Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.
Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.


The striatofugal fiber system in primates: a reevaluation of its organization based on single-axon tracing studies.
The current model of basal ganglia rests on the idea that the striatofugal system is composed of two separate (direct and indirect) pathways originating from distinct cell populations in the striatum. The striatum itself is divided into two major compartments, the striosomes and the matrix, which differ by their neurochemical makeup and input/output connections. Here, neurons located in either striosomes or the extrastriosomal matrix in squirrel monkeys were injected with biotin dextran amine, and their labeled axons were entirely reconstructed with a camera lucida. Twenty-four of 27 reconstructed axons arborized into the three main striatal targets (external pallidum, globus pallidus, and substantia nigra pars reticulata), a finding that is at odds with the concept of a dual striatofugal system. Axons of striosomal neurons formed several columnar terminal fields in the substantia nigra pars reticulata. These data indicate that the substantia nigra pars compacta is neither the only nor the main target of striosomal neurons, a finding that calls for a reevaluation of the organization of the striatonigral projection system.


Nanolipolee-007, a novel nanoparticle-based drug containing leelamine for the treatment of melanoma.
Malignant melanoma is a difficult cancer to treat due to the rapid development of resistance to drugs targeting single proteins. One response to this observation is to identify single pharmacologic agents that, due to a unique mechanism of action, simultaneously target multiple key pathways involved in melanoma development. Leelamine has been identified as functioning in this manner but has poor bioavailability in animals and causes lethality when administered intravenously. Therefore, a nanoliposomal-based delivery system has been developed, called Nanolipolee-007, which stably loads 60% of the compound. The nanoparticle was as effective at killing melanoma cells as leelamine dissolved in DMSO and was more effective at killing cultured melanoma compared with normal cells. Mechanistically, Nanolipolee-007 inhibited PI3K/Akt, STAT3, and MAPK signaling mediated through inhibition of cholesterol transport. Nanolipolee-007 inhibited the growth of preexisting xenografted melanoma tumors by an average of 64% by decreasing cellular proliferation, reducing tumor vascularization, and increasing cellular apoptosis, with negligible toxicity. Thus, a unique clinically viable nanoparticle-based drug has been developed containing leelamine for the treatment of melanoma that acts by inhibiting the activity of major signaling pathways regulating the development of this disease.


Reliability of 3-Dimensional Measures of Single-Leg Drop Landing Across 3 Institutions: Implications for Multicenter Research for Secondary ACL-Injury Prevention.
Due to the limitations of single-center studies in achieving appropriate sampling with relatively rare disorders, multicenter collaborations have been proposed to achieve desired sampling levels. However, documented reliability of biomechanical data is necessary for multicenter injury-prevention studies and is currently unavailable. To measure the reliability of 3-dimensional (3D) biomechanical waveforms from kinetic and kinematic variables during a single-leg landing (SLL) performed at 3 separate testing facilities. Multicenter reliability study. 3 laboratories. 25 female junior varsity and varsity high school volleyball players who visited each facility over a 1-mo period. Subjects were instrumented with 43 reflective markers to record 3D motion as they performed SLLs. During the SLL the athlete balanced on 1 leg, dropped down off of a 31-cm-high box, and landed on the same leg. Kinematic and kinetic data from both legs were processed from 2 trials across the 3 laboratories. Coefficients of multiple correlations (CMC) were used to statistically compare each joint angle and moment waveform for the first 500 ms of landing. Average CMC for lower-extremity sagittal-plane motion was excellent between laboratories (hip .98, knee .95, ankle .99). Average CMC for lower-extremity frontal-plane motion was also excellent between laboratories (hip .98, knee .80, ankle .93). Kinetic waveforms were repeatable in each plane of rotation (3-center mean CMC ≥.71), while knee sagittal-plane moments were the most consistent measure across sites (3-center mean CMC ≥.94). CMC waveform comparisons were similar relative to the joint measured to previously published reports of between-sessions reliability of sagittal- and frontal-plane biomechanics performed at a single institution. Continued research is needed to further standardize technology and methods to help ensure that highly reliable results can be achieved with multicenter biomechanical screening models.


Analysis of the mobility of signaling molecules in lymphocytes using fluorescence photobleaching techniques.
The earliest biochemical events at the plasma membrane that lead to gene activation appear to depend not only on the local concentration of signaling molecules, but also on the mobility of these molecules at the site of signaling. To elucidate the process of signal transduction after receptor engagement in the immune system, it is important to analyze the mobility of signaling molecules in living lymphocytes. Current knowledge of the changes in intracellular localization and dynamic movements of signaling molecules during lymphocyte activation is limited. Here, we describe a method for known as fluorescence recovery after photobleaching, used to measure the diffusion mobility of a signaling molecule in a T cell line after T cell receptor stimulation. This method is a useful tool in studies of spatiotemporal regulation in immunoreceptor signaling.


Emergence of dengue in tribal villages of Mandla district, Madhya Pradesh, India.
Dengue (DEN) is a rapidly spreading arboviral disease transmitted by Aedes mosquitoes. Although it is endemic in India, dengue virus (DENV) infection has not been reported from tribal areas of Madhya Pradesh. Investigations were conducted to establish the aetiology of sudden upsurge of cases with febrile illness in June 2013 from tribal villages of Mandla district of Madhya Pradesh, India. The rapid response team of the National Institute for Research in Tribal Health, Jabalpur, conducted clinical investigations and field surveys to collect the samples from suspected cases. Samples were tested using molecular and serological tools. Collected mosquitoes were identified and tested for the presence of virus using semi nested reverse transcriptase-polymerase chain reaction (nRT-PCR). The sequences were analysed to identify serotype and genotype of the virus. Of the 648 samples collected from 18 villages of Mandla, 321 (49.53%) were found to be positive for dengue. The nRT-PCR and sequencing confirmed the aetiology as dengue virus type 2. Eighteen per cent of patients needed hospitalization and five deaths were attributed to dengue. The virus was also detected from Aedes aegypti mosquito, which was incriminated as a vector. Phylogenetic analysis revealed that the dengue virus 2 detected belonged to cosmopolitan genotype of the virus. Dengue virus serotype 2 was detected as the aetiological agent in the outbreak in tribal villages of Mandla district of Madhya Pradesh. Conducive man-made environment favouring mosquitogenic conditions and seeding of virus could be the probable reasons for this outbreak. Urgent attention is needed to control this new threat to tribal population, which is already overburdened with other vector borne diseases.


Tomographic diffractive imaging of monolayer crystals at atomic resolution with onedimensional compact support.
A solution to the phase problem for diffraction by two-dimensional crystalline slabs is described, based on the application of a compact support normal to the slab. Specifically we apply the iterative Gerchberg-Saxton-Fienup algorithm to simulated three-dimensional transmission electron diffraction data from monolayer organic crystals. We find that oversampling normal to the monolayer alone does not solve the phase problem in this geometry in general. However, based on simulations for a crystalline monolayer (tetracyanoethylene), we find that convergence is obtained if phases are supplied from a few high-resolution electron microscope images recorded at small tilts to the beam direction. Since current cryomicroscopy methods required a large number of images to phase tomographic diffraction data, this method should greatly reduce the labor involved in data acquisition and analysis in cryo-electron microscopy of organic thin crystals by avoiding the need to record images at high tilt angles. We discuss also the use of laser tweezers as a method of supporting nanoparticles in TEM for diffractive imaging.


A systems approach to measuring the binding energy landscapes of transcription factors.
A major goal of systems biology is to predict the function of biological networks. Although network topologies have been successfully determined in many cases, the quantitative parameters governing these networks generally have not. Measuring affinities of molecular interactions in high-throughput format remains problematic, especially for transient and low-affinity interactions. We describe a high-throughput microfluidic platform that measures such properties on the basis of mechanical trapping of molecular interactions. With this platform we characterized DNA binding energy landscapes for four eukaryotic transcription factors; these landscapes were used to test basic assumptions about transcription factor binding and to predict their in vivo function.


Comparison of four feed proteases for improvement of nutritive value of poultry feather meal.
Feed industries are seeking new ways to cope with increased raw material costs, and one approach is to apply enzymatic treatment in the production of feed ingredients from animal by-products. Keratinases, a group of proteases, are capable of hydrolyzing keratin-rich material and have been applied in the production of cost-effective feather by-products for use as feed and fertilizers. The current study examined 4 commercial feed proteases from Bacillus subtilis, Bacillus licheniformis PWD-1, Aspergillus niger, and Serratia proteamaculans HY-3 used to hydrolyze chicken feather under different conditions. The degree of keratinolysis was monitored by measuring the release of NH(2) groups using o-phthalaldehyde (OPA) and by scanning electron microscopy. All 4 feed proteases were able to degrade feather at pH 5.5 and 7.0. The degree of hydrolysis was stimulated by the addition of reducing reagents such as dithiothreitol (DTT) and Na(2)SO(3). In general, the protease from B. subtilis was more efficient in degrading feather keratin compared to the other 3 feed proteases at both pH 5.5 and 7.0. For commercial production, the application of protease from B. subtilis is even more advantageous considering the lower cost-in-use.


Epigenetic protein families: a new frontier for drug discovery.
Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.


