Design of a new sensor for determination of the effects of tractor field usage in southern Spain: soil sinkage and alterations in the cone index and dry bulk density.
Variations in sinkage and cone index are of crucial importance when planning fieldwork, and for determining the trafficability of farm machinery. Many studies have highlighted the link between higher values of these parameters and dramatic decreases in crop yield. Variations in the dry bulk density and cone index of clayey soil in Southern Spain were measured following each of five successive passes over the same land with the three types of tractor most widely used in the area (tracked, two-wheel drive and four-wheel drive). In addition, sinkage (rut depth) of the running gear was measured using a laser microrelief profile meter. This device, which integrates three sensors, was specifically designed for these experiments, as was an electrical penetrometer to determine the cone index, and both instruments proved reliable and accurate in the field. The main goal of this study was to design, manufacture and test these new devices. The first pass caused most soil alteration when compared to successive passes for all types of tractor tested and soil conditions prevailing during the tests. (Heavier) four-wheel drive tractors were found to cause greater soil damage (sinkage, cone index and dry bulk density) than two-wheel drive and track tractors. There was no statistically significant difference between the two latter types. The greatest alterations were recorded in the top 10 cm of the soil. The results show that soil compaction should be avoided as much as possible. This can be achieved by ensuring that tractors always travel along the same tracks, especially in the wet season. At present these aspects are not considered by farmers in this area.


Development of a lentivirus vector-based assay for non-destructive monitoring of cell fusion activity.
Cell-to-cell fusion can be quantified by endowing acceptor and donor cells with latent reporter genes/proteins and activators of these genes/proteins, respectively. One way to accomplish this goal is by using a bipartite lentivirus vector (LV)-based cell fusion assay system in which the cellular fusion partners are transduced with a flippase-activatable Photinus pyralis luciferase (PpLuc) expression unit (acceptor cells) or with a recombinant gene encoding FLPeNLS+, a nuclear-targeted and molecularly evolved version of flippase (donor cells). Fusion of both cell populations will lead to the FLPe-dependent generation of a functional PpLuc gene. PpLuc activity is typically measured in cell lysates, precluding consecutive analysis of one cell culture. Therefore, in this study the PpLuc-coding sequence was replaced by that of Gaussia princeps luciferase (GpLuc), a secretory protein allowing repeated analysis of the same cell culture. In myotubes the spread of FLPeNLS+ may be limited due to its nuclear localization signal (NLS) causing low signal outputs. To test this hypothesis, myoblasts were transduced with LVs encoding either FLPeNLS+ or an NLS-less version of FLPe (FLPeNLS-) and subsequently co-cultured in different ratios with myoblasts containing the FLPe-activatable GpLuc expression cassette. At different times after induction of cell-to-cell fusion the GpLuc activity in the culture medium was determined. FLPeNLS+ and FLPeNLS- both activated the latent GpLuc gene but when the percentage of FLPe-expressing myoblasts was limiting, FLPeNLS+ generally yielded slightly higher signals than FLPeNLS- while at low acceptor-to-donor cell ratios FLPeNLS- was usually superior. The ability of FLPeNLS+ to spread through myofibers and to induce reporter gene expression is thus not limited by its NLS. However, at high FLPe concentrations the presence of the NLS negatively affected reporter gene expression. In summary, a rapid and simple chemiluminescence assay for quantifying cell-to-cell fusion progression based on GpLuc has been developed.


Effects of rhizodeposition of non-transgenic and transplastomic tobaccos on the soil bacterial community.
The effect of root-released compounds of transplastomic tobacco (Nicotiana tabacum) on the soil bacterial community structure, and their potential to support horizontal gene transfer (HGT) to bacteria have been studied. Soil microcosms were exposed to root-released compounds collected from transplastomic and non-transgenic tobacco cultivars. Cluster analysis of automated ribosomal intergenic spacer analysis (ARISA) profiles of the soil bacterial community after 48 h incubation grouped the transgenic cultivar apart from the non-transgenic, indicating that it had a rhizodeposition pattern different from the parental plants. However, these differences were less than between the two non-transgenic tobacco cultivars studied. NMR characterization of the root-released compounds showed some differences in chemical fingerprinting pattern between the transplastomic and the parental cultivar. However, the effect on bacterial community structure was transient, and tended to disappear after 96 h of incubation. The potential of root-released compounds as a source of transforming DNA for bacteria was investigated by using four potential recipient species. No transformants were obtained following exposure of all the recipients to the root-released compounds. Root-released compounds amended to transgene donor DNA decreased the transformation frequency of Acinetobacter baylyi strain ADP1200, while Azospirillum, Agrobacterium, and Sinorhizobium strains failed to develop competence also in the presence of an external added transgene source. Detection of plastid sequences by PCR suggested that a very low amount of fragmented plastid donor DNA was present in the root-released compounds.


Impact of anions on electrocatalytic activity in palladium nanoparticles supported on ionic liquid-carbon nanotube hybrids for the oxygen reduction reaction.
A series of palladium nanoparticles supported on carbon nanotubes (CNTs), which were functionalized covalently with imidazolium polymer salts with different anions, Pd/polyIL(X)-CNTs (IL=ionic liquid; X=Cl, Br, I, ClO(4), BF(4), PF(6)), were prepared to investigate the influence of imidazolim salt anions on electrocatalytic activity in the oxygen reduction reaction (ORR). The anions of the imidazolium moiety significantly impacted on the ORR kinetics in a 0.1 M solution of HClO(4). The electronically active surface area results are in good agreement with the order of the ORR kinetic activity of the supported Pd/polyIL(X)-CNTs (X: Cl>ClO(4)>BF(4)>Br≈PF(6)≫I). In contrast, owing to the facile anion exchange of halide anions with hydroxide anions, anion-dependent catalytic activity has not been observed in 0.1 M NaOH. Iterative ORR experiments in acid-base solutions demonstrated anion exchange on the electrode. These results indicate that subtly varied structures of the IL moiety profoundly influence the performance of IL-CNT hybrid materials and molecular-level control of interfacial interactions between the support material, catalysts, and electrolytes is important in the design of supported metal nanoparticle catalysts for fuel cells.


A preformed signaling complex mediates GnRH-activated ERK phosphorylation of paxillin and FAK at focal adhesions in L beta T2 gonadotrope cells.
Most receptor tyrosine kinases and G protein-coupled receptors (GPCRs) operate via a limited number of MAPK cascades but still exert diverse functions, and therefore signal specificity remains an enigma. Also, most GPCR ligands utilize families of receptors for mediation of diverse biological actions; however, the mammalian type I GnRH receptor (GnRHR) seems to be the sole receptor mediating GnRH-induced gonadotropin synthesis and release. Signaling complexes associated with GPCRs may thus provide the means for signal specificity. Here we describe a signaling complex associated with the GnRHR, which is a unique GPCR lacking a C-terminal tail. Unlike other GPCRs, this signaling complex is preformed, and exposure of L beta T2 gonadotropes to GnRH induces its dynamic rearrangement. The signaling complex includes c-Src, protein kinase C delta, -epsilon, and -alpha, Ras, MAPK kinase 1/2, ERK1/2, tubulin, focal adhesion kinase (FAK), paxillin, vinculin, caveolin-1, kinase suppressor of Ras-1, and the GnRHR. Exposure to GnRH (5 min) causes MAPK kinase 1/2, ERK1/2, tubulin, vinculin, and the GnRHR to detach from c-Src, but they reassociate within 30 min. On the other hand, FAK, paxillin, the protein kinase Cs, and caveolin-1 stay bound to c-Src, whereas kinase suppressor of Ras-1 appears in the complex only 30 min after GnRH stimulation. GnRH was found to activate ERK1/2 in the complex in a c-Src-dependent manner, and the activated ERK1/2 subsequently phosphorylates FAK and paxillin. In parallel, caveolin-1, FAK, vinculin, and paxillin are phosphorylated on Tyr residues apparently by GnRH-activated c-Src. Receptor tyrosine kinases and GPCRs translocate ERK1/2 to the nucleus to phosphorylate and activate transcription factors. We therefore propose that the role of the multiprotein signaling complex is to sequester a cytosolic pool of activated ERK1/2 to phosphorylate FAK and paxillin at focal adhesions.


Effects of particle settling on Rayleigh-Bénard convection.
The effect of particles falling under gravity in a weakly turbulent Rayleigh-Bénard gas flow is studied numerically. The particle Stokes number is varied between 0.01 and 1 and their temperature is held fixed at the temperature of the cold plate, of the hot plate, or the mean between these values. Mechanical, thermal, and combined mechanical and thermal couplings between the particles and the fluid are studied separately. It is shown that the mechanical coupling plays a greater and greater role in the increase of the Nusselt number with increasing particle size. A rather unexpected result is an unusual kind of reverse one-way coupling, in the sense that the fluid is found to be strongly influenced by the particles, while the particles themselves appear to be little affected by the fluid, despite the relative smallness of the Stokes numbers. It is shown that this result derives from the very strong constraint on the fluid behavior imposed by the vanishing of the mean fluid vertical velocity over the cross sections of the cell demanded by continuity.


Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans.
Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCε activation, as reflected by PKCε translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCε activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.


Multi-omics phenotyping of the gut-liver axis reveals metabolic perturbations from a low-dose pesticide mixture in rats.
Health effects of pesticides are not always accurately detected using the current battery of regulatory toxicity tests. We compared standard histopathology and serum biochemistry measures and multi-omics analyses in a subchronic toxicity test of a mixture of six pesticides frequently detected in foodstuffs (azoxystrobin, boscalid, chlorpyrifos, glyphosate, imidacloprid and thiabendazole) in Sprague-Dawley rats. Analysis of water and feed consumption, body weight, histopathology and serum biochemistry showed little effect. Contrastingly, serum and caecum metabolomics revealed that nicotinamide and tryptophan metabolism were affected, which suggested activation of an oxidative stress response. This was not reflected by gut microbial community composition changes evaluated by shotgun metagenomics. Transcriptomics of the liver showed that 257 genes had their expression changed. Gene functions affected included the regulation of response to steroid hormones and the activation of stress response pathways. Genome-wide DNA methylation analysis of the same liver samples showed that 4,255 CpG sites were differentially methylated. Overall, we demonstrated that in-depth molecular profiling in laboratory animals exposed to low concentrations of pesticides allows the detection of metabolic perturbations that would remain undetected by standard regulatory biochemical measures and which could thus improve the predictability of health risks from exposure to chemical pollutants.


