Tree of Life more than Taxon Sampling.
Phylogenomics, the use of large-scale data matrices in phylogenetic analyses, has been viewed as the ultimate solution to the problem of resolving difficult nodes in the tree of life. However, it has become clear that analyses of these large genomic data sets can also result in conflicting estimates of phylogeny. Here, we use the early divergences in Neoaves, the largest clade of extant birds, as a "model system" to understand the basis for incongruence among phylogenomic trees. We were motivated by the observation that trees from two recent avian phylogenomic studies exhibit conflicts. Those studies used different strategies: 1) collecting many characters [$\sim$ 42 mega base pairs (Mbp) of sequence data] from 48 birds, sometimes including only one taxon for each major clade; and 2) collecting fewer characters ($\sim$ 0.4 Mbp) from 198 birds, selected to subdivide long branches. However, the studies also used different data types: the taxon-poor data matrix comprised 68% non-coding sequences whereas coding exons dominated the taxon-rich data matrix. This difference raises the question of whether the primary reason for incongruence is the number of sites, the number of taxa, or the data type. To test among these alternative hypotheses we assembled a novel, large-scale data matrix comprising 90% non-coding sequences from 235 bird species. Although increased taxon sampling appeared to have a positive impact on phylogenetic analyses the most important variable was data type. Indeed, by analyzing different subsets of the taxa in our data matrix we found that increased taxon sampling actually resulted in increased congruence with the tree from the previous taxon-poor study (which had a majority of non-coding data) instead of the taxon-rich study (which largely used coding data). We suggest that the observed differences in the estimates of topology for these studies reflect data-type effects due to violations of the models used in phylogenetic analyses, some of which may be difficult to detect. If incongruence among trees estimated using phylogenomic methods largely reflects problems with model fit developing more "biologically-realistic" models is likely to be critical for efforts to reconstruct the tree of life. [Birds; coding exons; GTR model; model fit; Neoaves; non-coding DNA; phylogenomics; taxon sampling.].


Formation and dynamics of supported phospholipid membranes on a periodic nanotextured substrate.
We have studied and modeled the morphology and dynamics of fluid planar lipid bilayer membranes supported on a textured silicon substrate. The substrate is fabricated to have channels on its surface that are a few hundred nanometers across, with a channel depth of a few hundred nanometers perpendicular to the plane of observation. Using atomic force microscopy and quantitative fluorescence microscopy, we have shown that the bilayer assemblies conform to the underlying nanostructured substrate. As far as dynamics is concerned, when observed over length scales exceeding the dimensions of the nanostructured features, the macroscopic diffusion is anisotropic. However, the macroscopic anisotropy is well simulated using models of diffusion on the nanostructured surface that consider the lipids to diffuse homogeneously and isotropically on the supporting substrate. Consistent with previous observations on less well characterized or less periodic nanostructures, we find that the nanostructured substrate produces an effective anisotropy in macroscopic diffusion of the conformal membrane. More importantly, we demonstrate how quantitative analysis of dynamics probed by larger-scale fluorescence imaging can yield information on nanoscale thin-film morphology.


Divergent evolution of duplicate genes leads to genetic incompatibilities within A. thaliana.
Genetic incompatibilities resulting from interactions between two loci represent a potential source of postzygotic barriers and may be an important factor in evolution when they impair the outcome of interspecific crosses. We show that, in crosses between strains of the plant Arabidopsis thaliana, loci interact epistatically, controlling a recessive embryo lethality. This interaction is explained by divergent evolution occurring among paralogs of an essential duplicate gene, for which the functional copy is not located at the same locus in different accessions. These paralogs demonstrate genetic heterogeneity in their respective evolutionary trajectories, which results in widespread incompatibility among strains. Our data suggest that these passive mechanisms, gene duplication and extinction, could represent an important source of genetic incompatibilities across all taxa.


DNA probes in human disease.
Nucleic acid probes are able to detect the presence of particular sequences in a sample down to the level of a few hundred molecules. They can discriminate between similar sequences to a resolution of better than one part in 10(9). They are capable of detecting inherited defects in tissues where the phenotype is not being expressed, and in cases where the biochemical aberration is not understood. They can characterize acquired diseases in somatic cells (both tumours and infectious agents). Additionally, they can be used to characterize multifactorial (either polygenic or requiring an environmental stimulus to interact with a genetic predisposition) diseases. Nucleic acid 'fingerprints' provide an unequivocal identification of the origin of cells which may be applied in criminal law, civil law, and in the follow up to bone marrow transplants. In spite of this tremendous potential, there is still a large gap between their use in research laboratories and their widespread application in pathology laboratories. There are two basic reasons for this. The first is the number of labour-intensive steps involved in the various 'blotting' techniques which greatly reduces the rate at which assays may be performed. The second is the need to use probes labelled with isotopes which are short-lived and may require stringent safety measures to be employed. Recent work both in this laboratory and elsewhere is designed to circumvent both these problems.


Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components.
Mycobacterium tuberculosis infection is accompanied by acute and chronic inflammatory infiltrates associated with necrotizing granulomas in lung tissue. The cellular infiltrate is characterized by inflammatory cells which include neutrophils, lymphocytes, and macrophages. In animal and in vitro models of mycobacterial infection, cytokines including tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin-1 beta (IL-1 beta) participate in granulomatous inflammation. We hypothesized that interleukin-3, a potent chemoattractant for neutrophils and lymphocytes, could be released by activated alveolar macrophages after exposure to M. tuberculosis or its components and contribute to granulomatous lung inflammation. A quantitative immunoassay revealed that IL-8 protein release was significantly elevated in supernatants of macrophages and in lavage fluid obtained from patients with pulmonary tuberculosis compared to normal controls. In addition, Northern blots demonstrated striking up-regulation of IL-8 mRNA in macrophages from these patients. M. tuberculosis and its cell wall components lipoarabinomannan (LAM), lipomannan (LM), and phosphoinositolmannoside (PIM) stimulated IL-8 protein release and mRNA expression in vitro from alveolar macrophages, but deacylated LAM did not. Neutralizing antibodies to TNF-alpha and/or IL-1-alpha and beta blocked 83% of the stimulation. IL-8 synthesis and release is an early response of macrophages after phagocytosis of M. tuberculosis. Its production serves to attract both acute and chronic inflammatory cells of active infection and thus participates in the process of containment of the pathogen.


Single-cell analysis reveals T cell infiltration in old neurogenic niches.
The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.


Life-threatening hemorrhage after liver radiofrequency ablation successfully controlled by transarterial embolization.
A 59-year-old man underwent liver radiofrequency ablation under laparotomy for recurrent hepatic carcinoma located in the caudate lobe, however, near-fatal bleeding occurred 1 wk after the operation. The intra-operative ultrasound study during laparotomy revealed left hepatic artery pseudoaneurysm. Suture and packing with ribbon gauze was used to obtain hemostasis. A secondary hemorrhage followed 11 h later and hepatic angiography was performed immediately. Bleeding from the pseudoaneurysm in a branch of the left hepatic artery was found and the artery branch was embolized with coils. Other than slight bile leakage, post-embolization continued satisfactorily. Bleeding did not reoccur. The follow up visit 1 mo later found the pseudoaneurysm disappearing and no tumor recurrence.