Therapist adherence in the strong without anorexia nervosa (SWAN) study: A randomized controlled trial of three treatments for adults with anorexia nervosa.
To develop a psychotherapy rating scale to measure therapist adherence in the Strong Without Anorexia Nervosa (SWAN) study, a multi-center randomized controlled trial comparing three different psychological treatments for adults with anorexia nervosa. The three treatments under investigation were Enhanced Cognitive Behavioural Therapy (CBT-E), the Maudsley Anorexia Nervosa Treatment for Adults (MANTRA), and Specialist Supportive Clinical Management (SSCM). The SWAN Psychotherapy Rating Scale (SWAN-PRS) was developed, after consultation with the developers of the treatments, and refined. Using the SWAN-PRS, two independent raters initially rated 48 audiotapes of treatment sessions to yield inter-rater reliability data. One rater proceeded to rate a total of 98 audiotapes from 64 trial participants. The SWAN-PRS demonstrated sound psychometric properties, and was considered a reliable measure of therapist adherence. The three treatments were highly distinguishable by independent raters, with therapists demonstrating significantly more behaviors consistent with the actual allocated treatment compared to the other two treatment modalities. There were no significant site differences in therapist adherence observed. The findings provide support for the internal validity of the SWAN study. The SWAN-PRS was deemed suitable for use in other trials involving CBT-E, MANTRA, or SSCM.


Topical nasal steroids for treating nasal polyposis in people with cystic fibrosis.
Nasal polyps frequently occur in people with cystic fibrosis. Sinus infections have been shown to be a factor in the development of serious chest complications in these people. Nasal polyps have been linked to a higher risk of lower respiratory tract infections with Pseudomonas aeruginosa . Topical nasal steroids are of proven efficacy for treating nasal polyposis in the non-cystic fibrosis population. There is no clear current evidence for the efficacy of topical steroids for nasal polyps in people with cystic fibrosis. To assess the effectiveness of topical nasal steroids for treating symptomatic nasal polyps in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Latest search: 02 February 2011. Randomised and quasi-randomised controlled comparing the effects of topical nasal steroids to placebo in people with nasal polyps with cystic fibrosis. Two authors independently assessed risk of bias in the included trial and extracted data. One single-centred trial (46 participants) was identified comparing a topical steroid (betamethasone) to placebo. Twenty-two participants received the active drug.Subjective symptom scores, change in polyp size, and side effects were assessed. There was no difference in nasal symptom scores between the treatment and placebo groups. Betamethasone was effective in reducing the size of polyps, but was associated with increased reports of mild side effects, nasal bleeding and discomfort.Risk of bias was high since over 50% of people enrolled did not complete the study. Follow-up of patients was short (six weeks) also reducing the significance of the results for clinical practice. This review suggests topical steroids for nasal polyposis in patients with cystic fibrosis have no demonstrable effect on subjective nasal symptom scores. They have some effect in reducing the size of the polyps, but due to the small sample size, poor study completion rates and lack of follow-up, the study is at high risk of bias and evidence for efficacy is limited. Overall there is no clear evidence for using topical steroids in people with cystic fibrosis and nasal polyposis.A well-designed randomised controlled trial of adequate power and long-term follow-up is needed. Validated measures of symptoms and physical findings should be performed and quality of life issues addressed.


The lipopolysaccharide and beta-1,3-glucan binding protein gene is upregulated in white spot virus-infected shrimp (Penaeus stylirostris).
Pattern recognition proteins such as lipopolysaccharide and beta-1,3-glucan binding protein (LGBP) play an important role in the innate immune response of crustaceans and insects. Random sequencing of cDNA clones from a hepatopancreas cDNA library of white spot virus (WSV)-infected shrimp provided a partial cDNA (PsEST-289) that showed similarity to the LGBP gene of crayfish and insects. Subsequently full-length cDNA was cloned by the 5'-RACE (rapid amplification of cDNA ends) technique and sequenced. The shrimp LGBP gene is 1,352 bases in length and is capable of encoding a polypeptide of 376 amino acids that showed significant similarity to homologous genes from crayfish, insects, earthworms, and sea urchins. Analysis of the shrimp LGBP deduced amino acid sequence identified conserved features of this gene family including a potential recognition motif for beta-(1-->3) linkage of polysaccharides and putative RGD cell adhesion sites. It is known that LGBP gene expression is upregulated in bacterial and fungal infection and that the binding of lipopolysaccharide and beta-1,3-glucan to LGBP activates the prophenoloxidase (proPO) cascade. The temporal expression of LGBP and proPO genes in healthy and WSV-challenged Penaeus stylirostris shrimp was measured by real-time quantitative reverse transcription-PCR, and we showed that LGBP gene expression in shrimp was upregulated as the WSV infection progressed. Interestingly, the proPO expression was upregulated initially after infection followed by a downregulation as the viral infection progressed. The downward trend in the expression of proPO coincided with the detection of WSV in the infected shrimp. Our data suggest that shrimp LGBP is an inducible acute-phase protein that may play a critical role in shrimp-WSV interaction and that the WSV infection regulates the activation and/or activity of the proPO cascade in a novel way.


Study on antibacterial alginate-stabilized copper nanoparticles by FT-IR and 2D-IR correlation spectroscopy.
The objective of this study was to clarify the intermolecular interaction between antibacterial copper nanoparticles (Cu NPs) and sodium alginate (NaAlg) by Fourier transform infrared spectroscopy (FT-IR) and to process the spectra applying two-dimensional infrared (2D-IR) correlation analysis. To our knowledge, the addition of NaAlg as a stabilizer of copper nanoparticles has not been previously reported. It is expected that the obtained results will provide valuable additional information on: (1) the influence of reducing agent ratio on the formation of copper nanoparticles in order to design functional nanomaterials with increased antibacterial activity, and (2) structural changes related to the incorporation of Cu NPs into the polymer matrix. Cu NPs were prepared by microwave heating using ascorbic acid as reducing agent and NaAlg as stabilizing agent. The characterization of synthesized Cu NPs by ultraviolet visible spectroscopy, transmission electron microscopy (TEM), electron diffraction analysis, X-ray diffraction (XRD), and semiquantitative analysis of the weight percentage composition indicated that the average particle sizes of Cu NPs are about 3-10 nm, they are spherical in shape, and consist of zerovalent Cu and Cu₂O. Also, crystallite size and relative particle size of stabilized Cu NPs were calculated by XRD using Scherrer's formula and FT from the X-ray diffraction data. Thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry (DSC), FT-IR, second-derivative spectra, and 2D-IR correlation analysis were applied to studying the stabilization mechanism of Cu NPs by NaAlg molecules. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of stabilized Cu NPs against five bacterial strains (Staphylococccus aureus ATCC 6538P, Escherichia coli ATCC 25922 and O157: H7, and Salmonella enterica serovar Typhimurium ATCC 13311 and 14028) were evaluated with macrodilution, agar dilution plate count, and well-diffusion methods. On the basis of the semiquantitative analysis, there was a direct correlation between the reducing agent ratio and the percentage of zerovalent Cu. This was confirmed with the statistical analysis of population of Cu NPs from TEM micrographs. At lower reducing agent ratios, two phases coexist (Cu₂O and zerovalent Cu) due to incomplete reduction of copper ions by the reducing agent; however, at higher reducing agent ratios, the Cu NPs consist mainly of zerovalent Cu. Crystallite size and relative particle size of stabilized Cu NPs showed considerable differences in results and tendencies in respect to TEM analysis. However, the relative particle size values obtained from FT of XRD data agreed well with the histograms from the TEM observations. From FT results, the relative particle size and reducing agent ratio of stabilized Cu NPs showed an inverse correlation. The incomplete reduction of copper ions at lower reducing agent ratios was also confirmed by DSC studies. FT-IR and 2D-IR correlation spectra analysis suggested the first event involved in the stabilization of Cu NPs is their electrostatic interaction with -C=O of carboxylate groups of NaAlg, followed by the interaction with the available O-C-O⁻, and finally with the -OH groups. Bacterial susceptibility to stabilized nanoparticles was found to vary depending on the bacterial strains. The lowest MIC and MBC of stabilized Cu NPs ranged between 2 mg/L and 8 mg/L for all studied strains. Disk-diffusion studies with both E. coli strains revealed greater effectiveness of the stabilized Cu NPs compared to the positive controls (cloxacillin, amoxicillin, and nitrofurantoin). S. aureus showed the highest sensitivity to stabilized Cu NPs compared to the other studied strains. Cu NPs were successfully synthesized via chemical reduction assisted with microwave heating. Average particle size, polydispersity, and phase composition of Cu NPs depended mainly on the reducing agent ratio. Likewise, thermal stability and antibacterial activity of stabilized Cu NPs were affected by their phase composition. Because of the carboxylate groups in polymer chains, the structural changes of stabilized Cu NPs are different from those of NaAlg. NaAlg acted as a size controller and stabilizing agent of Cu NPs, due to their ability to bind strongly to the metal surface. Our study on the stabilizing agent-dependent structural changes of stabilized NPs is helpful for wide application of NaAlg as an important biopolymer.


A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane.
Zinc is essential to a wide range of cellular processes; therefore, it is important to elucidate the molecular mechanisms of zinc homeostasis. To date, no zinc transporters expressed at the enterocyte apical membrane, and so essential to mammalian zinc homeostasis, have been discovered. We identified hZTL1 as a human expressed sequence tag with homology to the basolateral enterocyte zinc transporter ZnT1 and deduced the full-length cDNA sequence by PCR. The protein of 523 amino acids belongs to the cation diffusion facilitator family of membrane transporters. Unusually, the predicted topology comprises 12 rather than 6 transmembrane domains. ZTL1 mRNA was detected by reverse transcription-PCR in a range of mouse tissues. A Myc-tagged hZTL1 clone was expressed in transiently transfected polarized human intestinal Caco-2 cells at the apical membrane. Expression of hZTL1 mRNA in Caco-2 cells increased with zinc supplementation of the nutrient medium; however, in the placental cell line JAR hZTL1 appeared not to be regulated by zinc. Heterologous expression of hZTL1 in Xenopus laevis oocytes increased zinc uptake across the plasma membrane. The localization, regulatory properties, and function of hZTL1 indicate a role in regulating the absorption of dietary zinc across the apical enterocyte membrane.