Regional left ventricular wall dynamics before and after sublingual administration of nitroglycerin.
Regional wall dynamics of the left ventricle before and after sublingual administration of 0.6 mg of nitroglycerin were determined from left ventricular angiograms in 27 patients undergoing coronary arteriography. Regional wall dynamics were quantitatively measured from 60/sec determinations of wall thickness and derived peak rate of systolic wall thickening (peak dTw/dt) in selected sites of the left ventricle. A total of 70 regions were studied. Analysis of the same segment before and after administration of nitroglycerin revealed that the mean change in peak dTw/dt was +1.97 cm/sec in segments with an initial peak dTw/dt of less than 5 cm/sec, in contrast to a change of +0.66 cm/sec in segments with an initial control value of 5 cm/sec or greater. Akinetic or dyskinetic areas did not show improvements after nitroglycerin. In 11 left ventriculograms, an area that was initially hypokinetic manifested an increase in rate of wall thickening after nitroglycerin. The mean increase in peak dTw/dt in anterior segments with electrocardiographic evidence of myocardial infarction was 0.18 cm/sec (P less than 0.05) after nitroglycerin, compared with a mean change of 1.33 cm/sec in anterior segments without such evidence. This study presents evidence for a regional myocardial response to nitroglycerin with differing responses within the same ventricle apparently depending upon the functional state of the underlying myocardium.


Class 1 (unique) tumor antigens of human melanoma. Identification of a 90,000 dalton cell surface glycoprotein by autologous antibody.
Analysis of the humoral immune response of patients with melanoma has identified a small group of individuals with antibody to cell surface antigens that are restricted to autologous melanoma cells. These antigens, referred to as Class I or unique tumor antigens, are demonstrated by reactions between serum and cultured melanoma cells from the same patient and absorption tests with autologous and allogeneic normal and malignant cells to determine antibody specificity. Five Class 1 melanoma antigens have been defined to date, but insight into the nature of these antigens has been limited because antibodies identifying these antigens lacked detectable immunoprecipitating activity. We have now defined a Class 1 melanoma antigen (designated FD) that is immunoprecipitated by autologous antibody. FD antigen is identified by an IgG antibody present in the sera of patient FD, and peak titers of this antibody in tests with cultured autologous melanoma cells are in the range of 1:2048. By absorption tests, FD antigen could not be detected on any other cell type, including 33 allogeneic melanomas. Prolonged culture of FD melanoma cells resulted in decreased expression of FD antigen, but sublines could be obtained with stable antigen expression. FD antigen is trypsin and heat sensitive, neuraminidase resistant, and is shed in the culture medium. Immunoprecipitation of 125I-labeled cell membrane preparations revealed a 90,000 dalton component of pI 5.5. Serum immunoprecipitating activity could be absorbed by autologous melanoma cells but not by autologous B cells or allogeneic cell lines. A component of the same molecular mass could be precipitated from lysates of cells metabolically labeled with [3H]mannose. The membrane form of the FD antigen binds strongly to Con A-Sepharose and can be eluted with methyl-alpha-D-mannoside. The identification of a precipitating Class I antigenic system of melanoma facilitates efforts to generate monoclonal antibodies to this tumor antigen and to clone its coding sequence.


Functional analysis of mutant mitochondrial DNA polymerase proteins involved in human disease.
DNA polymerase gamma (pol gamma) is the only DNA polymerase within the mitochondrion and is thus essential for replication and repair of mtDNA. POLG, the gene encoding the catalytic subunit of pol gamma, is a major locus for a wide spectrum of mitochondrial diseases with more than 100 known disease mutations. Thus, we need to understand how and why pol gamma defects lead to disease. By using an extensive array of methods, we are developing a clearer understanding of how defects in pol gamma contribute to disease. Furthermore, crucial knowledge concerning the role of pol gamma in mtDNA replication and repair can be acquired. Here we present the protocols to characterize mutant DNA pol gamma proteins, namely, assays for processive DNA synthesis, exonuclease activity, DNA binding, subunit interaction, and protein stability.


Denervation dynamically regulates integrin alpha7 signaling pathways and microscopic structures in rats.
Peripheral nerve injury causes serious problems in orthopedic and plastic surgeries. Cell adhesion molecules such as integrin alpha7 provoke cell binding and signaling pathways within myofibers. Expression profiles of integrin alpha7 signaling pathways and the molecule's microscopic structure were assessed to investigate the long-term dynamic changes in denervated rat skeletal muscle. A denervated rat skeletal muscle model was established by severing the sciatic nerve for 1 week, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 20 weeks, and 26 weeks. Molecular expressions were investigated by mRNA and Western blot. The structural alterations were detected by immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. The denervated muscle atrophy presented the following dynamic molecular alterations: an initial increase around postdenervation in week (PIW) 8 and then a subsequent decay of integrin alpha7, integrin downstream signaling pathway (Ras or Raf or, ERK1/2), Akt, cleaved caspase-3, fast myosin heavy chain (MHC), beta actin, and RhoA. We demonstrated that the expressions of multiple signaling molecules were highly upregulated at PIW 8 (p<0.01). Scanning electron microscopy findings of the surface textures of myofibers showed more severe damage at PIW 8 and subsequently became smoother. Inner structures of myofibers separated with discontinuity on transmission electron microscopy examinations. Our novel finding showed that time-series alterations of integrin alpha7 signaling molecules and surface microstructures in the long-term denervated rat skeletal muscle are biphasic and coherently dynamic. Persisted p-Akt elevation suggested that denervated muscle may regenerate if reinnervation or other treatment was performed.


Mean Platelet Volume and Major Adverse Cardiac Events following Percutaneous Coronary Intervention.
Mean platelet volume (MPV) has been introduced as a simple and accurate method for assessing platelet function, which can be used as a prognostic marker for cardiovascular events. We investigated whether pre-procedural MPV could predict major adverse cardiac events (MACE) in candidates for elective percutaneous coronary intervention (PCI). In this large retrospective cohort, we reviewed the clinical and follow-up data of 4199 candidates (mean age = 59.9 ± 10.3 years; female patients = 1440 [34.3%]) for elective PCI due to unstable angina (UA) or non-ST segment elevation myocardial infarction (NSTEMI). The primary endpoint of the study was the incidence of MACE defined as in-hospital mortality, cardiac death, nonfatal MI, target lesion revascularization (TLR) or target vessel revascularization (TVR). Based on the MPV level tertiles, patients were categorized into three groups for further comparison. Higher MPV was significantly associated with older age (P<0.001), hypertension (P<0.001), diabetes mellitus (P=0.003), history of previous CABG (P<0.001) and lower levels of serum triglyceride (P<0.001). The frequency of 1-year MACE was 176 (4.1%) with no significant difference between the MPV tertile groups. The highest MPV tertile could significantly predict MACE in the univariable model (hazard ratio = 1.51, 95% confidence interval: 1.05-2.17; P=0.026). In the adjusted model, the highest MPV tertile was a borderline predictor for MACE (hazard ratio = 1.62, 95% CI: 0.98-2.68; P=0.057). High MPV was associated with cardiovascular risk factors and older age while high MPV was a borderline independent predictor for 1-year MACE in the candidates for elective PCI.


Neurotrophins: which way did they go?
The classic view of the neurotrophin as a messenger produced by the postsynaptic cell that signals survival to the presynaptic cell has become expanded. Segal discusses the evidence that the neurotrophin brain-derived nerve growth factor (BDNF) can be also released from the presynaptic cell onto the dendritic spine of a postsynaptic cell to regulate the neuronal circuit in two directions: forward (from presynaptic cell to postsynaptic dendrite) and the classic backward direction (from postsynaptic cell to the presynaptic axon). These results remind us that in the brain, neurons exist in a complex circuit and one neuron's presynaptic cell is another neuron's postsynaptic cell. The evidence that a single growth factor may have different actions based on the localization of the receipt of the signal adds more complexity to the brain's neuronal circuitry.


Invasive group A Streptococcus disease in Australian children: 2016 to 2018 - a descriptive cohort study.
Invasive group A Streptococcus (iGAS) disease is serious and sometimes life-threatening. The Paediatric Active Enhanced Disease Surveillance (PAEDS) Network collects voluntary notifications from seven major Australian paediatric hospitals on patients with certain conditions, including iGAS disease. Our aims were to: 1) Describe the epidemiological distribution of paediatric iGAS disease in Australia and correlate this with influenza notifications, 2) Identify GAS strains commonly associated with invasive disease in children. IGAS and influenza notification data were obtained (from the PAEDS Network and the Australian Institute of Health and Welfare, respectively, for the period 1 July 2016 to 30 June 2018). Included iGAS patients had GAS isolated from a normally sterile body site. Data were described according to selected clinical and demographic characteristics, including by age group and Australian State, with proportions and minimum incidence rates estimated. A total of 181 patients were identified, with most (115, 63.5%) <5 years old. The mean annual minimum incidence rate was 1.6 (95% confidence interval: 1.1-2.3) per 100,000 children across the study period. An epidemiological correlation with the seasonal burden of influenza was noted. Contact prophylaxis was not consistently offered. Of 96 patients with emm-typing results available, 72.9% showed emm-1, -4 or - 12. Robust surveillance systems and cohesive patient management guidelines are needed. Making iGAS disease nationally notifiable would help facilitate this. Influenza vaccination may contribute to reducing seasonal increases in iGAS incidence. The burden of disease emphasises the need for ongoing progress in GAS vaccine development.