Impact on sludge inventory and control strategies using the benchmark simulation model no. 1 with the Bürger-Diehl settler model.
An improved one-dimensional (1-D) model for the secondary clarifier, i.e. the Bürger-Diehl model, was recently presented. The decisive difference to traditional layer models is that every detail of the implementation is in accordance with the theory of partial differential equations. The Bürger-Diehl model allows accounting for hindered and compressive settling as well as inlet dispersion. In this contribution, the impact of specific features of the Bürger-Diehl model on settler underflow concentration predictions, plant sludge inventory and mixed liquor suspended solids based control actions are investigated by using the benchmark simulation model no. 1. The numerical results show that the Bürger-Diehl model allows for more realistic predictions of the underflow sludge concentration, which is essential for more accurate wet weather modelling and sludge waste predictions. The choice of secondary settler model clearly has a profound impact on the operation and control of the entire treatment plant and it is recommended to use the Bürger-Diehl model as of now in any wastewater treatment plant modelling effort.


Coagulation factor IXa as a target for treatment and prophylaxis of venous thromboembolism.
Venous thromboembolism remains a frequent cause of vascular death. Despite advances in anticoagulant drug development, unmet needs remain, including limited treatment options for patients with severe renal impairment and the inability to fully reverse the effects of anticoagulants approved or in late-stage development. Because coagulation factor IXa plays a pivotal role in tissue factor-mediated thrombin generation, it represents an attractive target for anticoagulant development. This article discusses the rationale for factor IXa as an anticoagulant target and the potential role in venous thromboembolism prevention or management of the 2 factor IXa inhibitors that have undergone testing in phase 1 or 2 trials: TTP889, an oral, small-molecule compound, and RB006, an aptamer-based compound, the intravenous and subcutaneous formulations of which are the anticoagulant components of the REG1 and REG2 anticoagulation systems, respectively.


Nonselective cation channel activation during wound healing in the corneal endothelium.
Rabbit corneas were injured by mechanical or thermal trauma. At several time points after wounding, corneal endothelial cells were isolated and their ion channels examined using standard and amphotericin perforated-patch whole cell patch-clamp configurations. Within 15-24 h after mechanical or thermal trauma, a nonselective cation current was observed in 79% of the cells examined that was not present in unwounded or sham-wounded corneas. By 73 h postwounding, the current was present in only 10% of the cells examined. The wound healing-induced current is outwardly rectifying, activates at depolarized voltages, shows no sign of inactivation, and is inhibited by flufenamic acid, quinidine, and acetate. In addition to this new current, it was observed that endothelial cells from freeze-wounded corneas no longer expressed the transient K+ current seen in control, sham, and mechanically wounded corneas. Corneal endothelial superfusion experiments found no significant difference in swelling rates between control and flufenamic acid-superfused wounded corneas, indicating that the wound healing-induced channel is not involved in the stromal hydration maintenance function of the corneal endothelium.


ADP binding by the Culex quinquefasciatus mosquito D7 salivary protein enhances blood feeding on mammals.
During blood-feeding, mosquito saliva is injected into the skin to facilitate blood meal acquisition. D7 proteins are among the most abundant components of the mosquito saliva. Here we report the ligand binding specificity and physiological relevance of two D7 long proteins from Culex quinquefasciatus mosquito, the vector of filaria parasites or West Nile viruses. CxD7L2 binds biogenic amines and eicosanoids. CxD7L1 exhibits high affinity for ADP and ATP, a binding capacity not reported in any D7. We solve the crystal structure of CxD7L1 in complex with ADP to 1.97 Å resolution. The binding pocket lies between the two protein domains, whereas all known D7s bind ligands either within the N- or the C-terminal domains. We demonstrate that these proteins inhibit hemostasis in ex vivo and in vivo experiments. Our results suggest that the ADP-binding function acquired by CxD7L1 evolved to enhance blood-feeding in mammals, where ADP plays a key role in platelet aggregation.


Effects of channel modulators on cloned large-conductance calcium-activated potassium channels.
Through expression of the cloned mouse (mSlo) or human (hSlo) large-conductance (BK) Ca(2+)-activated K+ channel in Xenopus laevis oocytes and HEK 293 cells, we characterized the effects of reported blockers and openers of BK channels to initiate the study of the molecular determinants of BK channel modulation. In oocytes, iberiotoxin and charybdotoxin, peptidyl scorpion toxins, were both equally effective blockers of BK current, although iberiotoxin was significantly more potent than charybdotoxin. The structurally related peptide kaliotoxin was not a potent blocker of BK current. Paxilline, a fungal tremorgenic alkaloid, was an effective but complex blocker of BK current. Tetrandrine, a putative blocker of type II BK channels, and ketamine were relatively ineffective. The putative BK openers NS004 and NS1619, phloretin, niflumic acid, flufenamic acid, and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) increased BK current in oocytes at microM concentrations; many of these produced biphasic concentration-response relationships. Coapplication of representative blockers and openers revealed several patterns of interaction, including competitive and noncompetitive antagonism. NS1619, niflumic acid, and phloretin were tested by using excised inside-out membrane patches from HEK 293 cells and were found to increase the activity of hSlo BK channels and produce a leftward shift in the G/Gmax-versus-voltage relationship of these channels. These results represent the first comprehensive examination of the molecular pharmacology of BK channels.


Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice.
Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.


Dynamic and Contextual Information in HMM Modeling for Handwritten Word Recognition.
This study aims at building an efficient word recognition system resulting from the combination of three handwriting recognizers. The main component of this combined system is an HMM-based recognizer which considers dynamic and contextual information for a better modeling of writing units. For modeling the contextual units, a state-tying process based on decision tree clustering is introduced. Decision trees are built according to a set of expert-based questions on how characters are written. Questions are divided into global questions, yielding larger clusters, and precise questions, yielding smaller ones. Such clustering enables us to reduce the total number of models and Gaussians densities by 10. We then apply this modeling to the recognition of handwritten words. Experiments are conducted on three publicly available databases based on Latin or Arabic languages: Rimes, IAM, and OpenHart. The results obtained show that contextual information embedded with dynamic modeling significantly improves recognition.


The mucosal immune system and its integration with the mammary glands.
Mucosal immunity reduces the need for elimination of penetrating exogenous antigens by proinflammatory systemic immunity. The adult gut mucosa contains some 80% of the body's activated B cells-differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric immunoglobulin A (IgA), which, along with pentameric immunoglobulin M (IgM), can be exported by secretory epithelia expressing the polymeric immunoglobulin receptor. Immune exclusion of antigens is performed mainly by secretory IgA in cooperation with innate defenses, but, in newborns and in IgA deficiency, secretory IgM is important. In the gut, induction and regulation of mucosal immunity occurs primarily in gut-associated lymphoid tissue-particularly the Peyer's patches-and also in mesenteric lymph nodes. Terminal differentiation to PCs is accomplished in the lamina propria to which the activated memory/effector T and B cells home. Lactating mammary glands are part of the secretory immune system, and IgA antibodies in breast milk reflect antigenic stimulation of gut-associated lymphoid tissue and nasopharynx-associated lymphoid tissue such as the tonsils. Breast-milk antibodies are thus highly targeted against infectious agents and other exogenous antigens in the mother's environment, which are those likely to be encountered by the infant. Therefore breast-feeding represents an ingenious immunologic integration of mother and child.


Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.
Fatty acid binding proteins (FABPs) are small cytoplasmic proteins that are expressed in a highly tissue-specific manner and bind to fatty acids such as oleic and retinoic acid. Mice with a null mutation in aP2, the gene encoding the adipocyte FABP, were developmentally and metabolically normal. The aP2-deficient mice developed dietary obesity but, unlike control mice, they did not develop insulin resistance or diabetes. Also unlike their obese wild-type counterparts, obese aP2-/- animals failed to express in adipose tissue tumor necrosis factor-alpha (TNF-alpha), a molecule implicated in obesity-related insulin resistance. These results indicate that aP2 is central to the pathway that links obesity to insulin resistance, possibly by linking fatty acid metabolism to expression of TNF-alpha.


Confocal laser scanning microscopy analysis of S. epidermidis biofilms exposed to farnesol, vancomycin and rifampicin.
Staphylococcus epidermidis is the major bacterial species found in biofilm-related infections on indwelling medical devices. Microbial biofilms are communities of bacteria adhered to a surface and surrounded by an extracellular polymeric matrix. Biofilms have been associated with increased antibiotic tolerance to the immune system. This increased resistance to conventional antibiotic therapy has lead to the search for new antimicrobial therapeutical agents. Farnesol, a quorum-sensing molecule in Candida albicans, has been described as impairing growth of several different microorganisms and we have previously shown its potential as an adjuvant in antimicrobial therapy against S. epidermidis. However, its mechanism of action in S. epidermidis is not fully known. In this work we better elucidate the role of farnesol against S: epidermidis biofilms using confocal laser scanning microscopy (CLSM). 24 h biofilms were exposed to farnesol, vancomycin or rifampicin and were analysed by CLSM, after stained with a Live/Dead stain, a known indicator of cell viability, related with cell membrane integrity. Biofilms were also disrupted by sonication and viable and cultivable cells were quantified by colony forming units (CFU) plating. Farnesol showed a similar effect as vancomycin, both causing little reduction of cell viability but at the same time inducing significant changes in the biofilm structure. On the other hand, rifampicin showed a distinct action in S. epidermidis biofilms, by killing a significant proportion of biofilm bacteria. While farnesol is not very efficient at killing biofilm bacteria, it damages cell membrane, as determined by the live/dead staining, in a similar way as vancomycin. Furthermore, farnesol might induce biofilm detachment, as determined by the reduced biofilm biomass, which can partially explain the previous findings regarding its role as a possible chemotherapy adjuvant.


Passive magnetic shielding in MRI-Linac systems.
Passive magnetic shielding refers to the use of ferromagnetic materials to redirect magnetic field lines away from vulnerable regions. An application of particular interest to the medical physics community is shielding in MRI systems, especially integrated MRI-linear accelerator (MRI-Linac) systems. In these systems, the goal is not only to minimize the magnetic field in some volume, but also to minimize the impact of the shield on the magnetic fields within the imaging volume of the MRI scanner. In this work, finite element modelling was used to assess the shielding of a side coupled 6 MV linac and resultant heterogeneity induced within the 30 cm diameter of spherical volume (DSV) of a novel 1 Tesla split bore MRI magnet. A number of different shield parameters were investigated; distance between shield and magnet, shield shape, shield thickness, shield length, openings in the shield, number of concentric layers, spacing between each layer, and shield material. Both the in-line and perpendicular MRI-Linac configurations were studied. By modifying the shield shape around the linac from the starting design of an open ended cylinder, the shielding effect was boosted by approximately 70% whilst the impact on the magnet was simultaneously reduced by approximately 10%. Openings in the shield for the RF port and beam exit were substantial sources of field leakage; however it was demonstrated that shielding could be added around these openings to compensate for this leakage. Layering multiple concentric shield shells was highly effective in the perpendicular configuration, but less so for the in-line configuration. Cautious use of high permeability materials such as Mu-metal can greatly increase the shielding performance in some scenarios. In the perpendicular configuration, magnetic shielding was more effective and the impact on the magnet lower compared with the in-line configuration.


Accelerated lambing achieved by a photoperiod regimen consisting of alternating 4-month sequences of long and short days applied year-round.
The objective of this work was to evaluate the reproductive performance of ewes exposed to a photoperiodic regimen consisting of continuous alternating 4-mo periods of long days (LD: 16 h of light/d) and short days (SHD: 8 h of light/d) in an accelerated lambing program of 3 lambings in 2 yr. A total of 211 prolific Rideau Arcott ewes were assigned to the photoperiodic treatment, whereas 37 ewes were maintained under natural annual variation in day length (control group). Ewes under the photoperiod regimen were divided into 4 subgroups (A, B, C, D). All these groups of ewes were exposed to the same light regimen, but the LD and SHD light sequences were staggered by 2 mo to permit the evaluation of the effect of time and season of mating on performance of the ewes treated with the photoperiod. The control ewes were treated with intravaginal sponges in the out-of-season breeding periods (conventional approach). Each group of ewes was studied over 3 reproductive cycles. Two groups of rams exposed to alternating 2-mo sequences of LD and SHD were used for mating. The short mean interval between ram introduction and conception for the groups exposed to artificial photoperiod (9.4 d) confirmed the effectiveness of the treatment to induce intense sexual activity. For the 12 breeding periods studied (8 in out-of-season and 4 in sexual season), fertility rate of the ewes treated with photoperiod, mated at various times of year, was 91.6%, which is comparable with the fertility normally seen in the natural breeding season. The number of lambs born/ewe remained constant across reproductive cycles and was greater in photoperiod-treated groups (2.81 vs. 2.27 for photoperiod and control groups, respectively; P = 0.0002). Groups exposed to photoperiod treatment obtained better fertility rate than the control group in out-of-season breeding (91.1 vs. 76.3%; P = 0.016). Ewes managed under the photoperiod regimen produced 1.38 lambings/yr and 69% of them lambed 3 times in 2 yr. Overall, the ewes in the photoperiodic treatment produced annually 3.78 lambs/ewe. The reproductive performances achieved throughout the years indicate that the photoperiodic program tested, consisting of continuous alternating 4-mo periods of LD and SHD, allows control of the annual reproductive cycles in ewes.


Endemic, exotic and novel apicomplexan parasites detected during a national study of ticks from companion animals in Australia.
Apicomplexan tick-borne pathogens that cause disease in companion animals include species of Babesia Starcovici, 1893, Cytauxzoon Neitz & Thomas, 1948, Hepatozoon Miller, 1908 and Theileria Bettencourt, Franca & Borges, 1907. The only apicomplexan tick-borne disease of companion animals that is known to occur in Australia is babesiosis, caused by Babesia canis vogeli Reichenow, 1937 and Babesia gibsoni Patton, 1910. However, no molecular investigations have widely investigated members of Apicomplexa Levine, 1980 in Australian ticks that parasitise dogs, cats or horses, until this present investigation. Ticks (n = 711) removed from dogs (n = 498), cats (n = 139) and horses (n = 74) throughout Australia were screened for piroplasms and Hepatozoon spp. using conventional PCR and Sanger sequencing. The tick-borne pathogen B. vogeli was identified in two Rhipicephalus sanguineus Latreille ticks from dogs residing in the Northern Territory and Queensland (QLD). Theileria orientalis Yakimov & Sudachenkov, 1931 genotype Ikeda was detected in three Haemaphysalis longicornis Neumann ticks from dogs in New South Wales. Unexpectedly, the exotic tick-borne pathogen Hepatozoon canis James, 1905 was identified in an Ixodes holocyclus Neumann tick from a dog in QLD. Eight novel piroplasm and Hepatozoon species were identified and described in native ticks and named as follows: Babesia lohae n. sp., Babesia mackerrasorum n. sp., Hepatozoon banethi n. sp., Hepatozoon ewingi n. sp., Theileria apogeana n. sp., Theileria palmeri n. sp., Theileria paparinii n. sp. and Theileria worthingtonorum n. sp. Additionally, a novel cf. Sarcocystidae sp. sequence was obtained from Ixodes tasmani Neumann but could not be confidently identified at the genus level. Novel species of parasites in ticks represent an unknown threat to the health of companion animals that are bitten by these native tick species. The vector potential of Australian ticks for the newly discovered apicomplexans needs to be assessed, and further clinical and molecular investigations of these parasites, particularly in blood samples from dogs, cats and horses, is required to determine their potential for pathogenicity.