Experimental study and analysis of lubricants dispersed with nano Cu and TiO2 in a four-stroke two wheeler.
The present investigation summarizes detailed experimental studies with standard lubricants of commercial quality known as Racer-4 of Hindustan Petroleum Corporation (India) dispersed with different mass concentrations of nanoparticles of Cu and TiO2. The test bench is fabricated with a four-stroke Hero-Honda motorbike hydraulically loaded at the rear wheel with proper instrumentation to record the fuel consumption, the load on the rear wheel, and the linear velocity. The whole range of data obtained on a stationery bike is subjected to regression analysis to arrive at various relationships between fuel consumption as a function of brake power, linear velocity, and percentage mass concentration of nanoparticles in the lubricant. The empirical relation correlates with the observed data with reasonable accuracy. Further, extension of the analysis by developing a mathematical model has revealed a definite improvement in brake thermal efficiency which ultimately affects the fuel economy by diminishing frictional power in the system with the introduction of nanoparticles into the lubricant. The performance of the engine seems to be better with nano Cu-Racer-4 combination than the one with nano TiO2.


Preventive effects of Resveratrol against azoxymethane-induced testis injury in rats.
To evaluate the protective effects of Resveratrol (RES) on azoxymethane (AOM)-induced testicular damage using histopathology and biochemical analyses, 28 male rats were randomly divided into four groups. Groups were control, RES, AOM and ARES. At the end of the 7 weeks, following routine tissue processing procedure, testis sections were stained with haematoxylin-eosin and Masson's trichrome. The blood samples were taken for biochemical analysis of testosterone, total oxidative stress, total antioxidant status and oxidative stress index. Degenerative changes in the seminiferous tubules such as atrophy, loss in the number of germ cells and arrested spermatogenic cell, and increase in the connective tissue of the tunica albuginea in the groups with AOM treatment were found. RES treatment (ARES) reduced the number of affected seminiferous tubules significantly (p < .05) compared to AOM alone. The testosterone levels in AOM group were significantly lower than in the control group (p < .05). The total oxidative stress levels were significantly higher in AOM group compared to control group (p < .05). The total antioxidant status levels in ARES group were significantly higher than in the AOM group (p < .05). This study results suggest that an antioxidant like Resveratrol may be useful for decreasing the harmful effects of azoxymethane.


[Results of intradermal tests with toxoplasmin in a survey performed among mental patients admitted to the clinical surgical teaching hospital "10 de Octubre" in Havana].
Intradermal tests using toxoplasmin were performed among three hundred mentally handicapped patients admitted to the "10 de Octubre" Clinical-Surgical Teaching Hospital in Havana between 1976--1977 and 100 healthy subjects. A statistically significant difference between reactors among patients (54,7%) and reactors among healthy subjects (30,0%) was found. Results are compared to those from a similar paper performed in the Psychiatric Hospital of Havana in 1967. It is concluded that the higher the severity of affections the higher the percentage of reactors in the surveyed series.


Spirocyclic drimanes from the marine fungus Stachybotrys sp. strain MF347.
A novel spirocyclic drimane coupled by two drimane fragment building blocks 2 and a new drimane 1 were identified in mycelia and culture broth of Stachybotrys sp. MF347. Their structures were established by spectroscopic means. This is the first example of spirocyclic drimane coupled by a spirodihydrobenzofuranlactam unit and a spirodihydroisobenzofuran unit; and the connecting position being N-C instead of an N and N connecting unit. Strain MF347 produced also the known spirocyclic drimanes stachybocin A (12) and stachybocin B (11) featured by two sesquiterpene-spirobenzofuran structural units connected by a lysine residue; the known spirocyclic drimanes chartarlactam O (5); chartarlactam K (6); F1839A (7); stachybotrylactam (8); stachybotramide (9); and 2α-acetoxystachybotrylactam acetate (10); as well as ilicicolin B (13), a known sesquiterpene. The relative configuration of two known spirobenzofuranlactams (3 and 4) was determined. All compounds were subjected to biological activity tests. The spirocyclic drimane 2, 11, and 12, as well as the sesquiterpene 13, exhibited antibacterial activity against the clinically relevant methicillin-resistant Staphylococcus aureus (MRSA).


Treatment of saline wastewater in SBR aerobic granular reactors.
Fish canning effluents characterized by their salt content, up to 30 g NaCl/L, were treated, previously diluted to desired concentration, in a SBR where aerobic granular sludge was produced. The formation of mature aerobic granules occurred after 75 days of operation with 3.4 mm of diameter, SVI of 30 mL/g VSS and density around 60 g VSS/L-granule. Treated organic loading rates were up to 1.72 kg COD/(m3.d) with fully organic matter depletion. Ammonia nitrogen was removed via nitrification-denitrification up to 40% when nitrogen loading rates were of 0.18 kg N/(m3.d). The presence of salt in the treated effluent did not cause a detrimental effect on the operation of the reactor once the aerobic granules were formed.


How Well Do Molecular and Pedigree Relatedness Correspond, in Populations with Diverse Mating Systems, and Various Types and Quantities of Molecular and Demographic Data?
Kinship analyses are important pillars of ecological and conservation genetic studies with potentially far-reaching implications. There is a need for power analyses that address a range of possible relationships. Nevertheless, such analyses are rarely applied, and studies that use genetic-data-based-kinship inference often ignore the influence of intrinsic population characteristics. We investigated 11 questions regarding the correct classification rate of dyads to relatedness categories (relatedness category assignments; RCA) using an individual-based model with realistic life history parameters. We investigated the effects of the number of genetic markers; marker type (microsatellite, single nucleotide polymorphism SNP, or both); minor allele frequency; typing error; mating system; and the number of overlapping generations under different demographic conditions. We found that (i) an increasing number of genetic markers increased the correct classification rate of the RCA so that up to >80% first cousins can be correctly assigned; (ii) the minimum number of genetic markers required for assignments with 80 and 95% correct classifications differed between relatedness categories, mating systems, and the number of overlapping generations; (iii) the correct classification rate was improved by adding additional relatedness categories and age and mitochondrial DNA data; and (iv) a combination of microsatellite and single-nucleotide polymorphism data increased the correct classification rate if <800 SNP loci were available. This study shows how intrinsic population characteristics, such as mating system and the number of overlapping generations, life history traits, and genetic marker characteristics, can influence the correct classification rate of an RCA study. Therefore, species-specific power analyses are essential for empirical studies.


Predictive learning, prediction errors, and attention: evidence from event-related potentials and eye tracking.
Prediction error ("surprise") affects the rate of learning: We learn more rapidly about cues for which we initially make incorrect predictions than cues for which our initial predictions are correct. The current studies employ electrophysiological measures to reveal early attentional differentiation of events that differ in their previous involvement in errors of predictive judgment. Error-related events attract more attention, as evidenced by features of event-related scalp potentials previously implicated in selective visual attention (selection negativity, augmented anterior N1). The earliest differences detected occurred around 120 msec after stimulus onset, and distributed source localization (LORETA) indicated that the inferior temporal regions were one source of the earliest differences. In addition, stimuli associated with the production of prediction errors show higher dwell times in an eye-tracking procedure. Our data support the view that early attentional processes play a role in human associative learning.


Breast cancer posttreatment surveillance: diagnosis and management of recurrent disease.
Invasive breast cancer is the most common malignancy diagnosed in American women. The use of screening mammography and progress in adjuvant therapy has led to a steady decline in breast cancer mortality, and as the number of breast cancer survivors increases, there has been a marked increase in the number of patients enrolled in posttreatment surveillance programs.The majority of breast cancer recurrences occurs during the first decade after initial diagnosis with a peak incidence 2 to 5 years after diagnosis, although the number of recurrences for endocrine responsive cancer continues to rise afterward. The goal of posttreatment follow-up programs in patients with breast cancer is to detect potentially curable locoregional recurrences, second primary tumors, and the detection of systemic relapses. However, contrary to the long-held belief, most recurrences are symptomatic and occur during the interval between scheduled visits.


Toxicity mechanism in fetal lung fibroblast cells for multi-walled carbon nanotubes defined by chemical impurities and dispersibility.
Multi-walled carbon nanotubes (MWCNTs) are beneficial in a wide range of applications in fields such as electronics, optics and nano-medicine, so knowledge concerning their effect on human health is important. Physiochemical properties of MWCNTs can greatly affect their toxicity, however, there are no reports discussing the effect of size and chemical composition of MWCNTs on the toxic response of human lung cells. In this study, MWCNTs of two different purity grades were characterized and their toxic effects were compared on normal fetal lung fibroblast MRC-5 cells. The toxic effect on MRC-5 cells following 1-3 days exposure to low concentrations of research grade (RG) and industrial grade (IG) MWCNTs were studied using multiple biological assays. MWCNTs uptake in MRC-5 cells was analyzed using TEM. After physical and chemical analysis, RG-MWCNTs revealed contamination with MoS2 and were readily suspended in distilled water while IG-MWCNTs had no MoS2 contamination and much lower dispersibility. For a wide range of concentrations and exposure times, cells treated with RG-MWCNTs had distinctly reduced cell viability as compared to cells treated with IG-MWCNTs. Treatment with RG-MWCNTs resulted in high reactive oxygen/nitrogen species (ROS/RNS) levels indicating an oxidative stress mechanism while IG-MWCNT treated cells had low ROS/RNS amounts and a distorted cell membrane pointing towards a non-oxidative stress mechanism. Both agglomerates and individual MWCNTs were internalized efficiently by MRC-5 cells, which resulted in cell damage and ultimately cell death. Altogether, this study shows that the MoS2 contamination and size of MWCNTs' agglomerates affect the mechanism of toxicity in human fetal lung fibroblasts.