Histological evaluation of cellular response to a multifilament electrospun suture for tendon repair.
Rotator cuff tendon repair in humans is a commonly performed procedure aimed at restoring the tendon-bone interface. Despite significant innovation of surgical techniques and suture anchor implants, only 60% of repairs heal successfully. One strategy to enhance repair is the use of bioactive sutures that provide the native tendon with biophysical cues for healing. We investigated the tissue response to a multifilament electrospun polydioxanone (PDO) suture in a sheep tendon injury model characterised by a natural history of failure of healing. Eight skeletally mature English Mule sheep underwent repair with electrospun sutures. Monofilament sutures were used as a control. Three months after surgery, all tendon repairs healed, without systemic features of inflammation, signs of tumour or infection at necropsy. A mild local inflammatory reaction was seen. On histology the electrospun sutures were densely infiltrated with predominantly tendon fibroblast-like cells. In comparison, no cellular infiltration was observed in the control suture. Neovascularisation was observed within the electrospun suture, whilst none was seen in the control. Foreign body giant cells were rarely seen with either sutures. This study demonstrates that a tissue response can be induced in tendon with a multifilament electrospun suture with no safety concerns.


Postoperative washing of sutured wounds.
A best evidence topic was written according to the structured protocol. The three part question addressed was: [In patients undergoing closure of surgical wounds with sutures] does [keeping the wound dry for the first 48 h after closure] [reduce the incidence of surgical site infections (SSIs)]? 4 relevant papers were culled from the literature and appraised. The authors, date, country, population, study type, main outcomes, key results and study weaknesses were tabulated. Current NICE guidelines recommend cleaning surgical wounds with sterile saline only for the first 48 h following skin closure. We found no evidence that washing wounds with tap water during this period increases the incidence of SSIs compared to keeping them dry. Further randomised controlled trials will enable the construction of conclusive systematic reviews and meta-analyses.


A consistent formalism for the application of phantom and collimator scatter factors.
A coherent system for the use of scatter correction factors, determined at 10 cm depth, is described for dose calculations on the central axis of arbitrarily shaped photon beams. The system is suitable for application in both the fixed source-surface distance (SSD) and in the isocentric treatment set-up. This is in contrast to some other proposals where only one of these approaches forms the basis of the calculation system or where distinct quantities and data sets are needed. In order to derive the relations in the formalism, we introduced a separation of the phenomena related to the energy fluence in air and to the phantom scatter contribution to the dose. Both are used relative to quantities defined for the reference irradiation set-up. It is shown that dose calculations can be performed with only one set of basic beam data, obtained at a reference depth of 10 cm. These data consist for each photon beam quality of measured collimator and phantom scatter correction factors, in combination with a set of (percentage/relative) depth-dose or tissue-phantom ratio values measured along the central axis of the beam. Problems related to measurements performed at the depth of maximum absorbed dose, due to the electron contamination of the beam, are avoided in this way. Collimator scatter correction factors are obtained by using a mini-phantom, while phantom scatter correction factors are derived from measurements in a full scatter phantom in combination with the results of the mini-phantom measurements. For practical reasons the fixed SSD system was chosen to determine the data. Then, dose calculations in a fixed SSD treatment set-up itself are straightforward. Application in the isocentric treatment set-up needs simple conversion steps, while the inverse approach, from isocentric to fixed SSD, is described as well. Differences between the two approaches are discussed and the equations for the conversions are given.


A transgenic zebrafish line for in vivo visualisation of neutrophil myeloperoxidase.
The neutrophil enzyme myeloperoxidase (MPO) is a major enzyme made by neutrophils to generate antimicrobial and immunomodulatory compounds, notably hypochlorous acid (HOCl), amplifying their capacity for destroying pathogens and regulating inflammation. Despite its roles in innate immunity, the importance of MPO in preventing infection is unclear, as individuals with MPO deficiency are asymptomatic with the exception of an increased risk of candidiasis. Dysregulation of MPO activity is also linked with inflammatory conditions such as atherosclerosis, emphasising a need to understand the roles of the enzyme in greater detail. Consequently, new tools for investigating granular dynamics in vivo can provide useful insights into how MPO localises within neutrophils, aiding understanding of its role in preventing and exacerbating disease. The zebrafish is a powerful model for investigating the immune system in vivo, as it is genetically tractable, and optically transparent. To visualise MPO activity within zebrafish neutrophils, we created a genetic construct that expresses human MPO as a fusion protein with a C-terminal fluorescent tag, driven by the neutrophil-specific promoter lyz. After introducing the construct into the zebrafish genome by Tol2 transgenesis, we established the Tg(lyz:Hsa.MPO-mEmerald,cmlc2:EGFP)sh496 line, and confirmed transgene expression in zebrafish neutrophils. We observed localisation of MPO-mEmerald within a subcellular location resembling neutrophil granules, mirroring MPO in human neutrophils. In Spotless (mpxNL144) larvae-which express a non-functional zebrafish myeloperoxidase-the MPO-mEmerald transgene does not disrupt neutrophil migration to sites of infection or inflammation, suggesting that it is a suitable line for the study of neutrophil granule function. We present a new transgenic line that can be used to investigate neutrophil granule dynamics in vivo without disrupting neutrophil behaviour, with potential applications in studying processing and maturation of MPO during development.


A systematic review of Demographic and Health Surveys: data availability and utilization for research.
To systematically review the public health literature to assess trends in the use of Demographic and Health Survey (DHS) data for research from 1984 to 2010 and to describe the relationship between data availability and data utilization. The MEASURE DHS web site was searched for information on all population-based surveys completed under the DHS project between 1984 and 2010. The information collected included the country, type of survey, survey design, fieldwork period and certain special features, such as inclusion of biomarkers. A search of PubMed was also conducted to identify peer-reviewed articles published during 2010 that analysed DHS data and included an English-language abstract. Trends in data availability and in the use of DHS data for research were assessed through descriptive, graphical and bivariate linear regression analyses. In total, 236 household surveys under the DHS project were completed across 84 countries during 2010. The number of surveys per year has remained constant, although the scope of the survey questions has expanded. The inclusion criteria were met by 1117 peer-reviewed publications. The number of publications has increased progressively over the last quarter century, with an average annual increment of 4.3 (95% confidence interval, CI: 3.2-5.3) publications. Trends in the number of peer-reviewed publications based on the use of DHS data were highly correlated with trends in funding for health by the Government of the United States of America and globally. Published peer-reviewed articles analysing DHS data, which have increased progressively in number over the last quarter century, have made a substantial contribution to the public health evidence base in developing countries.


Xenobiotic response in Drosophila melanogaster: sex dependence of P450 and GST gene induction.
The effect of xenobiotics (phenobarbital and atrazine) on the expression of Drosophila melanogaster CYP genes encoding cytochromes P450, a gene family generally associated with detoxification, was analyzed by DNA microarray hybridization and verified by real-time RT-PCR in adults of both sexes. Only a small subset of the 86 CYP genes was significantly induced by the xenobiotics. Eleven CYP genes and three glutathione S-transferases (GST) genes were significantly induced by phenobarbital, seven CYP and one GST gene were induced by atrazine. Cyp6d5, Cyp6w1, Cyp12d1 and the ecdysone-inducible Cyp6a2 were induced by both chemicals. The constitutive expression of several of the inducible genes (Cyp6a2, Cyp6a8, Cyp6d5, Cyp12d1) was higher in males than in females, and the induced level similar in both sexes. Thus, the level of induction was consistently higher in females than in males. The female-specific and hormonally regulated yolk protein genes were significantly induced by phenobarbital in males and repressed by atrazine in females. Our results suggest that the numerous CYP genes of Drosophila respond selectively to xenobiotics, providing the fly with an adaptive response to chemically adverse environments. The xenobiotic inducibility of some CYP genes previously associated with insecticide resistance in laboratory-selected strains (Cyp6a2, Cyp6a8, Cyp12d1) suggests that deregulation of P450 gene expression may be a facile way to achieve resistance. Our study also suggests that xenobiotic-induced changes in P450 levels can affect insect fitness by interfering with hormonally regulated networks.


How people decide what they want to know.
Immense amounts of information are now accessible to people, including information that bears on their past, present and future. An important research challenge is to determine how people decide to seek or avoid information. Here we propose a framework of information-seeking that aims to integrate the diverse motives that drive information-seeking and its avoidance. Our framework rests on the idea that information can alter people's action, affect and cognition in both positive and negative ways. The suggestion is that people assess these influences and integrate them into a calculation of the value of information that leads to information-seeking or avoidance. The theory offers a framework for characterizing and quantifying individual differences in information-seeking, which we hypothesize may also be diagnostic of mental health. We consider biases that can lead to both insufficient and excessive information-seeking. We also discuss how the framework can help government agencies to assess the welfare effects of mandatory information disclosure.


Barriers to physical activity in chronic hemodialysis patients: a single-center pilot study in an Italian dialysis facility.
In patients on chronic dialysis a sedentary lifestyle is a strong, yet potentially modifiable, predictor of mortality. The present single-center pilot study evaluated social, psychological and clinical barriers that may hinder physical activity in this population. We explored the association between barriers to physical activity and sedentarism in adult patients at a chronic dialysis facility in Parma, Italy. We used different questionnaries exploring participation in physical activity, physical functioning, patient attitudes and preferences, and barriers to physical activity perceived by either patients or dialysis doctors and nurses. We enrolled 104 patients, (67 males, 65%), mean age 69 years (79% of patients older than 60 years); median dialysis vintage 60 months (range 8-440); mean Charlson score 5.55, ADL (Activities of Daily Living) score 5.5. Ninety-two participants (88.5%) reported at least one barrier to physical activity. At multivariable analysis, after adjusting for age and sex, feeling to have too many medical problems (OR 2.99, 95% CI 1.27 to 7.07; P=0.012), chest pain (OR 10.78, 95% CI 1.28 to 90.28; P=0.029) and sadness (OR 2.59, 95% CI 1.10 to 6.09; P=0.030) were independently associated with physical inactivity. Lack of time for exercise counseling and the firm belief about low compliance/interest by the patients toward exercise were the most frequent barriers reported by doctors and nurses. We identified a number of patient-related and health personnel-related barriers to physical activity in patients on chronic dialysis. Solutions for these barriers should be addressed in future studies aimed at increasing the level of physical activity in this population.


