Natural attenuation of trichloroethylene in fractured shale bedrock.
This paper describes one of the first well-documented field examples of natural attenuation of trichloroethylene (TCE) in groundwater in a fractured shale bedrock. The study was carried out adjacent to a former waste burial site in Waste Area Grouping 5 (WAG5) on the Oak Ridge Reservation, Oak Ridge, TN. A contaminant plume containing TCE and its daughter products were detected downgradient from the buried waste pits, with most of the contamination occurring in the upper 6 m of the bedrock. The monitoring well array consists of a 35-m-long transect of multilevel sampling wells, situated along a line between the waste pits and a seep which discharges into a small stream. Concentrations of volatile organic carbons (VOCs) were highest in the waste trenches and decreased with distance downgradient towards the seep. Sampling wells indicated the presence of overlapping plumes of TCE, cis-dichloroethylene (cDCE), vinyl chloride (VC), ethylene, ethane, and methane, with the daughter products extending further downgradient than the parent (TCE). This type of distribution suggests anaerobic biodegradation. Measurements of redox potential at the site indicated that iron-reduction, sulfate reduction, and potentially methanogensis were occurring and are conducive to dechlorination of TCE. Bacteria enrichment of groundwater samples revealed the presence of methanotrophs, methanogens, iron-reducing bacteria and sulfate-reducing bacteria, all of which have previously been implicated in anaerobic biodegradation of TCE. 16S rDNA sequence from DNA extracted from two wells were similar to sequences of organisms previously implicated in the anaerobic biodegradation of chlorinated solvents. The combined data strongly suggest that anaerobic biodegradation of the highly chlorinated compounds is occurring. Aerobic biodegradation may also be occurring in oxygenated zones, including near a seep where groundwater exits the site, or in the upper bedrock during seasonal fluctuations in water table elevation and oxygen levels.


Standard versus atrial fibrillation-specific management strategy (SAFETY) to reduce recurrent admission and prolong survival: pragmatic, multicentre, randomised controlled trial.
Patients are increasingly being admitted with chronic atrial fibrillation, and disease-specific management might reduce recurrent admissions and prolong survival. However, evidence is scant to support the application of this therapeutic approach. We aimed to assess SAFETY--a management strategy that is specific to atrial fibrillation. We did a pragmatic, multicentre, randomised controlled trial in patients admitted with chronic, non-valvular atrial fibrillation (but not heart failure). Patients were recruited from three tertiary referral hospitals in Australia. 335 participants were randomly assigned by computer-generated schedule (stratified for rhythm or rate control) to either standard management (n=167) or the SAFETY intervention (n=168). Standard management consisted of routine primary care and hospital outpatient follow-up. The SAFETY intervention comprised a home visit and Holter monitoring 7-14 days after discharge by a cardiac nurse with prolonged follow-up and multidisciplinary support as needed. Clinical reviews were undertaken at 12 and 24 months (minimum follow-up). Coprimary outcomes were death or unplanned readmission (both all-cause), measured as event-free survival and the proportion of actual versus maximum days alive and out of hospital. Analyses were done on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTRN 12610000221055). During median follow-up of 905 days (IQR 773-1050), 49 people died and 987 unplanned admissions were recorded (totalling 5530 days in hospital). 127 (76%) patients assigned to the SAFETY intervention died or had an unplanned readmission (median event-free survival 183 days [IQR 116-409]) and 137 (82%) people allocated standard management achieved a coprimary outcome (199 days [116-249]; hazard ratio 0·97, 95% CI 0·76-1·23; p=0·851). Patients assigned to the SAFETY intervention had 99·5% maximum event-free days (95% CI 99·3-99·7), equating to a median of 900 (IQR 767-1025) of 937 maximum days alive and out of hospital. By comparison, those allocated to standard management had 99·2% (95% CI 98·8-99·4) maximum event-free days, equating to a median of 860 (IQR 752-1047) of 937 maximum days alive and out of hospital (effect size 0·22, 95% CI 0·21-0·23; p=0·039). A post-discharge management programme specific to atrial fibrillation was associated with proportionately more days alive and out of hospital (but not prolonged event-free survival) relative to standard management. Disease-specific management is a possible strategy to improve poor health outcomes in patients admitted with chronic atrial fibrillation. National Health and Medical Research Council of Australia.


Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression.
The mouse 4T1 mammary carcinoma is a BALB/c-derived tumor that spontaneously metastasizes and induces immune suppression. Although >95% of wild type BALB/c mice die from metastatic 4T1 tumor even if the primary mammary tumor is surgically removed, >65% of BALB/c mice with a deleted Signal Transducer Activator of Transcription 6 (STAT6) gene survive post-surgery. STAT6-deficiency also confers enhanced immunity against spontaneously developing breast cancer since NeuT+/- mice that are STAT6-deficient develop mammary tumors later and survive longer than NeuT+/- mice that are STAT6-competent. Rejection of metastastic disease and survival of STAT6-deficient mice after removal of primary tumor involve three mechanisms: (1) The generation of M1 type macrophages that produce nitric oxide and are tumoricidal; (2) A decrease to normal in the elevated levels of myeloid suppressor cells that accumulate during primary tumor growth; and (3) CD8+ tumor-specific T lymphocytes. STAT6-deficient, but not wild type BALB/c, mice generate nitric oxide producing macrophages because they lack the STAT6 transcription factor which is necessary for signaling through the type 2 IL-4Ralpha complex, and which induces the production of arginase instead of nitric oxide.


The activation of protein kinase A pathway selectively inhibits anterograde axonal transport of vesicles but not mitochondria transport or retrograde transport in vivo.
To shed light on how axonal transport is regulated, we examined the possible roles of protein kinase A (PKA) in vivo suggested by our previous work (Sato-Yoshitake et al., 1992). Pharmacological probes or the purified catalytic subunit of PKA were applied to the permeabilized-reactivated model of crayfish walking leg giant axon, and the effect was monitored by the quantitative video-enhanced light microscopy and the quantitative electron microscopy. Dibutyryl cyclic AMP caused concentration-dependent transient reduction in the number of anterogradely transported small vesicles, while the retrogradely transported organelles and anterogradely transported mitochondria showed no decrease. This transient selective inhibition of anterograde vesicle transport was reversed by the application of a specific inhibitor of PKA (KT5720) in a concentration-dependent manner, and was reproduced by the application of the purified catalytic subunit of PKA and augmented by the application of adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S). Corresponding biochemical study showed that several axoplasmic proteins including kinesin were specifically phosphorylated by the activation of the PKA pathway. These findings suggest the possible roles of PKA in the regulation of the direction of the axonal transport in vivo. The finding that only vesicle transport but not mitochondria transport was inhibited also suggests that the transport of vesicles and that of mitochondria are differently regulated and might be supported by different motors.


Transcatheter aortic valve replacement in patients with pure native aortic valve regurgitation: A systematic review and meta-analysis.
This systematic review and meta-analysis sought to summarize the available evidence on the use of transcatheter aortic valve replacement (TAVR) in patients with Native Aortic Valve Regurgitation (NAVR) and compare outcomes between first and second generation valves. Owing to the improvements in transcatheter heart valve design and procedural success, TAVR has become increasingly performed in broader aortic valve pathologies. We searched Medline, Embase, Cochrane, and Scopus databases from 2007 to 2018 and performed a systematic review on reports with at least 10 patients with aortic valve regurgitation undergoing TAVR procedure. The main outcome of interest was all-cause mortality at 30 days. A total of 638 patients across 12 studies were included. Mean age ranged from 68 to 84. Society of Thoracic Surgeons score ranged from 5.4% to 13.1% and Logistic EuroSCORE ranged from 18.2% to 33%. The incidence rate of all-cause mortality at 30 days was found to be 11% (95% CI 7%-16%; I2 = 20.86%). All-cause mortality at 30 days for first generation valves had an incidence rate of 15% (95% CI 10%-20%; I2 = 10%) compared to 7% (95% CI 3%-13%; I2 = 37%) in second generation valves with subgroup interaction analysis P = 0.059. Device success incidence rate in second generation valves was 92% (95% CI 83%-99%; I2 = 67%) vs 68% (95% CI 59%-77%; I2 = 53%) in first generation valves with P = 0.001. TAVR appears to be a feasible treatment choice for NAVR patients at high risk for surgical valve replacement. Second generation valves show promising results in terms of short-term outcomes.