Papilledema in unicoronal synostosis: a rare finding.
Unicoronal synostosis results in frontal plagiocephaly and is preferably treated before the patient is 1 year of age to prevent intracranial hypertension (ICH). However, data on the prevalence of ICH in these patients is currently lacking. This study aimed to establish the prevalence of preoperative and postoperative signs of ICH in a large cohort of patients with unicoronal synostosis and to test whether there is a correlation between papilledema and occipitofrontal head circumference (OFC) curve stagnation in unicoronal synostosis. The authors included all patients with unicoronal synostosis treated before 2 years of age at a single center between 2003 and 2013. The presence of ICH was evaluated by routine fundoscopy. The OFC growth curve was analyzed for deflection and in relationship to signs of ICH. In total, 104 patients were included in this study, 84 (81%) of whom were considered to have nonsyndromic unicoronal synostosis. Preoperatively, none of the patients had papilledema as determined by fundoscopy (mean age at surgery 11 months). Postoperatively, 5% of patients with syndromic synostosis and 3% of those with nonsyndromic synostosis had papilledema, and this was confirmed by optical coherence tomography. Raised intracranial pressure was confirmed in 1 patient with syndromic unicoronal synostosis. Six of 78 patients had OFC stagnation, which was not significantly correlated to papilledema (p = 0.22). One child with syndromic unicoronal synostosis required repeated surgery for ICH (0.96%). Papilledema was not found in patients with unicoronal synostosis when they underwent surgery before the age of 1 year and was also very rare during follow-up. There was no relationship between papilledema and OFC stagnation.


Epidemiologic considerations in electroconvulsive therapy.
Data from the Monroe County (New York) Psychiatric Case Register were grouped for 1961 through 1965, 1966 through 1970, and 1971 through 1975 for comparisons of incidence, prevalence, mortality, and length of stay associated with electroconvulsive therapy (ECT). While incidence of first ECT series declined substantially from 1961 through 1965 to 1971 through 1975 in most age-sex groups, significant declines in prevalence of admissions involving ECT occurred only among young female patients. Both prevalence and incidence analyses showed increasing specificity over time of ECT use in cases of depression. Demographic characteristics associated with ECT were accounted for by diagnostic correlates. Mortality effects associated with use of ECT were not pronounced, though a lower rate of accidental and circulatory deaths in the ECT group was noted. Lengths of hospital stay for patients receiving ECT were generally longer than for other depression hospitalizations, both for first ECT and later ECT series.


Cognitive and behavioral status of low birth weight preterm children raised in a developing country at preschool age.
To assess cognitive and behavioral development at preschool age of children born preterm and with low birth weight and raised in a developing country. Prospective cross-sectional study of 80 neonates born in a university hospital in southern Brazil. Neuropsychological assessment at age 4-5 years included the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Conners' Parent Rating Scale-Revised, Denver test and neurological examination. Perinatal and early neuropsychomotor development information was collected from the database during follow-up. Results were related to birth weight, sex and gestational age. WPPSI scores were: total intelligence quotient (IQ) 88.00+/-16.96, verbal IQ 89.72+/-16.72, and executive IQ 88.12+/-15.71 for the group with less than 1,500 grams; and total IQ 91.11+/-14.73, verbal IQ 93.36+/-12.65, and executive IQ 90.20+/-16.06 for the group between 1,500 and 2,500 grams. The best scores were obtained in tests that evaluated capacity of abstraction and symbolization, picture completion and common perception, in which only 5% and 6.3% of the children had abnormal results, respectively. The lowest scores were obtained in tests that evaluated visual-motor coordination and flexibility-speed of reasoning, in which 27.5% and 16.3% of the children had abnormal results, respectively. A total of 32.5% had abnormal results in the arithmetic tests. Behaviors related to attention deficit/hyperactivity disorder (ADHD) were observed in 48% of the sample. Low score in the Bayley Mental Scale and abnormal result in the Denver test were significantly correlated to ADHD (p = 0.017 and p = 0.004). Abnormal results in the Bayley Mental Scale (p < 0.001), Denver test (p < 0.001) and neurological examination (p = 0.002) were associated with lower IQ. The results revealed an increased incidence of behavioral and cognitive disorders at preschool age.


The spread of tomato yellow leaf curl virus from the Middle East to the world.
The ongoing global spread of Tomato yellow leaf curl virus (TYLCV; Genus Begomovirus, Family Geminiviridae) represents a serious looming threat to tomato production in all temperate parts of the world. Whereas determining where and when TYLCV movements have occurred could help curtail its spread and prevent future movements of related viruses, determining the consequences of past TYLCV movements could reveal the ecological and economic risks associated with similar viral invasions. Towards this end we applied Bayesian phylogeographic inference and recombination analyses to available TYLCV sequences (including those of 15 new Iranian full TYLCV genomes) and reconstructed a plausible history of TYLCV's diversification and movements throughout the world. In agreement with historical accounts, our results suggest that the first TYLCVs most probably arose somewhere in the Middle East between the 1930s and 1950s (with 95% highest probability density intervals 1905-1972) and that the global spread of TYLCV only began in the 1980s after the evolution of the TYLCV-Mld and -IL strains. Despite the global distribution of TYLCV we found no convincing evidence anywhere other than the Middle East and the Western Mediterranean of epidemiologically relevant TYLCV variants arising through recombination. Although the region around Iran is both the center of present day TYLCV diversity and the site of the most intensive ongoing TYLCV evolution, the evidence indicates that the region is epidemiologically isolated, which suggests that novel TYLCV variants found there are probably not direct global threats. We instead identify the Mediterranean basin as the main launch-pad of global TYLCV movements.


Neonatal Presentation of Unremitting Inflammatory Bowel Disease.
Very-early-onset inflammatory bowel disease (VEO-IBD) has a distinct phenotype and should be considered a specific entity. VEO-IBD presents with very severe clinical pictures and is frequently known by an indeterminate colitis whose clinical remission is unmanageable. This study examines the case of a neonate with VEO-IBD, not responding to medical and surgical treatment. A 7-day-old Iranian female neonate presented with severe bloody diarrhea, poor feeding, abdominal distention, and dehydration suggesting severe proctocolitis due to an allergy to the protein in cow's milk. The condition did not respond to the elimination of diet for 1 month. Infections, celiac disease, and cystic fibrosis were excluded. Immunological investigations were negative, but antineutrophil cytoplasmic antibodies were positive. Due to the neonate's persistent symptoms and failure to thrive, upper and lower endoscopies were performed, showing ulcerative colitis. At the age of 4 months, she presented with signs and symptoms of toxic colitis and acute intestinal perforation, which prompted an emergency laparotomy. Due to the necrosis of the colon, hemicolectomy and colostomy were done. The patient was resuscitated and rehabilitated and was given glucocorticoid and mesalamine. We believe that the incidence of this problem is increasing, as is shown by the rise in the number of children under 10 years old being diagnosed. These patients require more aggressive therapeutic interventions than older IBD patients to achieve complete remission because they are more likely to have extensive colonic disease.


Importance of measurement site on assessment of lesion-specific ischemia and diagnostic performance by coronary computed tomography Angiography-Derived Fractional Flow Reserve.
Values of fractional flow reserve (FFRCT) by coronary computed tomography angiography (CTA) decline from the ostium to the terminal vessel, irrespective of stenosis severity. The purpose of this study is to determine if the site of measurement of FFRCT impacts assessment of ischemia and its diagnostic performance relative to invasive FFR (FFRINV). 1484 patients underwent FFRCT; 1910 vessels were stratified by stenosis severity (normal; <25%, 25-50%, 50-70%, and >70% stenosis). The rates of positive FFRCT (≤0.8) were determined by measuring FFRCT from the terminal vessel and from distal-to-the-lesion. Reclassification rates from positive to negative FFRCT were calculated. Diagnostic performance of FFRCT relative to FFRINV was evaluated in 182 vessels using linear regression, Bland Altman analysis, and receiver operating characteristic (ROC) curves. Positive FFRCT was identified in 24.9% of vessels using terminal vessel FFRCT and 10.1% using FFRCT distal-to-the-lesion (p < 0.001). FFRCT obtained distal-to-the-lesion resulted in reclassification of 59.6% of positive terminal FFRCT to negative FFRCT. Relative to FFRINV, there were improvements in specificity (50% to 86%, p < 0.001), diagnostic accuracy (65% to 88%, p < 0.001), positive predictive value (50% to 78%, p < 0.001), and area-under-the-curve (AUC, 0.83 to 0.91, p < 0.001) when FFRCT was measured distal-to-the-lesion. FFRCT values from the terminal vessel should not be used to assess lesion-specific ischemia due to high rates of false positive results. FFRCT measured distal-to-the-lesion improves the diagnostic performance of FFRCT relative to FFRINV, ensures that FFRCT values are due to lesion-specific ischemia, and could reduce the rate of unnecessary invasive procedures.