Clinical and demographic characteristics associated with the receipt of chemotherapy treatment among 7951 elderly metastatic colon cancer patients.
Among older individuals diagnosed with metastatic colon cancer (mCC) there is limited evidence available that describes the characteristics associated with advancing to second- and subsequent lines of treatment with chemotherapy/biologics. Our objective was to describe the trends and lines of treatment received among elderly mCC patients. Elderly beneficiaries diagnosed with mCC from 2003 to 2007 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. Beneficiaries were followed up until death or censoring. Treatment lines were classified in combinations of chemotherapies and biologics. Modified Poisson regression was used to predict receipt of lines of treatment. Analyses controlled for age, race/ethnicity, gender, marital status, state buy-in during diagnosis year, SEER-registry site, Charlson comorbidity index (CCI), poor performance indicators, surgery of primary site, and surgery of regional/distal sites. Among 7951 Medicare beneficiaries identified with mCC, 3266 initiated therapy. Of these, 1440 advanced to second-line treatment. Of these, 274 advanced to a subsequent-line treatment. Surgeries of the primary tumor site and of the regional/distal sites and marital status were the most significant variables associated with advancing through second- and subsequent-line treatments. Greater than 80 years of age, African American race, SEER-registry area, less than 6 months state buy-in assistance in mCC diagnosis year, and having poor performance indicators were inversely associated with receipt of second- or subsequent-line treatments. Among elderly individuals diagnosed with mCC, we identified demographic, clinical, and regional factors associated with receipt of second- and subsequent-line chemotherapy/biologics. Additional research is warranted to understand the role of physician versus patient preferences as well as geographic differences explaining why patients advance through lines of chemotherapy.


Chronically occluded inferior venae cavae: endovascular treatment.
To report the results of endoluminal recanalization and stent placement in patients with chronic occlusions of the inferior vena cava (IVC). Seventeen consecutive patients (12 male, five female patients; mean age, 40.6 years; age range, 15-77 years) with chronic IVC occlusions were treated during a 6-year period. The mean duration of symptoms was 32 months. Underlying active malignancy was the cause of occlusion in four patients. Five patients with superimposed acute thrombus underwent catheter-directed thrombolysis prior to IVC recanalization. Clinical patency was defined as absence or improvement of symptoms. Clinical follow-up was supplemented with ultrasonography, vena cavography, or both in 10 patients. Technical success was achieved in 15 (88%) patients. Additional thrombolytic therapy and stent placement was needed in two patients to maintain patency at 4 and 6 months after the procedure. Twelve patients had IVCs that remained patent after a mean follow-up of 19 months for a primary patency rate of 80%. The primary assisted patency rate was 87% (13 of 15). There were four deaths owing to underlying disease 6-21 months after the procedures. There were no procedure-related complications. Endoluminal recanalization and stent placement in chronically occluded IVCs has a good intermediate-term outcome and should be considered in patients who have symptoms and who often do not have adequate alternative therapy.


A review and characterization of the various perceptions of quality cancer care.
It is important to maintain high-quality cancer care while reducing spending. This requires an understanding of how stakeholders define "quality." The objective of this literature review was to understand the perceptions patients, physicians, and managed care professionals have about quality cancer care, especially chemotherapy. A computerized literature search was conducted for articles concerning quality cancer care in patients who received chemotherapy. Among >1100 identified sources, 25 presented interviews/survey results from stakeholders. Patients defined quality cancer care as being treated well by providers, having multiple treatment options, and being part of the decision-making process. Waiting to see providers, having problems with referrals, going to different locations for treatment, experiencing billing inaccuracies, and navigating managed care reimbursement negatively affected patients' quality-of-care perceptions. Providers perceived quality cancer care as making decisions based on the risks-benefits of specific chemotherapy regimens and patients' health status rather than costs. Providers objected to spending substantial time interacting with payers instead of delivering care to patients. Payers must control the costs of cancer care but do not want an adversarial relationship with providers and patients. Payers' methods of managing cancer more efficiently involved working with providers to develop assessment and decision-assist tools. Delivering quality cancer care is increasingly difficult because of the shortage of oncologists and rising costs of chemotherapy agents, radiation therapy, and imaging tests. The definition of quality cancer care differed among stakeholders, and healthcare reform must reflect these various needs to maintain and improve quality while controlling costs.


Pharmacological characterization of neural mechanisms regulating mucosal ion transport in mouse jejunum.
Neural regulation of electrolyte transport in mouse jejunum was investigated in vitro using: 1) a full-thickness intestinal segment (intact preparation) and 2) a mucosal preparation, consisting of only mucosa, basement membrane and muscularis mucosa. In Ussing chambers, intact tissues exhibited high- and low-frequency oscillations of basal transmural potential difference (PD) and short-circuit current (Isc), whereas mucosal tissues exhibited only low-frequency oscillation of these parameters. High-frequency oscillations of PD and Isc were found to originate from muscle activity. Under basal conditions, intact tissues exhibited net Na+ absorption and net Cl- secretion, whereas mucosal tissues displayed greater net Na+ absorption and net Cl- absorption. When applied to the serosal medium of intact tissues, tetrodotoxin, a neurotoxin, and chlorisondamine, a ganglionic blocking agent, caused a concentration-dependent reduction of basal PD and Isc, whereas atropine produced no significant effect; these agents were without effect in mucosal tissues. Furthermore, in intact tissues, tetrodotoxin caused significant increases in net Na+ absorption and net residual flux, attaining values that were comparable to those seen in mucosal tissues. Carbachol, a muscarinic agonist, and 1,1-dimethyl-4-phenylpiperizinium, a ganglionic stimulant, elicited concentration-dependent, transient increases of basal PD and Isc when applied to the serosal medium of intact tissues; in mucosal preparations, carbachol elicited greater changes of basal PD and Isc, whereas 1,1-dimethyl-4-phenylpiperizinium produced no significant effect. In intact tissues, Isc responses elicited by carbachol were antagonized by atropine, but not tetrodotoxin or chlorisondamine; Isc responses induced by 1,1-dimethyl-4-phenylpiperizinium, however, were blocked by tetrodotoxin or chlorisondamine, but not atropine. These results support the existence of a multisynaptic, and tonically active neural pathway which serves to limit intestinal Na+ transport at some point below the maximal absorptive capacity of the mucosa. Furthermore, cholinergic muscarinic and nicotinic receptors are present in distinct neural pathways that influence intestinal electrolyte transport in the small intestine of the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)


Temperature Dependence of the Air/Water Interface Revealed by Polarization Sensitive Sum-Frequency Generation Spectroscopy.
The temperature dependence of the vibrational sum-frequency generation (vSFG) spectra of the air/water interface is investigated using many-body molecular dynamics (MB-MD) simulations performed with the MB-pol potential energy function. The vSFG spectra calculated for different polarization combinations are then analyzed in terms of molecular autocorrelation and cross-correlation contributions. To provide molecular-level insights into interfacial hydrogen-bonding topologies, which give rise to specific spectroscopic features, the vSFG spectra are further investigated by separating contributions associated with water molecules donating zero, one, or two hydrogen bonds to neighboring water molecules. This analysis suggests that the low frequency shoulder of the free OH peak which appears at ∼3600 cm-1 is primarily due to intermolecular couplings between both singly and doubly hydrogen-bonded molecules.


Breast cancer risk in metabolically healthy but overweight postmenopausal women.
Adiposity is an established risk factor for postmenopausal breast cancer. Recent data suggest that high insulin levels in overweight women may play a major role in this relationship, due to insulin's mitogenic/antiapoptotic activity. However, whether overweight women who are metabolically healthy (i.e., normal insulin sensitivity) have elevated risk of breast cancer is unknown. We investigated whether overweight women with normal insulin sensitivity [i.e., homeostasis model assessment of insulin resistance (HOMA-IR) index, or fasting insulin level, within the lowest quartile (q1)] have increased breast cancer risk. Subjects were incident breast cancer cases (N = 497) and a subcohort (N = 2,830) of Women's Health Initiative (WHI) participants with available fasting insulin and glucose levels. In multivariate Cox models, metabolically healthy overweight women, defined using HOMA-IR, were not at elevated risk of breast cancer compared with metabolically healthy normal weight women [HRHOMA-IR, 0.96; 95% confidence interval (CI), 0.64-1.42]. In contrast, the risk among women with high (q3-4) HOMA-IRs was elevated whether they were overweight (HRHOMA-IR, 1.76; 95% CI, 1.19-2.60) or normal weight (HRHOMA-IR, 1.80; 95% CI, 0.88-3.70). Similarly, using fasting insulin to define metabolic health, metabolically unhealthy women (insulin q3-4) were at higher risk of breast cancer regardless of whether they were normal weight (HRinsulin, 2.06; 95% CI, 1.01-4.22) or overweight (HRinsulin, 2.01; 95% CI, 1.35-2.99), whereas metabolically healthy overweight women did not have significantly increased risk of breast cancer (HRinsulin, 0.96; 95% CI, 0.64-1.42) relative to metabolically healthy normal weight women. Metabolic health (e.g., HOMA-IR or fasting insulin) may be more biologically relevant and more useful for breast cancer risk stratification than adiposity per se.