Image correlation spectroscopy.
Membrane domains, such as caveolae and clathrin-coated pits, regulate cell signaling and protein internalization in the plasma membrane. Fluorescence imaging and microscopy provide an opportunity to determine the receptor protein dynamics of membrane microdomains. The family of image correlation spectroscopy (ICS) techniques provides powerful tools with which to measure the aggregation, clustering, and dynamics of proteins in the plasma membrane. ICS is used to calculate the cluster density and the degree of aggregation of plasma membrane proteins, whereas image cross-correlation spectroscopy (ICCS) measures the fraction of colocalization of two proteins. Dynamic image correlation spectroscopy (DICS) can be used to analyze protein dynamics on the cell surface during live-cell imaging.


Randomized trial of a question prompt list to increase patient active participation during interactions with black patients and their oncologists.
Communication during racially-discordant interactions is often of poor quality and may contribute to racial treatment disparities. We evaluated an intervention designed to increase patient active participation and other communication-related outcomes during interactions between Black patients and non-Black oncologists. Participants were 18 non-Black medical oncologists and 114 Black patients at two cancer hospitals in Detroit, Michigan, USA. Before a clinic visit to discuss treatment, patients were randomly assigned to usual care or to one of two question prompt list (QPL) formats: booklet (QPL-Only), or booklet and communication coach (QPL-plus-Coach). Patient-oncologist interactions were video recorded. Patients reported perceptions of the intervention, oncologist communication, role in treatment decisions, and trust in the oncologist. Observers assessed interaction length, patient active participation, and oncologist communication. The intervention was viewed positively and did not increase interaction length. The QPL-only format increased patient active participation; the QPL-plus-Coach format decreased patient perceptions of oncologist communication. No other significant effects were found. This QPL booklet is acceptable and increases patient active participation in racially-discordant oncology interactions. Future research should investigate whether adding physician-focused interventions might improve other outcomes. This QPL booklet is acceptable and can improve patient active participation in racially-discordant oncology interactions.


The epidemiology of sports and exercise related injury in the United Kingdom.
A national study of exercise related morbidity (ERM) in England and Wales was carried out using a postal questionnaire sent to 28,857 adults aged 16-45 years. The questionnaire asked about regular participation in sports or other recreational fitness activities involving physical exercise, and for details of any injuries occurring during a 28 d reference period. A return rate of 68% was achieved. Comparisons with other national data sources indicated that the information obtained was reliable. It is estimated that each year there are 29 million incidents resulting in new or recurrent injuries, however minor, of which 9.8 million (95% confidence interval 8.1 to 11.4 million) result in new 'substantive' injuries which are potentially serious, result in treatment, or in participants being unable to take part in their usual activities. Soccer accounted for more than 25% of all ERM, but the risk of a substantive injury in rugby was three times that in soccer. Over one third of ERM occurred in men aged 16-25 years. The most frequently reported injuries were sprains and strains of the lower limbs. Treatment was sought in approximately 25% of ERM incidents and 7% of all new ERM incidents involved attendance at a hospital accident and emergency department. The treatment provider most likely to be consulted was a general practitioner, but physiotherapists and complementary medicine practitioners were also consulted frequently. To maximize the health benefits of exercise, research strategies to reduce the volume and severity of ERM and to identify the most appropriate ways of managing ERM should be set.


Use of mammography in Peruvian women: An analysis of the 2018 Demographic and Health Survey.
Breast cancer is the second most prevalent neoplasm in women after cervical cancer in Peru. It is also the third leading cause of female mortality. The implementation of screening programs using mammography has led to a considerable reduction in the mortality of this cancer in high-income countries. To analyze the factors associated with mammography use in Peruvian women between the ages of 40 and 59. Secondary analysis of the 2018 Demographic and Health Survey in Peru. The national representative sample consisted of 4822 women between the ages of 40 and 59. The main outcome was the use of mammography during the last 24 months, with which we calculated percentages and crude and adjusted prevalence ratios (PR). 16.9% of the surveyed women reported a mammography exam. A higher proportion of mammography use was observed in women with a higher level of education (30.1%), higher wealth quintile (34.2%) and those from capital cities (26.9%). Multivariate analysis showed that only the highest wealth index quintile (prevalence ratio: 5.75; 95% confidence interval: 2.97 to 11.15) compared to the lowest quintile; and the 55 to 59 age group (prevalence ratio: 1.83; 95% confidence interval: 1.31 to 2.55) compared to the 40 to 44 age group, were significantly associated with mammography. The use of mammography as a preventive examination for breast cancer in Peru is still low compared to other countries. The association of mammography with the better-off quintile shows the inequalities of access to preventive health in the country.


Effects of physical activity and dietary calcium intake on bone mineral density and osteoporosis risk in a rural Thai population.
The objective of the study was to determine the effects of modifiable risk factors on bone mineral density in postmenopausal Thai women. Dietary calcium intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium intake was 236 +/- 188 g/day (mean +/- SD), while the energy expenditure was 2,118 +/- 656 kcal/day with 1.1 +/- 1.7 h of sunlight exposure. In multiple linear regression analysis, dietary calcium intake, energy expenditure, and years since menopause were significant and independent predictors of BMD at various sites. The three factors together accounted for between 35% and 45% of the variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores < or =-2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal radius. The risk of osteoporosis was higher in women with lower dietary calcium intake (< or =138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence interval [CI], 1.0 to 1.9), lower energy expenditure (< or =1,682 kcal; PRR, 1.7; 95% CI, 1.2 to 2.3), and greater years since menopause (> or =6 years; PRR, 2.6; 95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis risk due to the three factors was 70%. These results suggest that in the Thai population, low dietary calcium intake and low physical activity together with advancing years since menopause were independent risk factors for low BMD.


Adenovirus-mediated Drosophila melanogaster deoxyribonucleoside kinase mutants combined with gemcitabine harbor a safe cancer treatment profile.
The purpose of this analysis was to investigate the enzyme activity and specificity of adenovirus-mediated Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) mutants in combination with gemcitabine. Compared to herpes simplex type 1 thymidine kinases (HSV-TK) and other known dNKs, this Dm-dNK enzyme has a broader substrate specificity and a higher catalytic rate. We created the Dm-dNK mutants (dNKmut) by site-directed mutagenesis at the sites of 244E, 245S, 251S, and 252R, with the last 10 amino acids in the amino acid sequence randomly alternated. We subsequently evaluated the enzyme activity and substrate specificity. The engineered enzymes showed a relative increase in phosphorylation in the nucleoside analogs of gemcitabine (dFdC, 2',2'-difluoro-deoxycytidine) compared to the wild-type enzyme. The dNKmut enzymes were expressed in breast (Bcap37) and gastric (SGC-7901) cancer cell lines. In studying the sensitivity of the cell lines to dFdC, conditionally replicative adenovirus (CRAd) ZD55-dNKmut showed higher expression and enzymatic activity than the replication-defective adenovirus Ad-dNKmut in cancer cells, but with less cytotoxicity to cancer cells than that of Ad-dNKmut. Our data suggest that the triple phosphorylated dFdC catalyzed by dNKmut inhibited the replication of adenovirus with a simultaneous positive therapeutic effect on cancer cells. Therefore, concomitant use of the ZD55-dNKmut and dFdC could be a novel targeted strategy in suicide gene therapy with safe control of excessive virus replication.