Small RNA-Sequencing for Analysis of Circulating miRNAs: Benchmark Study.
Small RNA-sequencing (RNA-Seq) is being increasingly used for profiling of circulating microRNAs (miRNAs), a new group of promising biomarkers. Unfortunately, small RNA-Seq protocols are prone to biases limiting quantification accuracy, which motivated development of several novel methods. Here, we present comparison of all small RNA-Seq library preparation approaches that are commercially available for quantification of miRNAs in biofluids. Using synthetic and human plasma samples, we compared performance of traditional two-adaptor ligation protocols (Lexogen, Norgen), as well as methods using randomized adaptors (NEXTflex), polyadenylation (SMARTer), circularization (RealSeq), capture probes (EdgeSeq), or unique molecular identifiers (QIAseq). There was no single protocol outperforming others across all metrics. Limited overlap of measured miRNA profiles was documented between methods largely owing to protocol-specific biases. Methods designed to minimize bias largely differ in their performance, and contributing factors were identified. Usage of unique molecular identifiers has rather negligible effect and, if designed incorrectly, can even introduce spurious results. Together, these results identify strengths and weaknesses of all current methods and provide guidelines for applications of small RNA-Seq in biomarker research.


Temporal covariance model of human motion perception.
We propose a model of direction-sensitive units in human vision. It is a modified and elaborated version of a model by Reichardt [Z. Naturforsch . Teil B 12, 447 (1957)]. The model is applied to threshold experiments in which subjects view adjacent vertical bars with independently (typically sinusoidally), temporally modulated luminances. The subject must report whether the patterns moved to the left or to the right. According to the model, a basic motion-detecting unit consists of two subunits tuned to opposite directions. Each performs a spatial and temporal linear filtering of its input; outputs of the filters are multiplied, and the multiplied output is integrated (for a time that is long relative to the modulation period). The model's output consists of the difference between the subunit outputs. Direction of movement is indicated by the sign of the model output. Mathematical analysis of the model yielded several predictions that were confirmed experimentally. Specifically, we found that (1) performance with complex patterns can be predicted by spatiotemporal Fourier analysis that results in the segregation and linear addition in the output for different temporal frequencies; (2) under special conditions, performance depends on the product of adjacent bar amplitudes, offering strong support for the multiplication principle; (3) performance is unaffected by addition of stationary patterns; and (4) addition of homogeneous flicker normally produces no effect but under special conditions reverses perceived direction. These and other results confirm our model and reject several other models, including Reichardt 's original model.


Interactions of radiofrequency radiation-induced hyperthermia and 2-methoxyethanol teratogenicity in rats.
Radiofrequency (RF) radiation is used in a variety of workplaces. In addition to RF radiation, many workers are concurrently exposed to numerous chemicals; exposed workers include those involved with the microelectronics industry, plastic sealers, and electrosurgical units. The developmental toxicity of RF radiation is associated with the degree and duration of hyperthermia induced by the exposure. Previous animal research indicates that hyperthermia induced by an elevation in ambient temperature can potentiate the toxicity and teratogenicity of some chemical agents. We previously demonstrated that combined exposure to RF radiation (10 MHz) and the industrial solvent, 2-methoxyethanol (2ME), produces enhanced teratogenicity in rats. The purpose of the present research is to determine the effects of varying the degree and duration of hyperthermia induced by RF radiation (sufficient to maintain colonic temperatures at control [38.5], 39.0, 40.0, or 41.0 degrees C for up to 6 h) and 2ME (100 mg/kg) administered on gestation day 13 of rats. Focusing on characterizing the dose-response pattern of interactions, this research seeks to determine the lowest interactive effect level. Day 20 fetuses were examined for external and skeletal malformations. The results are consistent with previous observations. Significant interactions were observed between 2ME and RF radiation sufficient to maintain colonic temperatures at 41 degrees C for 1 h, but no consistent interactions were seen at lower temperatures even with longer durations. These data indicate that combined exposure effects should be considered when developing both RF radiation and chemical exposure guidelines and intervention strategies.


Changing Etiology in Liver Cirrhosis in Sapporo, Japan.
In Japan, preventive measures and antiviral therapy against acute or chronic viral infection had achieved remarkable progress in the 1980s or later. On the contrary, metabolic syndrome complicated with fatty liver has emerged as a public health concern to date. In the current study, we attempted to clarify etiological changes in liver cirrhosis treated in a single tertiary institute in Sapporo, Japan, from 1998 to 2016. Medical records of 1,166 patients (787 males, with mean of 64.9 ± 11.7 years), diagnosed as having liver cirrhosis for 19 years, were retrospectively reviewed to analyze etiology and clinical features. During the past 10 years, annual numbers of cirrhotic patients with chronic infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) decreased from 50 or more to 20 or less, and alcoholic liver disease or cryptogenic liver injury emerged as major cause of liver cirrhosis. Among 100 cirrhotic patients of unknown cause, nonalcoholic fatty liver disease (NAFLD) occupied almost 50% in 19 observational years. In order to control the rising trend in NAFLD related with metabolic syndrome, preventive measures including education in society would be required in Japan. How to cite this article: Kang J-H, Matsui T. Changing Etiology in Liver Cirrhosis in Sapporo, Japan. Euroasian J Hepato-Gastroenterol 2018;8(1):77-80.


Occurrence of arginine deiminase pathway enzymes in arginine catabolism by wine lactic Acid bacteria.
l-Arginine, an amino acid found in significant quantities in grape juice and wine, is known to be catabolized by some wine lactic acid bacteria. The correlation between the occurrence of arginine deiminase pathway enzymes and the ability to catabolize arginine was examined in this study. The activities of the three arginine deiminase pathway enzymes, arginine deiminase, ornithine transcarbamylase, and carbamate kinase, were measured in cell extracts of 35 strains of wine lactic acid bacteria. These enzymes were present in all heterofermentative lactobacilli and most leuconostocs but were absent in all the homofermentative lactobacilli and pediococci examined. There was a good correlation among arginine degradation, formation of ammonia and citrulline, and the occurrence of arginine deiminase pathway enzymes. Urea was not detected during arginine degradation, suggesting that the catabolism of arginine did not proceed via the arginase-catalyzed reaction, as has been suggested in some earlier studies. Detection of ammonia with Nessler's reagent was shown to be a simple, rapid test to assess the ability of wine lactic acid bacteria to degrade arginine, although in media containing relatively high concentrations (>0.5%) of fructose, ammonia formation is inhibited.


Novel inhibitors of poly(ADP-ribose) synthetase.
In a search for new inhibitors of the nuclear enzyme poly(ADP-ribose) synthetase, it was found that various benzamides substituted in the 3-position were the most inhibitory compounds found to date. Two of the benzamides, 3-aminobenzamide and 3-methoxybenzamide, were found to be competitive inhibitors, with Ki values or less than 2 microM.


SU-E-J-129: Target-Specific Optimization of Four-Dimensional Cone Beam Computed Tomography.
Undersampling artifacts are a major problem in four-dimensional cone-beam computed tomography (4D-CBCT) and may compromise evaluation of target motion. The role of the target characteristics in scan parameter selection has not been previously investigated. In this work, we evaluated 4D-CBCT performance by assessing the accuracy of target motion measurements for various target sizes and motions. The results may serve as patient-specific guidelines for selection of scan parameters in 4D-CBCT. We acquired 4D-CBCT scans of a moving phantom consisting of six water-filled sphere targets of sizes 10 to 37 mm, with various scan times ranging from 30 sec to 3 min. Two different (3-sec and 6-sec) periods of motions were tested. We used automatic image registration to extract the target motion trajectories and evaluated the accuracy of the measurement for the various target sizes and motions for various combinations of scan parameters. The most important object parameter to 4D-CBCT performance was the period of motion. Measurements for the 6-sec motion were always systematically less accurate than measurements for the 3-sec motion for 34 of 36 target sizes/motions for any given scan time. For any given target size, a 45-sec scan for the 3-sec motion yielded nearly equivalent accuracy to a 3-min scan for a 6-sec motion. The second most important parameter was the target size. A 1-min scan was needed for sub-mm motion measurement accuracy of 28-mm target, whereas a 1.5-min scan was needed for the 22-mm target. For all sizes and motions, temporal blurring was observed when the number of phases was fewer than 8. Scan time should be set according to target size and motion. We have provided figures that provide the minimum scan time needed to achieve the particular motion measurement accuracy for a particular size and period of motion.


Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-to-target" clinical management strategy using an evidence-based expert consensus process. A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7-10 on a 10-point rating scale (where 10=agree completely). The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn's disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0-1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target. Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life.