SpoVID functions as a non-competitive hub that connects the modules for assembly of the inner and outer spore coat layers in Bacillus subtilis.
During sporulation in Bacillus subtilis, a group of mother cell-specific proteins guides the assembly of the coat, a multiprotein structure that protects the spore and influences many of its environmental interactions. SafA and CotE behave as party hubs, governing assembly of the inner and outer coat layers. Targeting of coat proteins to the developing spore is followed by encasement. Encasement by SafA and CotE requires E, a region of 11 amino acids in the encasement protein SpoVID, with which CotE interacts directly. Here, we identified two single alanine substitutions in E that prevent binding of SafA, but not of CotE, to SpoVID, and block encasement. The substitutions result in the accumulation of SafA, CotE and their dependent proteins at the mother cell proximal spore pole, phenocopying a spoVID null mutant and suggesting that mislocalized SafA acts as an attractor for the rest of the coat. The requirement for E in SafA binding is bypassed by a peptide with the sequence of E provided in trans. We suggest that E allows binding of SafA to a second region in SpoVID, enabling CotE to interact with E and SpoVID to function as a non-competitive hub during spore encasement.


Global Associations between Air Pollutants and Chronic Obstructive Pulmonary Disease Hospitalizations. A Systematic Review.
Exacerbations are key events in chronic obstructive pulmonary disease (COPD), affecting lung function decline and quality of life. The effect of exposure to different air pollutants on COPD exacerbations is not clear. To carry out a systematic review, examining associations between air pollutants and hospital admissions for COPD exacerbations. MEDLINE, Embase, BIOSIS, Science Citation Index, and the Air Pollution Epidemiology Database were searched for publications published between 1980 and September 2015. Inclusion criteria were focused on studies presenting solely a COPD outcome defined by hospital admissions and a measure of gaseous air pollutants and particle fractions. The association between each pollutant and COPD admissions was investigated in metaanalyses using random effects models. Analyses were stratified by geographical clusters for investigation of the consistency of the evidence worldwide. Forty-six studies were included, and results for all the pollutants under investigation showed marginal positive associations; however, the number of included studies was small, the studies had high heterogeneity, and there was evidence of small-study bias. Geographical clustering of the effects of pollution on COPD hospital admissions was evident and reduced heterogeneity significantly. The most consistent association was between a 1-mg/m3 increase in carbon monoxide level and COPD-related admissions (odds ratio, 1.02; 95% confidence interval, 1.01-1.03). The heterogeneity was moderate, and there was a consistent positive association in both Europe and North America, although levels were clearly below World Health Organization guideline values. There is mixed evidence on the effects of environmental pollution on COPD exacerbations. Limitations of previous studies included the low spatiotemporal resolution of pollutants, inadequate control for confounding factors, and the use of aggregated health data that ignored personal characteristics. The need for more targeted exposure estimates in a large number of geographical locations is evident.


Landscape trends in Mid-Atlantic and Southeastern United States ecoregions.
Landscape pattern and composition metrics are potential indicators for broad-scale monitoring of change and for relating change to human and ecological processes. We used a probability sample of 20-km x 20-km sampling blocks to characterize landscape composition and pattern in five US ecoregions: the Middle Atlantic Coastal Plain, Southeastern Plains, Northern Piedmont, Piedmont, and Blue Ridge Mountains. Land use/and cover (LULC) data for five dates between 1972 and 2000 were obtained for each sample block. Analyses focused on quantifying trends in selected landscape pattern metrics by ecoregion and comparing trends in land cover proportions and pattern metrics among ecoregions. Repeated measures analysis of the landscape pattern documented a statistically significant trend in all five ecoregions towards a more fine-grained landscape from the early 1970s through 2000. The ecologically important forest cover class also became more fine-grained with time (i.e., more numerous and smaller forest patches). Trends in LULC, forest edge, and forest percent like adjacencies differed among ecoregions. These results suggest that ecoregions provide a geographically coherent way to regionalize the story of national land use and land cover change in the United States. This study provides new information on LULC change in the southeast United States. Previous studies of the region from the 1930s to the 1980s showed a decrease in landscape fragmentation and an increase in percent forest, while this study showed an increase in forest fragmentation and a loss of forest cover.


Strategies and challenges involved in the discovery of new chemical entities during early-stage tuberculosis drug discovery.
There is an increasing flow of new antituberculosis chemical entities entering the tuberculosis drug development pipeline. Although this is encouraging, the current number of compounds is too low to meet the demanding criteria required for registration, shorten treatment duration, treat drug-resistant infection, and address pediatric tuberculosis cases. More new chemical entities are needed urgently to supplement the pipeline and ensure that more drugs and regimens enter clinical practice. Most drug discovery projects under way exploit enzyme systems deemed essential in a specific Mycobacterium tuberculosis biosynthetic pathway or develop chemical scaffolds identified by phenotypic screening of compound libraries, specific pharmacophores or chemical clusters, and natural products. Because the development of a compound for treating tuberculosis is even longer than for treating other infection indications, the identification of selective, potent, and safe chemical entities early in the drug development process is essential to ensure that the pipeline is filled with new candidates that have the best chance to reach the clinic.


Association between sleep duration and hypertension in southwest China: a population-based cross-sectional study.
Hypertension is a major risk factor and cause of many non-communicable diseases in China. While there have been studies on various diet and lifestyle risk factors, we do not know whether sleep duration has an association to blood pressure in southwest China. This predictor is useful in low-resource rural settings. We examined the association between sleep duration and hypertension in southwest China. Population-based cross-sectional study. This study was part of the baseline survey of a large ongoing prospective cohort study, the China Kadoorie Biobank. Participants were enrolled in 15 townships of Pengzhou city in Sichuan province during 2004-2008. 55 687 participants aged 30-79 years were included. Sleep duration was assessed by a self-reported questionnaire. Hypertension was defined as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, or prior physician-diagnosed hypertension in hospitals at the township (community) level or above. The prevalence of hypertension was 25.17%. The percentages of subjects with sleep durations of <6, 6, 7, 8 and ≥9 hours were 17.20%, 16.14%, 20.04%, 31.95% and 14.67%, respectively. In multivariable-adjusted analyses, the increased ORs of having hypertension were across those who reported ≥9 hours of sleep (men: 1.16, 95% CI 1.04 to 1.30; women: 1.19, 95% CI 1.08 to 1.32; general population: 1.17, 95% CI 1.08 to 1.26). The odds of hypertension was relatively flat until around 6.81 hours of sleep duration and then started to increase rapidly afterwards in subjects and a J-shaped pattern was observed. There was a U-shaped relationship between sleep duration and hypertension in females. Long sleep duration was significantly associated with hypertension and a J-shaped pattern was observed among rural adults in southwest China, independent of potential confounders. However, this association was not obvious between short sleep duration and hypertension.


An internal health systems research portfolio assessment of a low-income country research institution.
In order to determine the type and amount of health systems research being conducted within ICDDR,B (also known as the Centre), a leading research institution in Bangladesh, an internal review of all on-going research protocols was conducted in September 2007. A review of all ongoing research protocols within the Centre was conducted. The names of the investigators and the institutional divisions of the protocols were removed in order to decrease the amount of reviewer bias. The building blocks of the World Health Organization's "Framework for Action" on health systems was used to categorize the protocols considered to be health systems research projects. Several additional items were collected, e.g. the highest level of education completed by the Principal Investigator. A total dollar value was placed on the health systems research portfolio of the institution based on the budgets of the selected protocols. As of September 2007 16 out of 118 (13.5%) reviewed protocols were considered to be health systems research projects. Results of the six building blocks of the health system categorization demonstrated that a majority of these protocols involved elements of health services delivery. There was very little engagement in more downstream systems and policy research that involved leadership and governance of the health system. Eleven of the HSR studies were local in scope, while there was only one study that has a multinational focus. The Centre's total dollar value for the health systems research project portfolio added up to US$ 3,723,331. This internal review can serve as a snap shot of on-going activities, and as a baseline for future assessments against which to monitor progress in the area of health systems research. Further, it can serve as a model for other institutions striving to assess and develop health systems research programmes and capacity.


Periodic presumptive treatment of curable sexually transmitted infections among sex workers: a systematic review.
Unprotected sex work remains a major driver of HIV/sexually transmitted infection (STI) epidemics in many countries. STI treatment can lower disease burden, complications and prevalence of HIV cofactors. Periodic presumptive treatment (PPT) has been used with sex workers to reduce their high burden of largely asymptomatic STIs. The objective of this review is to assess benefits and harms of PPT among female sex workers. We searched MEDLINE for studies related to sex work and STIs during 1990-2010, extracted data from eligible studies in duplicate and conducted meta-analysis by study design using random effects models. Two thousand, three hundred and fifteen articles were screened, 18 studies met inclusion criteria and 14 were included in meta-analyses. One published randomized controlled trial (RCT) reported significant reductions of gonorrhoea (Neisseria gonorrhoeae) [rate ratio (RR) 0.46, 95% confidence interval (CI) 0.31-0.68] and chlamydia (Chlamydia trachomatis) (RR 0.38, 95%CI 0.26-0.57), but no effect on serologic syphilis (RR 1.02, 95%CI 0.54-1.95). Similar results were seen for N. gonorrhoeae and C. trachomatis in pooled analyses, including data from one unpublished RCT and across study designs, and correlated with initial prevalence (R(2) = 0.155). One observational study reported genital ulcer disease (GUD) declines in sex workers, and two reported impact among male client populations for N. gonorrhoeae [odds ratio (OR) 0.60, 95% CI 0.38-0.94], C. trachomatis (OR 0.47, 95% CI 0.31-0.71) and GUD (OR 0.21, 95% CI 0.11-0.42). No studies reported evidence of risk compensation or antibiotic resistance. PPT can reduce prevalence of gonorrhoea, chlamydia and ulcerative STIs among sex workers in whom prevalence is high. Sustained STI reductions can be achieved when PPT is implemented together with peer interventions and condom promotion. Additional benefits may include impact on STI and HIV transmission at population level.