Effectiveness of Chêneau brace treatment for idiopathic scoliosis: prospective study in 79 patients followed to skeletal maturity.
Progressive idiopathic scoliosis can negatively influence the development and functioning of 2-3% of adolescents, with health consequences and economic costs, placing the disease in the centre of interest of the developmental medicine. The aim of this study was to evaluate the effectiveness of Chêneau brace in the management of idiopathic scoliosis. A prospective observational study according to SOSORT and SRS recommendations comprised 79 patients (58 girls and 21 boys) with progressive idiopathic scoliosis, treated with Chêneau brace and physiotherapy, with initial Cobb angle between 20 and 45 degrees, no previous brace treatment, Risser 4 or more at the final evaluation and minimum one year follow-up after weaning the brace. Achieving 50° of Cobb angle was considered surgical recommendation. At follow-up 20 patients (25.3%) improved, 18 patients (22.8%) were stable, 31 patients (39.2%) progressed below 50 degrees and 10 patients (12.7%) progressed beyond 50 degrees (2 of these 10 patients progressed beyond 60 degrees). Progression concerned the younger and less skeletally mature patients. Conservative treatment with Chêneau orthosis and physiotherapy was effective in halting scoliosis progression in 48.1% of patients. The results of this study suggest that bracing is effective in reducing the incidence of surgery in comparison with natural history.


Aromatase inhibitors for metastatic male breast cancer: molecular, endocrine, and clinical considerations.
Male breast cancer is a rare condition. Aromatase inhibitors are widely used for treating metastatic male breast cancer patients. In this setting, their use is not substantiated by prospective clinical trials, but is rather driven by similarities supposedly existing with breast cancer in postmenopausal women. This oversimplified approach was questioned by studies addressing the molecular and endocrine roots of the disease. In this manuscript, we discuss relevant aspects of the current use of aromatase inhibitors in metastatic male breast cancer in light of the most updated evidence on the molecular landscape of the disease and the specific changes in the hormonal background occurring with aging. We further point to strategies for blocking multiple hormonal pathway nodes with the goal of improving their therapeutic potential. We searched PubMed from its inception until March 2014 for relevant literature on the use of aromatase inhibitors in metastatic male breast cancer. Selected terms were combined and used both as medical headings and text words. The reference list of the suitable manuscripts was inspected for further publications. Aromatase inhibitors represent the mainstay of treatment in the metastatic setting. Yet, efforts aimed at sharpening the therapeutic potential of aromatase inhibitors still pose a challenge due to the paucity of data. The choice of dual hormonal (or sequential) therapy combining aromatase inhibitors with a GnRH analogue may represent a valid alterative, particularly if informed by cancer- and patient-related features including molecular, endocrine, and clinic characteristics.


Ultra-high dose rate dosimetry: Challenges and opportunities for FLASH radiation therapy.
The clinical translation of FLASH radiotherapy (RT) requires challenges related to dosimetry and beam monitoring of ultra-high dose rate (UHDR) beams to be addressed. Detectors currently in use suffer from saturation effects under UHDR regimes, requiring the introduction of correction factors. There is significant interest from the scientific community to identify the most reliable solutions and suitable experimental approaches for UHDR dosimetry. This interest is manifested through the increasing number of national and international projects recently proposed concerning UHDR dosimetry. Attaining the desired solutions and approaches requires further optimization of already established technologies as well as the investigation of novel radiation detection and dosimetry methods. New knowledge will also emerge to fill the gap in terms of validated protocols, assessing new dosimetric procedures and standardized methods. In this paper, we discuss the main challenges coming from the peculiar beam parameters characterizing UHDR beams for FLASH RT. These challenges vary considerably depending on the accelerator type and technique used to produce the relevant UHDR radiation environment. We also introduce some general considerations on how the different time structure in the production of the radiation beams, as well as the dose and dose-rate per pulse, can affect the detector response. Finally, we discuss the requirements that must characterize any proposed dosimeters for use in UDHR radiation environments. A detailed status of the current technology is provided, with the aim of discussing the detector features and their performance characteristics and/or limitations in UHDR regimes. We report on further developments for established detectors and novel approaches currently under investigation with a view to predict future directions in terms of dosimetry approaches, practical procedures, and protocols. Due to several on-going detector and dosimetry developments associated with UHDR radiation environment for FLASH RT it is not possible to provide a simple list of recommendations for the most suitable detectors for FLASH RT dosimetry. However, this article does provide the reader with a detailed description of the most up-to-date dosimetric approaches, and describes the behavior of the detectors operated under UHDR irradiation conditions and offers expert discussion on the current challenges which we believe are important and still need to be addressed in the clinical translation of FLASH RT.


Intestinal edema decreases intestinal contractile activity via decreased myosin light chain phosphorylation.
The purpose of this study was to investigate the effects of interstitial edema on intestinal contractile activity. Randomized animal study. University laboratory. Male Sprague-Dawley rats. Intestinal edema was induced in rats by a combination of fluid infusion and mesenteric venous hypertension. Rats were divided into four groups: CONTROL, sham; RESUS, saline infusion only; RESUS+VH, saline infusion and venous hypertension; and VH, venous hypertension only. Edema development, basal contractile activity, maximum agonist-induced contractile response (measured as total force generation during the first 2 mins after carbachol treatment), and myosin light chain phosphorylation were measured in the distal small intestine. The amount of interstitial fluid, indicated by the wet-to-dry ratio, increased significantly in both the RESUS and RESUS+VH groups as early as 30 mins after surgery compared with the CONTROL group. Whereas the tissue fluid remained significantly elevated in the RESUS+VH group up to 6 hrs after surgery, the RESUS group wet-to-dry ratios returned to CONTROL group levels by 2 hrs after surgery. Basal contractile activity was significantly less in the RESUS+VH group compared with either the RESUS group or the CONTROL group 6 hrs after surgery. Maximum contractile response decreased significantly in the RESUS+VH group compared with the RESUS group. Basal contractile activity and maximum contractile response did not change significantly in the VH group compared with the CONTROL group. The phosphorylated fraction of myosin light chain was significantly lower in the RESUS+VH group compared with the CONTROL group at 0.5, 2, and 6 hrs after surgery. We conclude that edema decreases myosin light chain phosphorylation, leading to decreased intestinal contractile activity.


High-intensity emergency department visits increased in California, 2002-09.
Increasing use of the emergency department (ED) is well documented, but little is known about the type and severity of ED visits or their distribution across safety-net and non-safety-net hospitals. We examined the rates of high-intensity ED visits--characterized by their use of advanced imaging, consultations with specialists, the evaluation of multiple systems, and highly complex medical decision making--by patients with a severe, potentially life-threatening illness in California from 2002 through 2009. Total annual ED visits increased by 25 percent, from 9.0 million to 11.3 million, but high-intensity ED visits nearly doubled, increasing 87 percent from 778,000 to 1.5 million per year. The percentage of ED visits with high-intensity care increased from 9 percent to 13 percent (a relative increase of 44 percent). Annual ED admissions increased by 39 percent overall; most of this increase was attributable to high-intensity ED admissions, which increased by 88 percent. Safety-net EDs experienced an increase in high-intensity visits of 157 percent, compared to an increase of 61 percent at non-safety-net EDs. These findings suggest a trend toward intensification of ED care, particularly at safety-net hospitals, whose patients may have limited access to care outside the ED.