Treatment of discontinuous emission of sewage sludge odours by a full scale biotrickling filter with an activated carbon polishing unit.
A SULPHUSTM biotrickling filter (BTF) and an ACTUSTM polishing activated carbon filter (ACF) were used at a wastewater treatment plant to treat 2,432 m3·h-1 of air extracted from sewage sludge processes. The project is part of Thames Water's strategy to reduce customer odour impact and, in this case, is designed to achieve a maximum discharge concentration of 1,000 ouE·m-3. The odour and hydrogen sulphide concentration in the input air was more influenced by the operation of the sludge holding tank mixers than by ambient temperature. Phosphorus was found to be limiting the performance of the BTF during peak conditions, hence requiring additional nutrient supply. Olfactometry and pollutant measurements demonstrated that during the high rate of change of intermittent odour concentrations the ACF was required to reach compliant stack values. The two stage unit outperformed design criteria, with 139 ouE·m-3 measured after 11 months of operation. At peak conditions and even at very low temperatures, the nutrient addition considerably increased the performance of the BTF, extending the time before activated carbon replacement over the one year design time. During baseline operation, the BTF achieved values between 266-1,647 ouE·m-3 even during a 6 day irrigation failure of the biofilm.


Pinceau organization in the cerebellum requires distinct functions of neurofascin in Purkinje and basket neurons during postnatal development.
Basket axon collaterals synapse onto the Purkinje soma/axon initial segment (AIS) area to form specialized structures, the pinceau, which are critical for normal cerebellar function. Mechanistic details of how the pinceau become organized during cerebellar development are poorly understood. Loss of cytoskeletal adaptor protein Ankyrin G (AnkG) results in mislocalization of the cell adhesion molecule Neurofascin (Nfasc) at the Purkinje AIS and abnormal organization of the pinceau. Loss of Nfasc in adult Purkinje neurons leads to slow disorganization of the Purkinje AIS and pinceau morphology. Here, we used mouse conditional knock-out techniques to show that selective loss of Nfasc, specifically in Purkinje neurons during early development, prevented maturation of the AIS and resulted in loss of Purkinje neuron spontaneous activity and pinceau disorganization. Loss of Nfasc in both Purkinje and basket neurons caused abnormal basket axon collateral branching and targeting to Purkinje soma/AIS, leading to extensive pinceau disorganization, Purkinje neuron degeneration, and severe ataxia. Our studies reveal that the Purkinje Nfasc is required for AIS maturation and for maintaining stable contacts between basket axon terminals and the Purkinje AIS during pinceau organization, while the basket neuron Nfasc in combination with Purkinje Nfasc is required for proper basket axon collateral outgrowth and targeting to Purkinje soma/AIS. Thus, cerebellar pinceau organization requires coordinated mechanisms involving specific Nfasc functions in both Purkinje and basket neurons.


Antigen-specific and non-specific helper activities derived from supernatants of human influenza virus-specific T-cell lines.
A T-cell line (H3) was established by culturing human peripheral blood mononuclear cells with influenza virus A/X31 and maintained in long term culture with Interleukin-2 (TCGF). Supernatants were prepared by culturing these cells overnight in the absence of Interleukin-2 but with A/X31 and irradiated autologous E rosette negative cells as a source of antigen presenting cells, and harvesting by centrifugation. The supernatants were shown to replace T cells in helping E- (B) cells to produce antibody specific to A/X31 which was measured by enzyme immunoassay (EIA). Although maximal help was obtained with autologous or semi allogeneic B cells (in the latter case bearing HLA-DR 3 loci) there was still significant antibody production with allogeneic combinations. The supernatants were subsequently fractionated into specific and non-specific helper activities by gel filtration, giving an approximate mol. wt of 50-70,000 and 10-30,000 for each respectively. The specific HF was shown to be genetically restricted in its action upon B cells and also to generate antibody to A/X31 only. The lower molecular weight material acted on any responding B cell regardless of HLA-DR type and produced antibody non-specifically in culture with E- cells even in the absence of antigen. The apparent lack of restriction was therefore due to the masking effect of non-specific and non-restricted HF(s) on the genetically restricted specific HF produced by this line.


"Molecular Activity Painting": Switch-like, Light-Controlled Perturbations inside Living Cells.
Acute subcellular protein targeting is a powerful tool to study biological networks. However, signaling at the plasma membrane is highly dynamic, making it difficult to study in space and time. In particular, sustained local control of molecular function is challenging owing to the lateral diffusion of plasma membrane targeted molecules. Herein we present "molecular activity painting" (MAP), a novel technology which combines photoactivatable chemically induced dimerization (pCID) with immobilized artificial receptors. The immobilization of artificial receptors by surface-immobilized antibodies blocks lateral diffusion, enabling rapid and stable "painting" of signaling molecules and their activity at the plasma membrane with micrometer precision. Using this method, we show that painting of the RhoA-myosin activator GEF-H1 induces patterned acto-myosin contraction inside living cells.