Repression of Wnt signaling by a Fer-type nonreceptor tyrosine kinase.
The Wnt signaling pathway must be properly modulated to ensure an appropriate output: pathological conditions result from either insufficient or excessive levels of Wnt signal. For example, hyperactivation of the Wnt pathway is associated with various cancers and subnormal Wnt signaling can lead to increased invasiveness of tumor cells. We found that the Caenorhabditis elegans ortholog of the Fer nonreceptor tyrosine kinase, FRK-1, limits Wnt signaling by preventing the adhesion complex-associated β-catenin, HMP-2, from participating in Wnt-dependent specification of the endoderm during embryogenesis. Removal of FRK-1 function results in relocalization of HMP-2 to the nucleus of epidermal cells, and allows it to substitute for WRM-1, the nuclear β-catenin that normally transduces the Wnt signal during endoderm development. APR-1, the C. elegans APC ortholog, is similarly required to prevent HMP-2 relocalization and keeps it from participating in Wnt signal transduction; this finding partially explains the paradoxical observation that APR-1 acts either negatively or positively in Wnt signaling, depending on context. The apparent hyperactivation of the Wnt response in the absence of FRK-1 leads to hyperproliferation in the endoderm, as is also seen when WRM-1 is overexpressed in wild-type embryos. The specification and proliferation activities of Wnt signaling are separable: although the Tcf/Lef factor POP-1 acts in Wnt-dependent endoderm specification, it is not apparently required for hyperproliferation resulting from excessive Wnt signaling. These findings highlight a role for a Fer-type kinase in setting the proper levels of Wnt signaling and demonstrate the importance of this modulation in ensuring appropriate cell division.


Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review.
Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients. Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE. In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity. Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC.


Bisphenol A induces a profile of tumor aggressiveness in high-risk cells from breast cancer patients.
Breast cancer outcome is highly variable. Whether inadvertent exposure to environmental xenobiotics evokes a biological response promoting cancer aggressiveness and a higher probability of tumor recurrence remains unknown. To determine specific molecular alterations which arise in high-risk breast tissue in the presence of the ubiquitous xenoestrogen, bisphenol A (BPA), we used nonmalignant random periareolar fine-needle aspirates in a novel functional assay. Early events induced by BPA in epithelial-stromal cocultures derived from the contralateral tissue of patients with breast cancer included gene expression patterns which facilitate apoptosis evasion, endurance of microenvironmental stress, and cell cycle deregulation without a detectable increase in cell numbers. This BPA response profile was significantly associated with breast tumors characterized by high histologic grade (P < 0.001) and large tumor size (P = 0.002), resulting in decreased recurrence-free patient survival (P < 0.001). Our assays show a biological "fingerprint" of probable prior exposure to endocrine-disrupting agents, and suggest a scenario in which their presence in the microenvironmental milieu of high-risk breast tissue could play a deterministic role in establishing and maintaining tumor aggressiveness and poor patient outcome.


Directed early axonal outgrowth from retinal transplants into host rat brains.
Axons from retinae transplanted to the brain stem of neonatal rats exhibit two patterns of outgrowth that can be experimentally uncoupled from each other depending upon the location of the graft. Retinae placed close to the surface of the rostral brain stem (as much as 5 mm from the tectum) emit axons that project toward the superior colliculus along the subpial margin of the rostral brain stem. In contrast, axons from grafts embedded deep within the midbrain parenchyma project through the neuropil directly to the overlying superior colliculus, as long as the retina is within about 1 mm of the tectal surface. The present study shows that, as long as the retina is located outside the superior colliculus, and regardless of whether the axons derive from grafts in subpial or intraparenchymal locations, the earliest projections are oriented towards the superior colliculus. We have also found, however, that axons from retinae transplanted directly onto the superior colliculus can form projections that extend along the subpial margin away from the tectum. There are several major conclusions that may be drawn from these observations. First, the final tectopetal, transplant-derived projection does not result from the reorganization of an initially random outgrowth but is directed from the start toward an appropriate region of termination. Second, it appears that the interaction of retinal axons with a primary target alters the ability of the growth cone to respond to directional cues along the optic tract. Thus, although adding support to the proposal that optic axons attain the superior colliculus through an interaction involving substrates distributed along the optic tract and diffusible factors originating in the target region, it is increasingly clear that such interactions are likely to be complex and hierarchical.


A Review of the National Physical Activity Plans of Six Countries.
Architects of the United States national physical activity plan can benefit from a thorough understanding of national physical activity plans from other nations. The purpose of this paper was to search for and analyze comprehensive national physical activity plan documents that can best inform the development of the U.S. plan. Electronic databases were searched for national physical activity plan documents, yielding 252 documents from 56 countries. After eliminating documents that were not written in English, did not address physical activity primarily, and did not meet our definition of a national physical activity plan, we were left with physical activity plans from 6 countries-Australia, United Kingdom, Scotland, Sweden, Northern Ireland, and Norway. Architects of the U.S. plan can learn as much from what was present in many documents as from what was absent. Examples of recommended components of national plans have been identified and highlighted for each of the 6 countries. Missing from all but 1 national plan document was a detailed process for accountability. Providing a clear path and detailed process of accountability will assist greatly in measuring short- and long-term success of the U.S. plan.


Defects of metabolism of fatty acids in the sudden infant death syndrome.
Two hundred consecutive cases of the sudden infant death syndrome were reviewed for the presence of fat in the liver; 14 showed diffuse panlobular microvesicular fatty change indistinguishable from that found in Reye's syndrome. Samples of frozen liver were available in five of the 14 cases; histochemical analysis showed well preserved cytochrome oxidase and succinate dehydrogenase activity in all five, uncharacteristic of Reye's syndrome. Fatty acyl-coenzyme A dehydrogenase activity in the liver was assayed biochemically in two of the same five cases with severe hepatic fatty infiltration; both showed a defect in medium chain acyl-coenzyme A dehydrogenase activity using the substrate octanoyl-coenzyme A. Both cases also showed cerebral oedema in association with fatty infiltration of renal tubules, myocardium, and skeletal muscle, characteristic of Reye's syndrome. It is concluded that diffuse panlobular microvesicular fatty change of the liver in victims of the sudden infant death syndrome, although essentially non-specific, indicates that the state of mitochondrial enzymes should be investigated.


Behavioral phenotypes of Disc1 missense mutations in mice.
To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.


Age-Related Differences in Socio-demographic and Behavioral Determinants of HIV Testing and Counseling in HPTN 043/NIMH Project Accept.
Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post-intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio-demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18-24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61-0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05-1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85-2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08-1.36), and marriage (aOR 1.55; 95% CI 1.37-1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18-24 vs. 25-32 years).


The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) to detect gene-environment interactions for cancer.
The Japan Multi-institutional Collaborative Cohort Study (J-MICC Study) launched in 2005, supported by a research grant for Scientific Research on Special Priority Areas of Cancer from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Although the main purpose is to confirm and detect gene-environment interactions of lifestyle-related diseases, mainly of cancer, through the cohort analyses, it includes cross-sectional analyses on lifestyle factors, biomarkers, and genotypes, as well as confirmation/ screening of new biomarkers usable for early diagnosis of cancer. The endpoints are cancer diagnosis and death. The participants diagnosed as cancer will be identified through population-based cancer registries, hospital cancer registries, mail questionnaires, questionnaires at repeated visits, death certificates, health insurance data, and second survey questionnaires. Subjects are individuals aged 35 to 69 years enrolled from respondents to study announcements in specified areas, inhabitants attending health checkup examinations by local governments, visitors at health checkup centers, and patients at a cancer hospital. The number of subjects was set to be 100,000 throughout Japan. The enrollment period is from April 2005 to March 2010. The second survey is scheduled 5 years after their enrollment. The participants will be followed until 2025. The J-MICC Central Office is placed at Nagoya University Graduate School of Medicine. Ten participating research groups (Cohort Study Executing Groups) send baseline data and blood samples (buffy coat, serum, and plasma) anonymized with an identification number (J-MICC ID) to the Central Office. The data of second survey and follow-up will be linked using J-MICC ID. This study is expected to produce many findings on lifestyle and genetic traits associated with lifestyle-related diseases including cancer among Japanese.


Transformation of stimulus value signals into motor commands during simple choice.
Decision-making can be broken down into several component processes: assigning values to stimuli under consideration, selecting an option by comparing those values, and initiating motor responses to obtain the reward. Although much is known about the neural encoding of stimulus values and motor commands, little is known about the mechanisms through which stimulus values are compared, and the resulting decision is transmitted to motor systems. We investigated this process using human fMRI in a task where choices were indicated using the left or right hand. We found evidence consistent with the hypothesis that value signals are computed in the ventral medial prefrontal cortex, they are passed to regions of dorsomedial prefrontal cortex and intraparietal sulcus, implementing a comparison process, and the output of the comparator regions modulates activity in motor cortex to implement the choice. These results describe the network through which stimulus values are transformed into actions during a simple choice task.


Emergency gynecologic imaging.
Acute pelvic pain in the female patient can have myriad presentations and, depending on the diagnosis, profound consequences. In the pregnant patient with pelvic pain or bleeding, an ectopic pregnancy must be first excluded. Ultrasound is important in determining the size and location of the ectopic pregnancy, and presence of bleeding, which in turn helps guide treatment decisions. Subchorionic or subplacental bleeds in an intrauterine pregnancy may also present with vaginal bleeding with consequences dependent on gestational age and size of bleed. In the postpartum female suspected to have retained products of conception, sonographic findings may vary from a thickened endometrial stripe to an echogenic mass with associated marked vascularity, often mimicking an arterial-venous malformation. In the nonpregnant patient, early diagnosis and treatment of ovarian torsion can preserve ovarian function. Other causes of peritoneal irritation may also cause acute pelvic pain including a ruptured hemorrhagic cyst or ruptured endometrioma. When pelvic inflammatory disease is suspected, imaging is used to evaluate for serious associated complications including the presence of a tuboovarian abscess or peritonitis. While leiomyomas of the uterus are largely asymptomatic, a leiomyoma that undergoes necrosis, torsion or prolapse through the cervix may be associated with acute severe pain or bleeding. The imaging features of these and other important clinical entities in the female pelvis will be presented.