The burden of mental illness and addiction in ontario.
Public Health Ontario and the Institute for Clinical Evaluative Sciences have collaborated to estimate the burden of illness attributable to mental disorder and addictions in Ontario. Health-adjusted life years were used to estimate burden. It is conceptually similar to disability-adjusted life years that were used in the global burden of disease studies. Data sources for the mental illnesses and addictions used in our study included health administrative data for the province of Ontario, survey data from Statistics Canada and the Centre for Addiction and Mental Health, vital statistics data from the Ontario Office of the Registrar General, and US epidemiologic survey data. The 5 conditions with the highest burden are: major depression, bipolar affective disorder, alcohol use disorders (AUDs), social phobia, and schizophrenia. The burden of depression is double the next highest mental health condition (that is, bipolar affective disorder) and is more than the combined burden of the 4 most common cancers in Ontario. AUDs were the only disease group that had a substantial proportion of burden attributable to early death. The burden estimates for the other conditions were primarily due to disability. The burden of these conditions in Ontario is as large or larger than other conditions, such as cancer and infectious diseases, owing in large part to the high prevalence, chronicity, and age of onset for most mental disorders and addiction problems. The findings serve as an important baseline for future evaluation of interventions intended to address the burden of mental health and addictions.


Driving after cerebral damage: a model with implications for evaluation.
Evaluation of the ability of cerebrally injured patients to return to driving is an important task for rehabilitation specialists. These evaluations require predictively valid methods of assessment based on identification of relevant skills and abilities. The present study tested a hypothetical model for driving after cerebral injury and determined its use in evaluating fitness to drive. Thirty-five patients with cerebral damage due to head injury or cerebrovascular accident participated in the study. All were administered (a) a predriver evaluation, that is, a battery of neuropsychological tests chosen a priori to test the model, (b) a simulator evaluation, and (c) a behind-the-wheel evaluation consisting of driving on a protected course and in traffic. The results showed that 93% of the driving outcome in traffic was explained cumulatively by findings from the predriver and simulator evaluations as well as from behavioral and operational measures during evaluation on the protected lot. These results supported the predictive validity of the model and are discussed in terms of methodology for evaluation of return to driving.


Probing the mechanical properties of brain cancer cells using a microfluidic cell squeezer device.
Despite being invasive within surrounding brain tissues and the central nervous system, little is known about the mechanical properties of brain tumor cells in comparison with benign cells. Here, we present the first measurements of the peak pressure drop due to the passage of benign and cancerous brain cells through confined microchannels in a "microfluidic cell squeezer" device, as well as the elongation, speed, and entry time of the cells in confined channels. We find that cancerous and benign brain cells cannot be differentiated based on speeds or elongation. We have found that the entry time into a narrow constriction is a more sensitive indicator of the differences between malignant and healthy glial cells than pressure drops. Importantly, we also find that brain tumor cells take a longer time to squeeze through a constriction and migrate more slowly than benign cells in two dimensional wound healing assays. Based on these observations, we arrive at the surprising conclusion that the prevailing notion of extraneural cancer cells being more mechanically compliant than benign cells may not apply to brain cancer cells.


Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma.
Dolastatin-10 is a natural, cytotoxic peptide with microtubule-inhibitory and apoptotic effects. It has demonstrated in vitro and in vivo efficacy in the DU-145 human prostate cancer model. A Phase II clinical trial was designed in patients with hormone-refractory prostate cancer. Dolastatin-10 was administered at a dose of 400 microg/m2 i.v. every 3 weeks. Dose escalation to 450 microg/m2 was permitted. Toxicity evaluation was conducted every 2 weeks, and assessment of response was done at the end of every two cycles. Sixteen patients were enrolled between October 1998 to December 1999. The median age was 71 years (range, 59-79 years). Median prostate-specific antigen value was 108 ng/ml (range, 15.3-1672 ng/ml). Of the 15 eligible patients, 7 were Caucasian and 8 were African-American. Eight patients had bone-only metastases, and seven had measurable disease with or without bone metastases. A total of 56 cycles have been administered. Only 2 patients required dose adjustment because of toxicity, and in 5 patients, dose escalation was feasible to 450 microg/m2. The major toxicities observed were grade 3 and 4 neutropenia in 8 patients and grade 3 neuropathy in 1 patient. All 15 patients are evaluable for response. Three patients demonstrated stable disease; 2 of these had bone disease, and 1 had nodal metastasis. All others had disease progression. Dolastatin-10 is very well tolerated in this elderly, pretreated population but lacks significant clinical activity as a single agent.


Numerical simulations of drumlin formation.
We summarize the present form of the instability theory for drumlin formation, which describes the coupled subglacial flow of ice, water and sediment. This model has evolved over the last 20 years, and is now at the point where it can predict instabilities corresponding to ribbed moraine, drumlins and mega-scale glacial lineations, but efforts to provide numerical solutions of the model have been limited. The present summary adds some slight nuances to previously published versions of the theory, notably concerning the constitutive description of the subglacial water film and its flow. A new numerical method is devised to solve the model, and we show that it can be solved for realistic values of most of the parameters, with the exception of that corresponding to the water film thickness. We show that evolved bedforms can be three-dimensional and of the correct sizes, and we explore to some extent the variation of the solutions with the model's parameters.


Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α.
The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.


Adolescent self-harm: a school-based study in Northern Ireland.
The prevalence of adolescent self-harm in Northern Ireland (NI) and its associated factors are unknown. Given the established relationship between conflict and mental health, and NI׳s recent history of conflict, it is important to investigate the factors associated with self-harm in NI. This study aimed to determine the prevalence of self-harm in NI adolescents and the factors associated with it, including exposure to the NI conflict. Observational study of 3596 school pupils employing an anonymous self-report survey. Information was obtained on demographic characteristics, lifestyle, life events and problems, exposure to the NI conflict, social and internet influences, and psychological variables. Self-harm was reported by 10% of respondents. In univariate analyses, exposure to the NI conflict was associated with self-harm alongside established risk factors. In multivariate analyses, bullying and exposure to self-harm were associated with lifetime self-harm in both girls and boys. Alcohol use, drug use, physical and sexual abuse, and self-esteem were also associated with self-harm in girls. In boys, absence of exercise, sexual orientation concerns, anxiety and impulsivity were additional risk factors. The internet/social media and the self-harm of others were also key influences. This is a cross-sectional study. The rate of self-harm was lower than elsewhere in the UK/Ireland. The study highlights the factors which should be considered in terms of risk assessment. In addition to established risk factors, the findings suggest that more research on the legacy of the NI conflict as well as the influence of new technologies warrant urgent attention.