Walking for transport versus recreation: a comparison of participants, timing, and locations.
Walking is the most common physical activity for adults with important implications for urban planning and public health. Recreational walking has received considerably more attention than walking for transport, and differences between them remain poorly understood. Using time-use data collected from 1971 randomly-chosen adults in Halifax, Canada, we identified walking for transport and walking for recreation events, and then computed participation rates, occurrences, mean event durations, and total daily durations in order to examine the participants and timing, while the locations were examined using origin-destination matrices. We compared differences using McNemar's test for participation rates, Wilcoxon test for occurrences and durations, and Chi-Square test for locations. Results illustrate many significant differences between the 2 types of walking, related to participants, timing, and locations. For example, results indicate a daily average of 3.1 walking for transport events, each lasting 8 minutes on average, compared with 1.4 recreational walking events lasting 39 minutes on average. Results also indicate more than two-thirds of recreational walks are home-based, compared with less than one-fifth of transport walks. This research highlights the importance of both types of walking, while also casting suspicion on the traditional home-based paradigm used to measure "walkability."


Myosin motor function: the ins and outs of actin-based membrane protrusions.
Cells build plasma membrane protrusions supported by parallel bundles of F-actin to enable a wide variety of biological functions, ranging from motility to host defense. Filopodia, microvilli and stereocilia are three such protrusions that have been the focus of intense biological and biophysical investigation in recent years. While it is evident that actin dynamics play a significant role in the formation of these organelles, members of the myosin superfamily have also been implicated as key players in the maintenance of protrusion architecture and function. Based on a simple analysis of the physical forces that control protrusion formation and morphology, as well as our review of available data, we propose that myosins play two general roles within these structures: (1) as cargo transporters to move critical regulatory components toward distal tips and (2) as mediators of membrane-cytoskeleton adhesion.


Predictive factors for positive coronary angiography in out-of-hospital cardiac arrest patients.
Coronary angiography is often performed in survivors of out-of-hospital cardiac arrest, but little is known about the factors predictive of a positive coronary angiography. Our aim was to determine these factors. In this 7-year retrospective study (January 2000-December 2006) conducted by a French out-of-hospital emergency medical unit, data were collected according to Utstein style guidelines on all out-of-hospital cardiac arrest patients with suspected coronary disease who recovered spontaneous cardiac activity and underwent early coronary angiography. Coronary angiography was considered positive if a lesion resulting in more than a 50% reduction in luminal diameter was observed or if there was a thrombus at an occlusion site. Among the 4621 patients from whom data were collected, 445 were successfully resuscitated and admitted to hospital. Of these, 133 were taken directly to the coronary angiography unit, 95 (71%) had at least one significant lesion, 71 (53%) underwent a percutaneous coronary intervention, and 30 survived [23%, 95% confidence interval (CI): 16-30]. According to multivariate analysis, the factors predictive of a positive coronary angiography were a history of diabetes [odds ratio (OR): 7.1, 95% CI: 1.4-36], ST segment depression on the out-of-hospital ECG (OR: 5.4, 95% CI: 1.1-27.8), a history of coronary disease (OR: 5.3, 95% CI: 1.4-20.1), cardiac arrest in a public place (OR: 3.7, 95% CI: 1.3-10.7), and ventricular fibrillation or ventricular tachycardia as initial rhythm (OR: 3.1, 95% CI: 1.1-8.6). Among the factors identified, diabetes and a history of coronary artery were strong predictors for a positive coronary angiography, whereas ST segment elevation was not as predictive as expected.