A new zebrafish model of oro-intestinal pathogen colonization reveals a key role for adhesion in protection by probiotic bacteria.
The beneficial contribution of commensal bacteria to host health and homeostasis led to the concept that exogenous non-pathogenic bacteria called probiotics could be used to limit disease caused by pathogens. However, despite recent progress using gnotobiotic mammal and invertebrate models, mechanisms underlying protection afforded by commensal and probiotic bacteria against pathogens remain poorly understood. Here we developed a zebrafish model of controlled co-infection in which germ-free zebrafish raised on axenic living protozoa enabled the study of interactions between host and commensal and pathogenic bacteria. We screened enteric fish pathogens and identified Edwardsiella ictaluri as a virulent strain inducing a strong inflammatory response and rapid mortality in zebrafish larvae infected by the natural oro-intestinal route. Using mortality induced by infection as a phenotypic read-out, we pre-colonized zebrafish larvae with 37 potential probiotic bacterial strains and screened for survival upon E. ictaluri infection. We identified 3 robustly protective strains, including Vibrio parahaemolyticus and 2 Escherichia coli strains. We showed that the observed protective effect of E. coli was not correlated with a reduced host inflammatory response, nor with the release of biocidal molecules by protective bacteria, but rather with the presence of specific adhesion factors such as F pili that promote the emergence of probiotic bacteria in zebrafish larvae. Our study therefore provides new insights into the molecular events underlying the probiotic effect and constitutes a potentially high-throughput in vivo approach to the study of the molecular basis of pathogen exclusion in a relevant model of vertebrate oro-intestinal infection.


Listeria monocytogenes is resistant to lysozyme through the regulation, not the acquisition, of cell wall-modifying enzymes.
Listeria monocytogenes is a Gram-positive facultative intracellular pathogen that is highly resistant to lysozyme, a ubiquitous enzyme of the innate immune system that degrades cell wall peptidoglycan. Two peptidoglycan-modifying enzymes, PgdA and OatA, confer lysozyme resistance on L. monocytogenes; however, these enzymes are also conserved among lysozyme-sensitive nonpathogens. We sought to identify additional factors responsible for lysozyme resistance in L. monocytogenes. A forward genetic screen for lysozyme-sensitive mutants led to the identification of 174 transposon insertion mutations that mapped to 13 individual genes. Four mutants were killed exclusively by lysozyme and not other cell wall-targeting molecules, including the peptidoglycan deacetylase encoded by pgdA, the putative carboxypeptidase encoded by pbpX, the orphan response regulator encoded by degU, and the highly abundant noncoding RNA encoded by rli31. Both degU and rli31 mutants had reduced expression of pbpX and pgdA, yet DegU and Rli31 did not regulate each other. Since pbpX and pgdA are also present in lysozyme-sensitive bacteria, this suggested that the acquisition of novel enzymes was not responsible for lysozyme resistance, but rather, the regulation of conserved enzymes by DegU and Rli31 conferred high lysozyme resistance. Each lysozyme-sensitive mutant exhibited attenuated virulence in mice, and a time course of infection revealed that the most lysozyme-sensitive strain was killed within 30 min of intravenous infection, a phenotype that was recapitulated in purified blood. Collectively, these data indicate that the genes required for lysozyme resistance are highly upregulated determinants of L. monocytogenes pathogenesis that are required for avoiding the enzymatic activity of lysozyme in the blood.


[Medication errors with concentrated potassium intravenous solutions: Data of the literature, context and prevention].
Accidental direct intravenous injection of a concentrated solution of potassium often leads to patient death. In France, recommendations of healthcare agencies to prevent such accidents cover only preparation and intravenous infusion conditions. Accidents continue to occur in French hospitals. These facts demonstrate that these recommendations are insufficient and ineffective to prevent such deaths, especially those occurring during a catheter flushing. This article reviews the measures able to reduce the number of accidents. Countries which removed concentrated ampoules from ward stocks observed a decrease of the number of accidental deaths. This withdrawal, recommended by the World Health Organization, is now part of standards in studies aimed at determining the safety of care in hospitals. However, removal alone is insufficient to eliminate the risk. The combination with other measures should be considered. These measures are the provision of a combination of diluted intravenous ready to use solutions, the promotion of the oral route with tablets and oral solutions for potassium replenishment and to make available products with safeguards to prevent single shot intravenous injection. Studies aimed at determining the consequences on preventing concentrated potassium accidents of a widespread distribution of isotonic sodium chloride pre-filled ready-to-use syringes for catheter flushing should be performed.


Relaxation oscillation in Er3+-doped and Yb3+/Er3+ co-doped fiber grating lasers.
Relaxation oscillations in Er(3+)-doped and Yb(3+)/Er(3+) co-doped fiber grating lasers were investigated. Intensity noise models were established for both cases in which the fluctuations of pump power and cavity loss were analyzed. Simulation indicates that the relaxation oscillation is induced by the pump power fluctuation, and fluctuation of the cavity loss can broaden the relaxation oscillation peak and enhance the amplitude. The relaxation oscillation of a laser with Er(3+)-doped fiber exhibits a lower frequency and larger amplitude than that of an Yb(3+)/Er(3+) co-doped fiber grating laser. Distributed Bragg reflector fiber grating lasers with Er(3+)-doped fiber and Yb(3+)/Er(3+) co-doped fiber were fabricated, and the relaxation oscillations were measured. For the former, the relaxation oscillation frequency is at the magnitude of several hundreds of kilohertz and linearly shifts toward the higher frequency with the pump power. For the latter, no obvious relaxation oscillation was measured.


Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. I. Mechanism and evidence of functional significance.
Tenidap is a novel anti-inflammatory and antiarthritic agent that in clinical studies of rheumatoid arthritis patients, displays symptomatic efficacy superior to nonsteroidal anti-inflammatory drugs (NSAIDs) and equivalent to combinations of NSAIDs and second line agents. Clinical and preclinical biochemical studies have demonstrated that tenidap combines cytokine modulation with suppression of prostaglandin biosynthesis. To better understand tenidap's mechanism of action, in vitro studies of intracellular pH (pHi) were conducted. In cells loaded with the pH-sensitive fluorescence dye 2',7'-bis-(2-carboxyethyl)-5-(and -6) carboxyfluorescein, tenidap, but not NSAIDs, caused a rapid and sustained acidification of the cytoplasmic compartment. Tenidap did not act as a proton ionophore, as it did not dissipate the low pH within lysosomes. Mammalian cells regulate pHi through the concerted action of a number of specific transport proteins, including sodium-proton antiporters and chloride-bicarbonate exchangers. Tenidap did not alter pHi via inhibition of the sodium-proton antiporter, but inhibited activity of chloride-bicarbonate exchangers, as did UK5099, a known anion-transport inhibitor that also lowers pHi. This similar activity suggests that the pHi change is coupled to anion transport inhibition. As a result of the pHi change, tenidap affected pH-dependent cellular activities. Tenidap inhibited mannose 6-phosphate receptor-mediated endocytosis, inhibited protein synthesis, and stimulated accumulation of the amino acid leucine. Effects on these cellular processes rapidly reversed when tenidap was removed from the culture medium. Tenidap's in vitro activities were highly dependent on the medium composition; protein content, pH, and bicarbonate concentration all were important factors that influenced activity. These results indicate that tenidap is a potent anion-transport inhibitor and modulator of pHi. Within the appropriate cell or tissue microenvironment, these activities may contribute to tenidap's novel therapeutic profile.


[Factors associated with benzodiazepine prescription by local health services in Coronel Fabriciano, Minas Gerais State, Brazil].
Numerous countries have witnessed increasing misuse of benzodiazepines. This cross-sectional study assessed the factors associated with prescription of benzodiazepines for users of the Municipal Health Service in Colonel Fabriciano, Minas Gerais State, Brazil. Data were collected from official records on drug prescription (n = 1,866) from September to October 2006. Bivariate and multivariate analyses using Poisson regression were performed. Prolonged benzodiazepine use was independently associated with benzodiazepine type and patient participation in health programs. Concomitant use of other psychoactive drugs was independently associated with age and participation in health programs. Type of benzodiazepine (clonazepam or diazepam) was independently associated with age and gender, as well as with participation in health programs. Factors associated with benzodiazepine prescription show the problem's extent and should be considered in planning interventions to rationalize the use of these drugs in Brazil, particularly through health program planning.


Efficacy of acidic electrolyzed water for microbial decontamination of cucumbers and strawberries.
An examination was made of the efficacy of acidic electrolyzed water (AcEW, 30 ppm free available chlorine), ozonated water (5 ppm ozone), and a sodium hypochlorite solution (NaOCl, 150 ppm free available chlorine) for use as potential sanitizers of cucumbers and strawberries. AcEW and NaOCl reduced the aerobic mesophiles naturally present on cucumbers within 10 min by 1.4 and 1.2 log CFU per cucumber, respectively. The reduction by ozonated water (0.7 log CFU per cucumber) was significantly less than that of AcEW or NaOCl (P < or = 0.05). Cucumbers washed in alkaline electrolyzed water for 5 min and then treated with AcEW for 5 min showed a reduction in aerobic mesophiles that was at least 2 log CFU per cucumber greater than that of other treatments (P < or = 0.05). This treatment was also effective in reducing levels of coliform bacteria and fungi associated with cucumbers. All treatments offered greater microbial reduction on the cucumber surface than in the cucumber homogenate. Aerobic mesophiles associated with strawberries were reduced by less than 1 log CFU per strawberry after each treatment. Coliform bacteria and fungi associated with strawberries were reduced by 1.0 to 1.5 log CFU per strawberry after each treatment. Microbial reduction was approximately 0.5 log CFU per strawberry greater on the strawberry surface than in the strawberry homogenate. However, neither treatment was able to completely inactivate or remove the microorganisms from the surface of the cucumber or strawberry.