Reproduction in dairy cows following progesterone insert presynchronization and resynchronization protocols.
The objectives of this study were to evaluate the effects of an intravaginal insert containing progesterone (CIDR, controlled internal drug releasing) administered in presynchronization and resynchronization protocols on cyclicity, detection of estrus, pregnancy rate, and pregnancy loss to first AI; reinsemination patterns; and pregnancy rates to second postpartum AI before and after the time of first-service pregnancy diagnosis in dairy cows. Holstein cows (n = 1,052) were blocked by parity and BCS at 3 +/- 3 d in milk (study d 0 = day of calving) and assigned randomly to 1 of 3 presynchronization treatments. During the presynchronization programs, all cows received 2 injections of PGF2alpha, on study d 35 and 49. Cows enrolled in the control presynchronization treatment received AI after detected estrus from study d 49 to 62. Cows enrolled in the CIDR estrus-detection (CED) presynchronization treatment received a CIDR insert from study d 42 to 49 and AI on detection of estrus from d 49 to 62. Cows enrolled in the CIDR timed AI (CTAI) presynchronization treatment received the same treatment as CED, but were subjected to timed AI on study d 72 after the Ovsynch (GnRH, 7 d PGF2alpha, 2 d GnRH, 24 h timed AI) protocol. The control and CED cows not inseminated by study d 62 were enrolled in the Ovsynch protocol on the same day and received timed AI on study d 72. After first AI, cows were assigned to no resynchronization (RCON) or resynchronization with a CIDR insert (RCIDR) between 14 and 21 d after AI. Blood samples collected on study d 35, 49, and 62 were analyzed for concentrations of progesterone and cows were classified as anestrous when progesterone was < 1.0 ng/mL in the first 2 samples. On study d 62, anestrous cows with progesterone > or = 1.0 ng/mL were classified as having resumed cyclicity. Pregnancy was diagnosed at 31 and 60 d after first AI and at 42 d after second AI. A greater proportion of anestrous cows in CED and CTAI became cyclic by d 62 postpartum than control cows. Resynchronization with the CIDR insert increased the pregnancy rate at 31 d after first AI in CED and CTAI, and at 60 d after AI in all cows because of reduced pregnancy loss. These results indicate that presynchronization with the CIDR insert increased induction of cyclicity in anestrous cows and that resynchronization with the CIDR insert did not affect the reinsemination rate but did reduce pregnancy loss and increased the pregnancy rate at 60 d after first AI.


Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy.
The changes in brain function that perpetuate opiate addiction are unclear. In our studies of human narcolepsy, a disease caused by loss of immunohistochemically detected hypocretin (orexin) neurons, we encountered a control brain (from an apparently neurologically normal individual) with 50% more hypocretin neurons than other control human brains that we had studied. We discovered that this individual was a heroin addict. Studying five postmortem brains from heroin addicts, we report that the brain tissue had, on average, 54% more immunohistochemically detected neurons producing hypocretin than did control brains from neurologically normal subjects. Similar increases in hypocretin-producing cells could be induced in wild-type mice by long-term (but not short-term) administration of morphine. The increased number of detected hypocretin neurons was not due to neurogenesis and outlasted morphine administration by several weeks. The number of neurons containing melanin-concentrating hormone, which are in the same hypothalamic region as hypocretin-producing cells, did not change in response to morphine administration. Morphine administration restored the population of detected hypocretin cells to normal numbers in transgenic mice in which these neurons had been partially depleted. Morphine administration also decreased cataplexy in mice made narcoleptic by the depletion of hypocretin neurons. These findings suggest that opiate agonists may have a role in the treatment of narcolepsy, a disorder caused by hypocretin neuron loss, and that increased numbers of hypocretin-producing cells may play a role in maintaining opiate addiction.


Health checks in general practice: another example of inverse care?
To assess attendance at and the characteristics of patients attending health checks for cardiovascular disease offered in a general practice over a period of five years (1984-9). Medical record audit and postal questionnaire survey. One general practice in Oxfordshire with a socially diverse population. 1101 Men and 1110 women aged 35-64 registered with the practice. Age, sex, marital state, social class, smoking habits, alcohol consumption, and diet. Of the 2211 men and women in the target age group (35-64) in 1989, 1458 (65.9%) had been offered screening and 963 (43.6%) had attended for a health check. Attenders were more likely to be women, aged greater than or equal to 45, married, non-smokers, and of higher social class than patients who did not respond to the invitation. The relative likelihood of non-attendance was 1.24 for smokers, 1.20 for the overweight, 1.16 for heavy drinkers, and 1.28 for those with a less healthy diet, even after adjustment for age, sex, marital state, and social class. After five years of offering health checks, opportunistically (to men) and in the context of cervical smear tests (to women), less than half of the eligible patients had attended. The likelihood of acceptance of an invitation to attend was inversely related to the patient's cardiovascular risk for all factors measured except age. A coherent strategy to reduce cardiovascular disease depends on more careful targeting of scarce health service resources and more emphasis on public health measures (such as dietary regulation and tobacco taxation). Doctors should be careful not to absolve the government of its public health obligations by substituting unproved preventive interventions aimed at the individual patient.


Coronary calcium significantly affects quantitative analysis of coronary ultrasound: importance for atherosclerosis progression/regression studies.
Coronary atherosclerosis is a dynamic process, which progresses differently in coronary segments containing noncalcified or calcified plaques. This may have implications for the study of the effects of therapy on progression/regression. To test this hypothesis, we performed a post-hoc analysis on data of a randomized trial in which perindopril treatment was compared with placebo on progression/regression of atherosclerosis with regard to the degree of calcification. The intracoronary ultrasound data of 118 patients, who were enrolled in the multicentre, double-blinded randomized trial (PERSPECTIVE), were analysed. Vessel, lumen and plaque areas were measured in 711 5-mm-long matched coronary segments (perindopril 360, placebo 351). Each individual intracoronary ultrasound cross-section was binary labelled for the presence of calcium (yes/no), and the degree of calcium was assessed as a percentage of length. The segments were classified into three groups: 0-25, 25-50 and 50-100% (percentage of length) calcification. Coronary plaques with no or little calcium (0-25%) regressed on perindopril and did not change on placebo (-0.33+/-1.74 vs. -0.03+/-1.66, respectively; P = 0.04). Plaques containing moderate calcium (group 25-50%) did not change and plaques with severe amounts of calcification (group 50-100%) equally progressed. Noncalcified plaques may be amenable to regression with ACE inhibitor treatment. The method, which considers the amount of calcium content in a plaque, may lead to new insights for quantitative analysis of the effects of therapy in progression/regression studies of atherosclerosis.


A Flexible Photoactive Titanium Metal-Organic Framework Based on a [Ti(IV)3(μ3-O)(O)2(COO)6] Cluster.
The synthesis of titanium-carboxylate metal-organic frameworks (MOFs) is hampered by the high reactivity of the commonly employed alkoxide precursors. Herein, we present an innovative approach to titanium-based MOFs by the use of titanocene dichloride to synthesize COK-69, the first breathing Ti MOF, which is built up from trans-1,4-cyclohexanedicarboxylate linkers and an unprecedented [Ti(IV)3(μ3-O)(O)2(COO)6] cluster. The photoactive properties of COK-69 were investigated in depth by proton-coupled electron-transfer experiments, which revealed that up to one Ti(IV) center per cluster can be photoreduced to Ti(III) while preserving the structural integrity of the framework. The electronic structure of COK-69 was determined by molecular modeling, and a band gap of 3.77 eV was found.