Unique expression of MUC3, MUC5AC and cytokeratins in salivary gland carcinomas.
The differential diagnosis of salivary gland carcinoma is often difficult because of the confusing histopathological features of the different types of salivary gland carcinomas. The expression of MUC3, MUC5AC, MUC6, cytokeratin (CK)7 and CK20 was studied in 20 mucoepidermoid carcinomas (MEC), 20 adenoid cystic carcinomas (AdCC), and 11 acinic cell carcinomas (ACC). All the cases (51/51, 100%) were positive for CK7, but they were not positive for CK20. All the cases (100%) of the MEC were positive for MUC5AC, while all MEC (100%) were negative for MUC3. Only two cases (10%) were positive for MUC6. All cases (100%) of AdCC were negative for MUC3, MUC5AC and MUC6. Eight cases (73%) of ACC were positive for MUC3, but all the cases (100%) were negative for MUC5AC and MUC6. It is concluded that the positive expression of MUC5AC is very unique to MEC, and that the positive expression of MUC3 is very unique to ACC. These findings will be very useful for the differential diagnosis of the salivary gland carcinomas.


Phase I/II study of liposome-complexed mitoxantrone in patients with advanced breast cancer.
The toxicity of escalating doses of liposome-complexed mitoxantrone (LCM) was evaluated in 22 women with histological/cytological diagnosis of metastatic breast cancer (21 pts) or adenocarcinoma of unknown primary origin (1 pt). All patients but one had been pretreated with chemotherapy. LCM was given IV as a 1h-infusion, repeated every 3 weeks, from a starting dose of 3 mg/m2, corresponding to 1/3 of the MELD10. An intra-patient dose escalation scheme, with an increase per cycle of 3 mg/m2 up to 12 mg/m2, and then by 2 mg/m2 was applied, treatment being continued until tumour progression, or toxicity, or up to a maximum of 6 cycles, whichever occurred first. Granulocytopenia was dose-limiting, with a GNC count of less than 0.5 x 10(3)/microliters after 30%, 28%, 50% and 50% of the cycles given at 16, 18, 20 and 22-24 mg/m2, respectively. The lowest GNC count occurred usually 2 weeks after treatment, with recovery in the following week. Gastro-intestinal toxicity, mucositis and alopecia were rare and of mild degree. Two patients, with a subtotal neoplastic involvement of the liver and a pretreatment grade 4 liver impairment, died because of acute liver failure a few days after treatment. The maximum tolerable dose was defined at 22 mg/m2 and 18 mg/m2, given every 3 weeks for 6 cycles, was the regimen recommended for phase II studies. Seven previously untreated patients with metastatic breast cancer have been so far treated. The pattern of toxicity of LCM (specific, short-lasting granulocytopenia; negligible, non cumulative non hematological toxicity) was confirmed.(ABSTRACT TRUNCATED AT 250 WORDS)


Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor.
Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of (45)Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of (45)Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RARα/β/γ) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RARα enhanced the release of (45)Ca and mRNA expression of Rankl, whereas agonists with affinity to RARβ/γ or RARγ had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RARα antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on (45)Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR(dim) mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RARα receptors, a response that can be inhibited by monomeric GR.


Probing the molecular mechanisms of quartz-binding peptides.
Understanding the mechanisms of biomineralization and the realization of biology-inspired inorganic materials formation largely depends on our ability to manipulate peptide/solid interfacial interactions. Material interfaces and biointerfaces are critical sites for bioinorganic synthesis, surface diffusion, and molecular recognition. Recently adapted biocombinatorial techniques permit the isolation of peptides recognizing inorganic solids that are used as molecular building blocks, for example, as synthesizers, linkers, and assemblers. Despite their ubiquitous utility in nanotechnology, biotechnology, and medicine, the fundamental mechanisms of molecular recognition of engineered peptides binding to inorganic surfaces remain largely unknown. To explore propensity rules connecting sequence, structure, and function that play key roles in peptide/solid interactions, we combine two different approaches: a statistical analysis that searches for highly enriched motifs among de novo designed peptides, and, atomistic simulations of three experimentally validated peptides. The two strong and one weak quartz-binding peptides were chosen for the simulations at the quartz (100) surface under aqueous conditions. Solution-based peptide structures were analyzed by circular dichroism measurements. Small and hydrophobic residues, such as Pro, play a key role at the interface by making close contact with the solid and hindering formation of intrapeptide hydrogen bonds. The high binding affinity of a peptide may be driven by a combination of favorable enthalpic and entropic effects, that is, a strong binder may possess a large number of possible binding configurations, many of which having relatively high binding energies. The results signify the role of the local molecular environment among the critical residues that participate in solid binding. The work herein describes molecular conformations inherent in material-specific peptides and provides fundamental insight into the atomistic understanding of peptide/solid interfaces.


Barriers to formal emergency obstetric care services' utilization.
Access to appropriate health care including skilled birth attendance at delivery and timely referrals to emergency obstetric care services can greatly reduce maternal deaths and disabilities, yet women in sub-Saharan Africa continue to face limited access to skilled delivery services. This study relies on qualitative data collected from residents of two slums in Nairobi, Kenya in 2006 to investigate views surrounding barriers to the uptake of formal obstetric services. Data indicate that slum dwellers prefer formal to informal obstetric services. However, their efforts to utilize formal emergency obstetric care services are constrained by various factors including ineffective health decision making at the family level, inadequate transport facilities to formal care facilities and insecurity at night, high cost of health services, and inhospitable formal service providers and poorly equipped health facilities in the slums. As a result, a majority of slum dwellers opt for delivery services offered by traditional birth attendants (TBAs) who lack essential skills and equipment, thereby increasing the risk of death and disability. Based on these findings, we maintain that urban poor women face barriers to access of formal obstetric services at family, community, and health facility levels, and efforts to reduce maternal morbidity and mortality among the urban poor must tackle the barriers, which operate at these different levels to hinder women's access to formal obstetric care services. We recommend continuous community education on symptoms of complications related to pregnancy and timely referral. A focus on training of health personnel on "public relations" could also restore confidence in the health-care system with this populace. Further, we recommend improving the health facilities in the slums, improving the services provided by TBAs through capacity building as well as involving TBAs in referral processes to make access to services timely. Measures can also be put in place to enhance security in the slums at night.


Interleukin 2 and stimulator lymphoblastoid cells will induce human thymocytes to bind and kill K562 targets.
Human thymocytes cultured in the presence of IL-2 and an irradiated B cell line became cytotoxic to K562 target cells. Thymocytes cultured alone or with only IL-2 exhibited almost no killing, but thymocytes cultured in the presence of stimulator cells alone exhibited low levels of cytotoxic activity. Removal of Fc gamma receptor-bearing cells from the activated thymocyte population almost completely abolished the binding and lytic activity. Separation of thymocytes into Fc microns+ and Fc microns-cells before culturing with IL-2 and stimulator cells revealed that only the Fc microns+ subpopulation developed into K562 killer cells. These findings indicate that modulation of Fc microns to Fc gamma receptors on the thymocyte cell surface is part of the maturation process of this particular subset of cytotoxic cells. Morphologically, most of the activated Fc gamma+ K562-binding cells were large, granulated lymphocytes. Only very few of the round, nongranulated small thymocytes were bound to K562 target cells.


Protective Effects of Eugenol against Hepatotoxicity Induced by Arsenic Trioxide: An Antileukemic Drug.
Arsenic trioxide (As2O3) has shown effectiveness in the treatment of leukemia, but it is also associated with hepatotoxicity. Given antileukemic drug-induced oxidative stress and toxicity, this study focused on the mitigatory role of eugenol, a monoterpene compound from clove oil, in the hepatic tissue of Wistar rats. Twenty-four male Wistar rats (180-250 g) were randomly divided into 4 groups (6 rats per group): normal control rats, rats treated with As2O2 (4 mg/kg bwt), rats treated with eugenol (5 mg/kg bwt), and rats receiving co-treatment with As2O3 (4 mg/kg bwt) and eugenol (5 mg/kg bwt), all of which orally administered for a period of 30 days. The Tukey test (Origin version 7, Origin Lab Corporation, Northampton, USA) was applied to analyze the one-way analysis of variance (ANOVA) between the different groups. A P value less than 0.05 was considered significant. Oral administration of As2O3 significantly induced hepatic damage, evident from increased levels of aspartate transaminase and alanine transaminase (P=0.01 and P<0.001, respectively). Moreover, a decrease in the activities of enzymatic and nonenzymatic antioxidants altered electrolyte concentration and increased the rate of lipid peroxidation (P=0.04) and the level of nitric oxide (P=0.01). Accumulation studies and histopathological analyses confirmed the biochemical variations. Co-treatment with eugenol (5 mg/kg bwt) exhibited hepatoprotective effects as manifested by the decreased rate of arsenic accumulation, lipid peroxidation, and nitric oxide level along with normalized levels of antioxidants and maintained histology of the liver. Eugenol may be used in combination with arsenic trioxide in chemotherapy to reduce oxidative damage to the hepatic system.