Impact of Scoliosis Severity on Functional Capacity in Patients With Adolescent Idiopathic Scoliosis.
The aim of this study is to evaluate the walked distance and physiological responses during incremental shuttle walk test in patients with different degrees of adolescent idiopathic scoliosis (AIS). We evaluated 20 healthy teenagers and 46 patients with AIS; they were divided into 2 groups: AIS > 45° and AIS < 45°. The volunteers performed an incremental shuttle walk test, and the following physiological responses were quantified: oxygen consumption, tidal volume, ventilation, and the incremental shuttle walked distance. Respiratory muscle strength was quantified, pulmonary function test was performed, and the forced vital capacity and expiratory volume in the first second were obtained. Patients with AIS > 45° presented significant reduced incremental shuttle walked distance compared with the AIS < 45° and control group [447 (85), 487 (95), and 603 (85), respectively]. Patients with AIS also showed reduced forced vital capacity (P = .001) and expiratory volume in the first second (P = .005) compared with control group. Moderate correlations between forced vital capacity (r = -.506) and tidal volume (r = -.476) with scoliosis angles were found. The incremental shuttle walk test was capable of identifying reduced functional capacity in patients with different degrees of AIS. Moreover, the severity of spinal curvature may exert influence on ventilatory and metabolic variables.


Stimuli-responsive and cellular targeted nanoplatforms for multimodal therapy of skin cancer.
Interdisciplinary applications of nanopharmaceutical sciences have tremendous potential for enhancing pharmacokinetics, efficacy and safety of cancer therapy. The limitations of conventional therapeutic platforms used for skin cancer therapy have been largely overcome by the use of nanoplatforms. This review discusses various nanotechnological approaches experimented for the treatment of skin cancer. The review describes various polymeric, lipidic and inorganic nanoplatforms for efficient therapy of skin cancer. The stimuli-responsive nanoplatforms such as pH-responsive as well as temperature-responsive platforms have also been reviewed. Different strategies for potentiating the nanoparticles application for cancer therapy such as surface engineering, conjugation with drugs, stimulus-responsive and multimodal effect have also been discussed and compared with the available conventional treatments. Although, nanopharmaceuticals face challenges such as toxicity, cost and scale-up, efforts put-in to improve these drawbacks with continuous research would deliver exciting and promising results in coming days.


Environmental and Genetic Factors Explain Differences in Intraocular Scattering.
To study the relative impact of genetic and environmental factors on the variability of intraocular scattering within a classical twin study. A total of 64 twin pairs, 32 monozygotic (MZ) (mean age: 54.9 ± 6.3 years) and 32 dizygotic (DZ) (mean age: 56.4 ± 7.0 years), were measured after a complete ophthalmologic exam had been performed to exclude all ocular pathologies that increase intraocular scatter as cataracts. Intraocular scattering was evaluated by using two different techniques based on a straylight parameter log(S) estimation: a compact optical instrument based in the principle of optical integration and a psychophysical measurement. Intraclass correlation coefficients (ICC) were used as descriptive statistics of twin resemblance, and genetic models were fitted to estimate heritability. No statistically significant difference was found for MZ and DZ groups for age (P = 0.203), best-corrected visual acuity (P = 0.626), cataract gradation (P = 0.701), sex (P = 0.941), optical log(S) (P = 0.386), or psychophysical log(S) (P = 0.568), with only a minor difference in equivalent sphere (P = 0.008). Intraclass correlation coefficients between siblings were similar for scatter parameters: 0.676 in MZ and 0.471 in DZ twins for optical log(S); 0.533 in MZ twins and 0.475 in DZ twins for psychophysical log(S). For equivalent sphere, ICCs were 0.767 in MZ and 0.228 in DZ twins. Conservative estimates of heritability for the measured scattering parameters were 0.39 and 0.20, respectively. Correlations of intraocular scatter (straylight) parameters in the groups of identical and nonidentical twins were similar. Heritability estimates were of limited magnitude, suggesting that genetic and environmental factors determine the variance of ocular straylight in healthy middle-aged adults.


Short-Term Change in Couples' Conflict Following a Transition to Parenthood Intervention.
Conflict among couples was examined following a transition to parenthood intervention to determine both short-term efficacy of the program and elucidate the process of change postintervention. A randomized clinical trial design was used to examine conflict in couples who participated in a transition to parenthood psycho-educational workshop compared with controls. The beginnings of improved communication in conflict were evident at 3 months postbirth through decreased husband contempt and increased husband positive affect during conflict in a sample that demonstrated more substantial improvement at 1 year postintervention. Increases in husband positive affect in the workshop group at 3 months postbirth predicted more positive and less negative wife affect during conflict at 1 year postbirth. Results suggest that some indicators of intervention efficacy were evident, postintervention change can be gradual, husbands may be more receptive to implementing change shortly after birth, and early changes can be associated with later positive outcomes. Findings have implications for preparing couples for the gradual and complex nature of change associated with intervention.