Evolution and diversification of the plant gibberellin receptor GID1.
The plant gibberellin (GA) receptor GID1 shows sequence similarity to carboxylesterase (CXE). Here, we report the molecular evolution of GID1 from establishment to functionally diverse forms in eudicots. By introducing 18 mutagenized rice GID1s into a rice gid1 null mutant, we identified the amino acids crucial for GID1 activity in planta. We focused on two amino acids facing the C2/C3 positions of ent-gibberellane, not shared by lycophytes and euphyllophytes, and found that adjustment of these residues resulted in increased GID1 affinity toward GA4, new acceptance of GA1 and GA3 carrying C13-OH as bioactive ligands, and elimination of inactive GAs. These residues rendered the GA perception system more sophisticated. We conducted phylogenetic analysis of 169 GID1s from 66 plant species and found that, unlike other taxa, nearly all eudicots contain two types of GID1, named A- and B-type. Certain B-type GID1s showed a unique evolutionary characteristic of significantly higher nonsynonymous-to-synonymous divergence in the region determining GA4 affinity. Furthermore, these B-type GID1s were preferentially expressed in the roots of Arabidopsis, soybean, and lettuce and might be involved in root elongation without shoot elongation for adaptive growth under low-temperature stress. Based on these observations, we discuss the establishment and adaption of GID1s during plant evolution.


Predicting groundwater redox status on a regional scale using linear discriminant analysis.
Reducing conditions are necessary for denitrification, thus the groundwater redox status can be used to identify subsurface zones where potentially significant nitrate reduction can occur. Groundwater chemistry in two contrasting regions of New Zealand was classified with respect to redox status and related to mappable factors, such as geology, topography and soil characteristics using discriminant analysis. Redox assignment was carried out for water sampled from 568 and 2223 wells in the Waikato and Canterbury regions, respectively. For the Waikato region 64% of wells sampled indicated oxic conditions in the water; 18% indicated reduced conditions and 18% had attributes indicating both reducing and oxic conditions termed "mixed". In Canterbury 84% of wells indicated oxic conditions; 10% were mixed; and only 5% indicated reduced conditions. The analysis was performed over three different well depths, <25m, 25 to 100 and >100m. For both regions, the percentage of oxidised groundwater decreased with increasing well depth. Linear discriminant analysis was used to develop models to differentiate between the three redox states. Models were derived for each depth and region using 67% of the data, and then subsequently validated on the remaining 33%. The average agreement between predicted and measured redox status was 63% and 70% for the Waikato and Canterbury regions, respectively. The models were incorporated into GIS and the prediction of redox status was extended over the whole region, excluding mountainous land. This knowledge improves spatial prediction of reduced groundwater zones, and therefore, when combined with groundwater flow paths, improves estimates of denitrification.


Lipidomics Reveals Seasonal Shifts in a Large-Bodied Hibernator, the Brown Bear.
Prior to winter, heterotherms retain polyunsaturated fatty acids ("PUFA"), resulting in enhanced energy savings during hibernation, through deeper and longer torpor bouts. Hibernating bears exhibit a less dramatic reduction (2-5°C) in body temperature, but lower their metabolism to a degree close to that of small hibernators. We determined the lipid composition, via lipidomics, in skeletal muscle and white adipose tissues ("WAT"), to assess lipid retention, and in blood plasma, to reflect lipid trafficking, of winter hibernating and summer active wild Scandinavian brown bears (Ursus arctos). We found that the proportion of monounsaturated fatty acids in muscle of bears was significantly higher during winter. During hibernation, omega-3 PUFAs were retained in WAT and short-length fatty acids were released into the plasma. The analysis of individual lipid moieties indicated significant changes of specific fatty acids, which are in line with the observed seasonal shift in the major lipid categories and can be involved in specific regulations of metabolisms. These results strongly suggest that the shift in lipid composition is well conserved among hibernators, independent of body mass and of the animals' body temperature.


Improving the Usability of Virtual Reality Neuron Tracing with Topological Elements.
Researchers in the field of connectomics are working to reconstruct a map of neural connections in the brain in order to understand at a fundamental level how the brain processes information. Constructing this wiring diagram is done by tracing neurons through high-resolution image stacks acquired with fluorescence microscopy imaging techniques. While a large number of automatic tracing algorithms have been proposed, these frequently rely on local features in the data and fail on noisy data or ambiguous cases, requiring time-consuming manual correction. As a result, manual and semi-automatic tracing methods remain the state-of-the-art for creating accurate neuron reconstructions. We propose a new semi-automatic method that uses topological features to guide users in tracing neurons and integrate this method within a virtual reality (VR) framework previously used for manual tracing. Our approach augments both visualization and interaction with topological elements, allowing rapid understanding and tracing of complex morphologies. In our pilot study, neuroscientists demonstrated a strong preference for using our tool over prior approaches, reported less fatigue during tracing, and commended the ability to better understand possible paths and alternatives. Quantitative evaluation of the traces reveals that users' tracing speed increased, while retaining similar accuracy compared to a fully manual approach.


Soluble CD23 (Fc epsilon RII) and interleukin 1 synergistically induce early human thymocyte maturation.
The ability of human thymus-derived CD7+CD2-CD3- cells to acquire mature T cell antigens was assessed. Purified CD7+ thymocytes were incubated with rIL-1, rIL-2, and/or recombinant soluble CD23 (rsCD23). Short-term incubation of these cells with only rsCD23 + rIL-1 induced mature T cell antigen expression on at least half of the cells. The induction of CD2 was functionally significant, as these cells became able to respond to CD2 triggering and could proliferate in response to IL-2. Possible sources of CD23 in the thymus are under investigation.


How should I regulate my emotions if I want to run faster?
The present study investigated the effects of emotion regulation strategies on self-reported emotions and 1600 m track running performance. In stage 1 of a three-stage study, participants (N = 15) reported emotional states associated with best, worst and ideal performance. Results indicated that a best and ideal emotional state for performance composed of feeling happy, calm, energetic and moderately anxious whereas the worst emotional state for performance composed of feeling downhearted, sluggish and highly anxious. In stage 2, emotion regulation interventions were developed using online material and supported by electronic feedback. One intervention motivated participants to increase the intensity of unpleasant emotions (e.g. feel more angry and anxious). A second intervention motivated participants to reduce the intensity of unpleasant emotions (e.g. feel less angry and anxious). In stage 3, using a repeated measures design, participants used each intervention before running a 1600 m time trial. Data were compared with a no treatment control condition. The intervention designed to increase the intensity of unpleasant emotions resulted in higher anxiety and lower calmness scores but no significant effects on 1600 m running time. The intervention designed to reduce the intensity of unpleasant emotions was associated with significantly slower times for the first 400 m. We suggest future research should investigate emotion regulation, emotion and performance using quasi-experimental methods with performance measures that are meaningful to participants.


βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.
Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.


Quantification of Yield Losses Caused by Barley yellow dwarf virus in Wheat and Oats.
Grain yield data obtained from five field experiments in Western Australia from 1992 to 1994, in which insecticide applications suppressed the spread of Barley yellow dwarf virus (BYDV) in wheat and oats, were used to quantify the relationships between incidence of BYDV and yield gaps, 500-seed weight, and percent shriveled grain. Yield gaps ranged from 0 to 2,700 kg/ha, and the relationship between yield gap and incidence of BYDV was always linear. Single point yield loss models revealed that BYDV infection explained most of the variation in yield gaps. There was a significant linear relationship between incidence of BYDV and 500-seed weight for wheat, but not for oats. The percent shriveled grain always increased with an increase in incidence of BYDV in wheat but not in oats. Cost-benefit relationships were determined for the return on investment when deploying imidacloprid-treated seed and/or one or two foliar applications of pyrethroid insecticides to reduce incidence of BYDV and to decrease the yield gaps in wheat and oats due to BYDV.