A cluster randomised controlled trial of a manualised cognitive behavioural anger management intervention delivered by supervised lay therapists to people with intellectual disabilities.
Anger is a frequent problem for many people with intellectual disabilities, and is often expressed as verbal and/or physical aggression. Cognitive-behaviour therapy (CBT) is the treatment of choice for common mental health problems, but CBT has only recently been adapted for people with intellectual disabilities. Anger is the main psychological presentation in which controlled trials have been used to evaluate CBT interventions for people with intellectual disabilities but these do not include rigorous randomised studies. To evaluate (1) the impact of a staff-delivered manualised CBT anger management intervention on (a) reported anger among people with mild to moderate intellectual disabilities, and (b) anger coping skills, aggression, mental health, quality of life and costs of health and social care; (2) factors that influence outcome; and (3) the experience of service users, lay therapists and service managers. A cluster randomised controlled trial based on 30 day centres (15 intervention and 15 control). Intention-to-treat comparisons of outcomes used a two-level linear regression model to allow for clustering within centres with baseline outcome levels as a covariate. Comparison of cost data used non-parametric bootstrapping. Qualitative analysis used interpretative phenomenological analysis and thematic analysis. Recruited day centres had four-plus service users with problem anger who were prepared to participate, two-plus staff willing to be lay therapists, a supportive manager and facilities for group work, and no current anger interventions. A total of 212 service users with problem anger were recruited. Thirty-three were deemed ineligible (30 could not complete assessments and three withdrew before randomisation). Retention at follow-up was 81%, with 17 withdrawals in each arm. Two to four staff per centre were recruited as lay therapists. Eleven service users, nine lay therapists and eight managers were interviewed. The manualised intervention comprised 12 weekly 2-hour group sessions supplemented by 'homework'. Lay therapists received training and ongoing supervision from a clinical psychologist. Treatment fidelity, group attendance and resources used in intervention delivery were monitored. The primary outcome was the service user-rated Provocation Index (PI), a measure of response to hypothetical situations that may provoke anger. Secondary trial outcomes were the key worker-rated PI; the service user- and key worker-rated Profile of Anger Coping Skills (PACS); the service user-rated PACS imaginal provocation test (PACS-IPT), a measure of response to actual situations known to provoke anger; aggression; mental health; self-esteem; quality of life; and health and social care resource use. Assessments were administered before randomisation and at 16 weeks and 10 months after randomisation. Fourteen treatment groups were delivered, each with 12 sessions lasting an average of 114 minutes, with a mean of 4.9 service users and 2.0 lay therapists. The mean hourly cost per service user was £ 25.26. The mean hourly excess cost over treatment as usual was £ 12.34. There was no effect of intervention on the primary outcome - self-rated PI. There was a significant impact on the following secondary outcomes at the 10-month follow-up: key worker-rated PI, self-rated PACS-IPT and self- and key worker-rated PACS. Key workers and home carers reported significantly lower aggression at 16 weeks, but not at 10 months. There was no impact on mental health, self-esteem, quality of life or total cost of health and social care. Service users, key workers and service managers were uniformly positive. The intervention was effective at changing anger coping skills and staff-rated anger. Impact on self-rated anger was equivocal. With hindsight there are reasons, from an analysis of factors influencing outcomes, to think that self-rated PI was not a well-chosen primary outcome. Widespread implementation of manualised lay therapist-led but psychologist-supervised anger management CBT for people with mild to moderate intellectual disabilities is recommended.


Dynamics of 3D carcinoma cell invasion into aligned collagen.
Carcinoma cells frequently expand and invade from a confined lesion, or multicellular clusters, into and through the stroma on the path to metastasis, often with an efficiency dictated by the architecture and composition of the microenvironment. Specifically, in desmoplastic carcinomas such as those of the breast, aligned collagen tracks provide contact guidance cues for directed cancer cell invasion. Yet, the evolving dynamics of this process of invasion remains poorly understood, in part due to difficulties in continuously capturing both spatial and temporal heterogeneity and progression to invasion in experimental systems. Therefore, to study the local invasion process from cell dense clusters into aligned collagen architectures found in solid tumors, we developed a novel engineered 3D invasion platform that integrates an aligned collagen matrix with a cell dense tumor-like plug. Using multiphoton microscopy and quantitative analysis of cell motility, we track the invasion of cancer cells from cell-dense bulk clusters into the pre-aligned 3D matrix, and define the temporal evolution of the advancing invasion fronts over several days. This enables us to identify and probe cell dynamics in key regions of interest: behind, at, and beyond the edge of the invading lesion at distinct time points. Analysis of single cell migration identifies significant spatial heterogeneity in migration behavior between cells in the highly cell-dense region behind the leading edge of the invasion front and cells at and beyond the leading edge. Moreover, temporal variations in motility and directionality are also observed between cells within the cell-dense tumor-like plug and the leading invasive edge as its boundary extends into the anisotropic collagen over time. Furthermore, experimental results combined with mathematical modeling demonstrate that in addition to contact guidance, physical crowding of cells is a key regulating factor orchestrating variability in single cell migration during invasion into anisotropic ECM. Thus, our novel platform enables us to capture spatio-temporal dynamics of cell behavior behind, at, and beyond the invasive front and reveals heterogeneous, local interactions that lead to the emergence and maintenance of the advancing front.


Interaction of moisture with sodium starch glycolate.
The relationship between the apparent moisture content and moisture sorption of modified starches was investigated. Samples of sodium starch glycolate (SSG), pregelatinized starch (PGS) and potato starch (PS) were stored for various times at 44% or 75% relative humidity (RH) to produce samples with moisture contents of up to 14%, as determined by loss on drying (LOD). Evaluation of LOD and mass gain data suggested that measured mass gain equated to predicted LOD values for PGS and PS. However, in SSG there was a nonstoichiometric relationship between mass gain and predicted LOD. In addition, samples of SSG displayed hysteresis during dynamic vapor sorption (DVS) cycling in that an apparent mass loss of about 2-3% was observed for two of the SSGs, with PS and PGS exhibiting reversibility. In some cases, SSG exhibited an apparent mass loss during the DVS cycle at with 50% RH. These observations suggest that one or more of the components of SSG "interact" with moisture. Because X-ray diffraction suggested there was no dramatic change in the crystallinity of SSG, an exchange of residual SSG solvent, alcohol, with moisture may, in part, explain the moisture sorption behavior of SSG.


Reablement in a small municipality, a survival analysis.
Reablement is a municipal service given to patients at home. The purpose of the service is to assist recovery after hospital discharges or other sudden changes in a patient's functional level. The service is often provided by a team of nurses, physiotherapists, and occupational therapists. The purpose of this paper is to compare users of this service to users who receive traditional home care services. Outcomes to be measured are risk of long-term care and mortality. All users of health and care services in a Norwegian municipality were eligible for inclusion. Data was extracted from the local user administrative database. Users were divided in two groups: those who received reablement and those home care users who did not receive reablement service. Propensity score matching was used to match users based on age, sex, and level of functioning in activities of daily living (ADL). Survival analysis was deployed to test if the reablement users had different risk of becoming long-term care users, and whether the mortality rate differed for this group. 153 reablement users were included in the study. These were matched to 153 non-reablement home care users. The groups had similar distributions of age, sex, and level of functioning when starting their service trajectories. Regressions showed that reablement users had lower risk of using long-term care services in the study period (time at risk up to 4 years), and lower mortality. However, none of these estimates were statistically significant. The study indicates that the reablement users in one municipality had lower use of long -term care and lower mortality when properly estimated, but numbers were too small for statistical significance to be found.


Treatment patterns and prognosis in patients with human immunodeficiency virus and primary central system lymphoma.
The incidence of human immunodeficiency virus (HIV)-associated primary central nervous system lymphoma (PCNSL) has decreased in the era of highly active anti-retroviral therapy, but PCNSL continues to be a prominent AIDS-defining illness. Using surveillance epidemiology and end results, cancer registry data linked with Medicare, we identified PCNSL cases diagnosed from 1994 to 2002. The effects of comorbidity, year of diagnosis, and sociodemographic characteristics on the odds of receiving treatment were assessed. One hundred and eighty-four patients with both HIV and PCNSL were identified. Forty-six per cent were treated with radiation therapy (RT) alone, 10% received RT and chemotherapy, 4% received chemotherapy alone, and 40% received no treatment. No time trends in treatment patterns were observed, and no sociodemographic factors were associated with receipt of treatment. Median survival was 2 months. Age did not impact survival. Survival was improved for patients diagnosed with PCNSL after 1996 (p = 0.028). Despite improved treatment for both diseases over the past decade, survival remains dismal in this cohort of Medicare/Medicaid beneficiaries with HIV-related PCNSL. These results may not apply to the general HIV population.


Using the RE-AIM framework to evaluate a community-based summer camp for children with obesity: a prospective feasibility study.
Increasing rates of childhood overweight and obesity highlight a need for the evaluation of lifestyle interventions. The purpose of the study was to determine the Reach, Effectiveness, Adoption, Implementation and Maintenance of a novel family-focused program targeting children with obesity (i.e., the Children's Health and Activity Modification Program [C.H.A.M.P.]) using the RE-AIM framework, an evaluation tool for community-based health interventions. A single-centre, single cohort interventional feasibility study was conducted over the course of two years. Children with obesity and their families completed a 4-week group-based lifestyle intervention in Year 1 (n = 15; M age = 10.6; 53% female) and/or Year 2 (n = 25; M age = 10.6; 56% female). Outcome variables were measured pre- and post-intervention, as well as 6- and 12-months following completion of the formal program. Overall, C.H.A.M.P. had high reach in terms of participant representativeness. In addition, participation in the program was associated with significantly improved standardized body mass index (BMI-z), body fat percentage, lean mass percentage, and child- and parent-proxy reported quality of life (QOL; effectiveness/individual maintenance). Furthermore, a number of community partnerships were built, strengthened, and maintained prior to, during, and following implementation of the two-year program (adoption/setting maintenance, respectively). Finally, the intervention was delivered as intended as evidenced by high adherence to the schedule, attendance rates, and cost effectiveness (implementation). Based on RE-AIM metrics, C.H.A.M.P. appears to be a promising childhood obesity program. The findings reported will inform researchers and practitioners on how to design and implement future community-based programs addressing pediatric obesity. ISRCTN Registry, Study ID ISRCTN13143236. Registered 27 March 2015.