The dog as an animal model for bladder and urethral urothelial carcinoma: Comparative epidemiology and histology.
Despite the recent approval of several novel agents for patients with metastatic urothelial carcinoma (UC), survival in this setting remains poor. As such, continued investigation into novel therapeutic options remains warranted. Pre-clinical development of novel treatments requires an animal model that accurately simulates the disease in humans. The aim of the present study was to evaluate the dog as an animal model for human UC. A total of 260 cases of spontaneous, untreated canine primary urethral and urinary bladder UC, were epidemiologically and histologically assessed and classified based on the current 2016 World Health Organization (WHO) tumor classification system. Canine data was compared with human data available from scientific literature. The mean age of dogs diagnosed with UC was 10.22 years (range, 4-15 years), which is equivalent to 60-70 human years. The results revealed a high association between UC diagnosis with the female sex [odds ratio (OR) 3.51; 95% confidence interval (CI) 2.57-4.79; P<0.001], surgical neutering (OR 4.57; 95% CI 1.87-11.12; P<0.001) and breed (OR 15.11 for Scottish terriers; 95% CI 8.99-25.41; P<0.001). Based on the 2016 WHO tumor (T), node and metastasis staging system, the primary tumors were characterized as T1 (38%), T2a (28%), T2b (13%) and T3 (22%). Non-papillary, flat subgross tumor growth was strongly associated with muscle invasion (OR 31.00; P<0.001). Irrespective of subgross growth pattern, all assessable tumors were invading beyond the basement membrane compatible with infiltrating UC. Conventional, not further classifiable infiltrating UC was the most common type of tumor (90%), followed by UC with divergent, squamous and/or glandular differentiation (6%). Seven out of the 260 (2.8%) cases were classified as non-urothelial based on their histological morphology. These cases included 5 (2%) squamous cell carcinomas, 1 (0.4%) adenocarcinoma and 1 (0.4%) neuroendocrine tumor. The 2 most striking common features of canine and human UC included high sex predilection and histological tumor appearance. The results support the suitability of the dog as an animal model for UC and confirm that dogs also spontaneously develop rare UC subtypes and bladder tumors, including plasmacytoid UC and neuroendocrine tumor, which are herein described for the first time in a non-experimental animal species.


Breast milk jaundice in the newborn. A real entity.
I have reviewed clinical trials that provide data relative to the comparative rates, means, or odds ratio of jaundiced normal breast-fed newborns vs jaundiced normal formula-fed newborns. A pooled analysis of 12 studies revealed moderate jaundice (serum bilirubin level, greater than or equal to 12 mg/dL) in 514 of 3,997 breast-fed vs 172 of 4,255 formula-fed newborns. An analysis of six of these 12 studies demonstrated severe jaundice (serum bilirubin level, greater than or equal to 15 mg/dL) in 54 of 2,655 breast-fed vs ten of 3,002 formula-fed newborns. Eleven of 13 studies found breast-fed newborns to have a higher mean serum bilirubin level. One study of 12,023 newborns found a significant (odds ratio, 1.80) relationship between breast-feeding and jaundice of the newborn. In conclusion, breast-feeding is one common cause of jaundice in normal newborns in the first week of life and beyond.


Tolerability of a salmeterol xinafoate/fluticasone propionate hydrofluoroalkane metered-dose inhaler in adolescent and adult patients with persistent asthma: a 52-week, open-label, stratified, parallel-group, multicenter study.
Many patients with asthma require an inhaled long-acting beta(2)-agonist (LABA) in addition to an inhaled corticosteroid to adequately control their disease. The purpose of this study was to assess the long-term tolerability of a salmeterol xinafoate/ fluticasone propionate (SFC) hydrofluoroalkane metered-dose inhaler (MDI) at 3 different doses BID. This 52-week, open-label, stratified, parallel-group study assessed SFC in patients with persistent asthma. Patients, aged > or = 12 years, with a diagnosis of asthma for > or = 6 months, and a percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) between 40% and 90% were enrolled between January 1999 and June 1999. The last patient completed the 12-month study in June 2000. Patients were allowed to continue their current asthma treatment during run-in, with the exception that short-acting beta(2)-agonists (SABAs), LABAs, and oral bronchodilators were not to be used 6, 12, and 24 hours, respectively, prior to the randomization visit. During the open-label randomized treatment period, patients were instructed to discontinue all other asthma medications with the exception of the albuterol MDI to use on an as-needed basis. Patients were assigned to treatment based on their existing asthma regimen: SABA monotherapy or LABA with or without fluticasone propionate (FP) <250 microg/d or equivalent (group 1); FP 250 to 500 microg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 microg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 microg/actuation (group 1), 25/125 microg/actuation (group 2), or 25/250 pg/actuation (group 3). The primary end point was tolerability as assessed by adverse events (AEs). AEs were determined via diary cards and investigator inquiry at visits. Serious AEs were defined as death, any life-threatening event, hospitalization, disability, congenital anomaly in the patient's offspring, or other important medical events judged by the investigator to be serious. Other outcomes included clinical laboratory tests (hematology, chemistry, electrolytes), 24-hour urinary-free cortisol excretion, 12-lead electrocardiograms, oropharyngeal examinations, vital signs, clinic visit lung function tests (FEV(1) and PEF), daily diary card entries of morning PEF, and rescue medication usage. Of the 372 patients assessed for eligibility, 325 from 22 centers across Canada were enrolled and randomized to treatment. Group 1 consisted of 98 patients (55% women; 86% white; mean age, 37 years; mean [SD] weight, 79 [20] kg). Group 2 consisted of 109 patients (46% women; 94% white; mean age, 44 years; mean [SD] weight, 80 [17] kg). Group 3 consisted of 118 patients (47% women; 90% white; mean age, 45 years; mean [SD] weight, 80 [18] kg). A total of 15 adolescents (aged 12-17 years) comprised 11%, 2%, and 2% of groups 1, 2, and 3, respectively. Treatments were well tolerated, and 274 (84%) of the 325 patients enrolled completed the study. Upper respiratory tract infection was the most common AE reported: 52%, 37%, and 49% of patients in groups 1, 2, and 3, respectively. Twenty (6%) patients withdrew because of an AE, with worsening asthma being the most frequent reason (n = 9). None of the serious AEs (11 [3 %]) were considered drug related by the investigators. Improvements in FEV(1) and PEF and re- duction in symptomatic albuterol use occurred during the first 4 weeks and were maintained in all groups throughout the 52-week study. BID doses of SFC hydrofluoroalkane 50/100 pg, 50/250 pg, and 50/500 pg administered via MDI for 52 weeks were well tolerated in this population of adolescents and adults with persistent asthma.


Phase diagram of inverse patchy colloids assembling into an equilibrium laminar phase.
We numerically study the phase behavior of colloidal particles with two charged patches at the poles and an oppositely charged equatorial belt. Interactions between particles are described using the inverse patchy colloid model, where the term inverse emphasizes the difference with respect to conventional patchy particles: as a consequence of the heterogeneous charge distribution, the patches on the particle surface repel each other, whereas the patches and non-patch regions mutually attract. For the model parameters considered in this work, the system exhibits an unusual equilibrium phase diagram characterized by a broad region where a novel structure composed of parallel colloidal monolayers is stable.


Early age at menopause is associated with increased risk of dementia and mortality in women with Down syndrome.
In a prospective longitudinal cohort study of dementia and mortality in persons with Down syndrome aged 45 years and older, 85 postmenopausal women were followed for a mean follow-up time of 4.3 years (range 0.0 to 7.4 years). The effect of age at menopause on age at diagnosis of dementia and survival was estimated using correlation analysis and Cox Proportional Hazard Model. We found a significant correlation between age at menopause and age at diagnosis of dementia (rho=0.52; p< 0.001), and between age at menopause and age at death (rho=0.49; p=0.01). Early age at menopause is associated with a 1.8 fold increased risk of dementia: Hazard Ratio (HR): 1.82 (95%Confidence Interval (CI): 1.31-2.52) and with risk of death: HR: 2.05 (95%CI: 1.33-3.16). Our study suggests that age at menopause in women with Down syndrome is a determinant of age at onset of dementia and mortality.


Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis.
The amino acid sequences of ten proteins with intracellular half-lives less than 2 hours contain one or more regions rich in proline (P), glutamic acid (E), serine (S), and threonine (T). These PEST regions are generally, but not always, flanked by clusters containing several positively charged amino acids. Similar inspection of 35 proteins with intracellular half-lives between 20 and 220 hours revealed that only three contain a PEST region. On the basis of this information, it was anticipated that caseins, which contain several PEST sequences, would be rapidly degraded within eukaryotic cells. This expectation was confirmed by red blood cell-mediated microinjection of 125I-labeled caseins into HeLa cells where they exhibited half-lives of less than 2 hours. The rapid degradation of injected alpha- and beta-casein as well as the inverse correlation of PEST regions with intracellular stability indicate that the presence of these regions can result in the rapid intracellular degradation of the proteins containing them.