Improved performance of gravity-driven membrane filtration for seawater pretreatment: Implications of membrane module configuration.
As a low energy and chemical free process, gravity-driven membrane (GDM) filtration has shown a potential for seawater pretreatment in our previous studies. In this study, a pilot submerged GDM reactor (effective volume of 720 L) was operated over 250 days and the permeate flux stabilized at 18.6 ± 1.4 L/m2h at a hydrostatic pressure of 40 mbar. This flux was higher than those in the lab-scale GDM reactor (16.3 ± 0.2 L/m2h; effective volume of 8.4 L) and in the filtration cell system (2.7 ± 0.6 L/m2h; feed side volume of 0.0046 L) when the same flat sheet membrane was used. Interestingly, when the filtration cell was submerged into the GDM reactor, the flux (17.2 L/m2h) was comparable to the submerged membrane module. Analysis of cake layer morphology and foulant properties indicated that a thicker but more porous cake layer with less accumulation of organic substances (biopolymers and humics) contributed to the improved permeate flux. This phenomenon was possibly associated with longer residence time of organic substances and sufficient space for the growth, predation, and movement of the eukaryotes in the GDM reactor. In addition, the permeate flux of the submerged hollow fibre membrane increased with decreasing packing density. It is thought that the movement of large-sized eukaryotes could be limited when the space between hollow fibres was reduced. In terms of pretreatment, the GDM systems effectively removed turbidity, viable cells, and transparent exopolymer particles from the feed seawater. Importantly, extending the reactor operation time produced a permeate with less assimilable organic carbon and biopolymers. Thus, the superior quality of the GDM permeate has the potential to alleviate subsequent reverse osmosis membrane fouling for seawater treatment.


Origin, spread and demography of the Mycobacterium tuberculosis complex.
The evolutionary timing and spread of the Mycobacterium tuberculosis complex (MTBC), one of the most successful groups of bacterial pathogens, remains largely unknown. Here, using mycobacterial tandem repeat sequences as genetic markers, we show that the MTBC consists of two independent clades, one composed exclusively of M. tuberculosis lineages from humans and the other composed of both animal and human isolates. The latter also likely derived from a human pathogenic lineage, supporting the hypothesis of an original human host. Using Bayesian statistics and experimental data on the variability of the mycobacterial markers in infected patients, we estimated the age of the MTBC at 40,000 years, coinciding with the expansion of "modern" human populations out of Africa. Furthermore, coalescence analysis revealed a strong and recent demographic expansion in almost all M. tuberculosis lineages, which coincides with the human population explosion over the last two centuries. These findings thus unveil the dynamic dimension of the association between human host and pathogen populations.


Microfabrication inside capillaries using multiphase laminar flow patterning
The reaction of species in solutions flowing laminarly (without turbulent mixing) inside capillaries was used as the basis for a broadly applicable method of microfabrication. In this method, patterning occurs as a result of transport of reactive species to interfaces within the capillary by laminar flow. A wide range of chemistries can be used to generate structures with feature sizes of less than 5 micrometers and with spatial localization to within 5 micrometers. The method is applicable to the patterning of metals, organic polymers, inorganic crystals, and ceramics on the inner walls of preformed capillaries, using both additive and subtractive processes.


HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function.
The HERG (human ether-à-go-go-related gene) protein, which underlies the cardiac repolarizing current I(Kr), is the unintended target for many pharmaceutical agents. Inadvertent block of I(Kr), known as the acquired long QT syndrome (aLQTS), is a leading cause for drug withdrawal by the United States Food and Drug Administration. Hence, an improved understanding of the regulatory factors that protect most individuals from aLQTS is essential for advancing clinical therapeutics in broad areas, from cancer chemotherapy to antipsychotics and antidepressants. Here, we show that the K(+) channel regulatory protein KCR1, which markedly reduces I(Kr) drug sensitivity, protects HERG through glucosyltransferase function. KCR1 and the yeast alpha-1,2-glucosyltransferase ALG10 exhibit sequence homology, and like KCR1, ALG10 diminished HERG block by dofetilide. Inhibition of cellular glycosylation pathways with tunicamycin abrogated the effects of KCR1, as did expression in Lec1 cells (deficient in glycosylation). Moreover, KCR1 complemented the growth defect of an alg10-deficient yeast strain and enhanced glycosylation of an Alg10 substrate in yeast. HERG itself is not the target for KCR1-mediated glycosylation because the dofetilide response of glycosylation-deficient HERG(N598Q) was still modulated by KCR1. Nonetheless, our data indicate that the alpha-1,2-glucosyltransferase function is a key component of the molecular pathway whereby KCR1 diminishes I(Kr) drug response. Incorporation of in vitro data into a computational model indicated that KCR1 expression is protective against arrhythmias. These findings reveal a potential new avenue for targeted prevention of aLQTS.


Ab-initio coupled-cluster study of 16O.
We report converged results for the ground and excited states and matter density of 16O using realistic two-body nucleon-nucleon interactions and coupled-cluster methods and algorithms developed in quantum chemistry. Most of the binding is obtained with the coupled-cluster singles and doubles approach. Additional binding due to three-body clusters (triples) is minimal. The coupled-cluster method with singles and doubles provides a good description of the matter density, charge radius, charge form factor, and excited states of a one-particle, one-hole nature, but it cannot describe the first-excited 0(+) state. Incorporation of triples has no effect on the latter finding.


Symbiosis between Frankia and actinorhizal plants: root nodules of non-legumes.
In actinorhizal symbioses, filamentous nitrogen-fixing soil bacteria of the genus Frankia induce the formation of nodules on the roots of a diverse group of dicotyledonous plants representing trees or woody shrubs, with one exception, Datisca glomerata. In the nodules, Frankia fixes nitrogen and exports the products to the plant cytoplasm, while being supplied with carbon sources by the host. Possibly due to the diversity of the host plants, actinorhizal nodules show considerable variability with regard to structure, oxygen protection mechanisms and physiology. Actinorhizal and legume-rhizobia symbioses are evolutionary related and share several features.


Intraoperative application of topical mitomycin C 0.05% for pterygium surgery.
Pterygium recurrence is a common problem encountered by ophthalmic surgeons. Several methods have been suggested to avoid these recurrences. We studied the recurrence rate of pterygium after administration of a single intraoperative dosage of topical mitomycin C 0.05%. A retrospective analysis of fifty eyes in forty-nine patients who underwent pterygium excision by the same surgeon using intraoperative topical mitomycin C during the years 2002--2003. Mitomycin concentration was 0.05% applied to pterygium and adjacent areas after undermining and separation from sclera but prior to excision for three minutes. Postoperative follow up time was 12 months. The pterygium recurred in 4 (8%) eyes. Another four eyes (8%) had a cosmetically acceptable recurrence of < 2.0 mm. The only complication was a corneal dellen in one eye. Intraoperative administration of mitomycin C at 0.05% is safe and effective in preventing pterygium recurrences.


ACG Clinical Guideline: Alcoholic Liver Disease.
Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.


High-degree atrioventricular block, asystole, and electro-mechanical dissociation complicating non-ST-segment elevation myocardial infarction.
Non-ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs. Patients with NSTEMI in the EARLY ACS, PLATO, and TRACER trials were included in the pooled cohort (N = 29,677). Logistic regression was used to identify factors associated with in-hospital high-degree AV block and asystole or EMD, and Kaplan-Meier methods were used to assess mortality. High-degree AV block occurred in 112 (0.4%) patients, asystole in 157 (0.5%), and EMD in 38 (0.1%). Pacemakers were inserted in 241 patients (0.8%) during the index hospitalization: 30 (12%) for AV block. Among patients with high-degree AV block, we observed more frequent right coronary artery lesions (47% vs 29%). Age, diabetes, lower heart rate, and lower blood pressure were associated with high-degree AV block. Higher Killip class, ST-segment depression, prior myocardial infarction, and peripheral vascular disease were most strongly associated with asystole or EMD. Ten-day unadjusted survival was 90% for patients with high-degree AV block and 43% for those with asystole or EMD. Although high-degree AV block, asystole, and EMD were infrequent complications of NSTEMI, they were associated with substantial short-term mortality. Only 1 in 8 pacemakers placed in NSTEMI patients during the acute hospitalization was for high-degree AV block.


Paternal nicotine exposure in rats produces long-lasting neurobehavioral effects in the offspring.
Studies of intergenerational effects of parental chemical exposure have principally focused on maternal exposure, particularly for studies of adverse neurobehavioral consequences on the offspring. Maternal nicotine exposure has long been known to cause adverse neurobehavioral effects on the offspring. However, paternal toxicant exposure has also been found to cause neurobehavioral toxicity in their offspring. Recent work suggests that paternal nicotine exposure can have epigenetic effects, although it remains unclear whether such changes lead to neurobehavioral effects. In the current study, we investigated the effects of paternal nicotine exposure on neurobehavioral development of their offspring. Male Sprague-Dawley rats were exposed to 0 or 2 mg/kg/day nicotine (sc) for 56 consecutive days with two consecutive 2ML4 osmotic minipumps. Following treatment, these males were mated with drug-naïve female rats. Offspring of both sexes were tested in a behavioral battery to assess locomotion, emotional function and cognition. Paternal nicotine exposure did not impact offspring viability, health or growth. However, behavioral function of the offspring was significantly altered by paternal nicotine exposure. Male offspring with paternal nicotine exposure exhibited locomotor hyperactivity in the Figure-8 apparatus when tested during adolescence. When retested in adulthood and regardless of sex, offspring of the nicotine exposed father showed significantly reduced habituation of locomotor activity over the course of the session. Compared to controls, female offspring of nicotine-exposed fathers showed significantly reduced response latency in the radial arm maze test. In addition to locomotor hyperactivity, the offspring of nicotine-exposed fathers also showed significantly diminished habituation in the novel object recognition test. These results indicate that chronic paternal nicotine exposure can impact the behavior of offspring, producing locomotor hyperactivity and impaired habituation.