lasA and lasB genes of Pseudomonas aeruginosa: analysis of transcription and gene product activity.
The lasA gene was the first of the Pseudomonas aeruginosa genes involved in proteolysis and elastolysis to be cloned and sequenced. Its function and significance have been studied by genetic approaches (D. S. Toder, M. J. Gambello, and B. H. Iglewski, Mol. Microbiol. 5:2003-2010, 1991) and by attempts to purify an active fragment of the protein (J. E. Peters and D. R. Galloway, J. Bacteriol. 172:2236-2240, 1990). To further study LasA in vivo, we have constructed and characterized an insertional mutant in the lasA gene in strain PAO1 (PAO-A1) and in the lasB insertional mutant, PAO-B1. Analysis of these isogenic strains demonstrates that the lasA lesion diminished elastolysis more than proteolysis and that LasA is required for staphylolytic activity. Despite previous suggestions that lasB elastase cleaves the LasA protein, the size of the LasA protein was the same whether or not lasB elastase was present. Expression of lasA in a lasR-negative mutant, PAO-R1, demonstrated that the LasA protein is produced in an active form in the absence of (lasB) elastase or alkaline protease and is itself a protease with elastolytic activity. We also observed that PAO-A1 was closer to the parental phenotype, with respect to elastolytic and proteolytic activities, than the previously characterized, chemically induced lasA mutant PAO-E64. Quantification of promoter activity with lasA::lacZ and lasB::lacZ fusions suggests that PAO-E64 harbors a mutation in a gene which regulates expression of both lasA and lasB.


Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney.
Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor+ (p75NTR+) fibroblasts and homeostatic chemokine-producing fibroblasts inside TLTs, and retinoic acid-producing fibroblasts around TLTs. Deletion of CD4+ cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.


Motor proficiency associated with vestibular deficits in children with hearing impairments.
The purpose of this study was to investigate the relationship of vestibular function to motor proficiency, including balance, in children with hearing impairments. Thirteen children with normal hearing and 29 children with hearing impairments, ranging in age from 7 to 13 years, were classified into categories based on vestibular function using neuro-otologic measures (ie, vestibulo-ocular reflex function and posturography). Children in each category were tested for motor proficiency using clinical assessment measures (eg, balance, muscle tone, and coordination). The test results indicated that the children with hearing impairments and normal peripheral vestibular function (n = 7) exhibited normal motor proficiency, including balance. The children with hearing impairments and loss of peripheral vestibular sensitivity (n = 19) also demonstrated normal motor proficiency, except for balance ability. The children with hearing impairments and sensory organization deficits (n = 3), however, exhibited motor deficits in many areas. The results of this study indicate that motor proficiency in children with hearing impairments depends on vestibular function. Interventions for motor deficits in children with hearing impairments, therefore, must consider vestibular function as well as motor performance.


Isolation and characterisation of a melon cDNA clone encoding phytoene synthase.
A cDNA clone (MEL5), encoding a protein homologous to phytoene synthase (PSY), has been isolated from a climacteric melon fruit cDNA library, using the tomato cDNA clone TOM5 [34] as a heterologous probe. MEL5 hybridised to a transcript of 1.65 kb which suggested that the 1.36 kb clone, isolated originally, was not full-length. The missing 5' end was isolated by a reverse transcriptase-polymerase chain reaction (RT-PCR)-based method. This enabled the full sequence of the protein to be deduced and the cleavage site of the transit peptide for chromoplast import to be predicted. Northern analysis of RNA extracted from fruit samples of different ripening stages as well as from roots, leaves and flower petals was used to examine the expression pattern of the corresponding mRNA. The corresponding mRNA. The transcript corresponding to MEL5 is present at low quantities in unripe (green) fruit, reaches its highest levels when the fruit turns from green to orange and persists at lower levels during later ripening stages. A similar transcript was also detected in flower petals and in trace amounts in leaves and roots. Genomic Southern analysis indicates that the clone is homologous to a low-copy-number gene family. Sequence analysis showed a high degree of conservation among plant PSYs.


Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study.
FEV(1) is used for the classification of disease severity and is a good predictor of COPD mortality. However, it is a poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD. Progressive reduction in inspiratory capacity (IC) during exercise reflects dynamic hyperinflation and is a good predictor of decreased exercise ability as well as increased exertional dyspnea. In animal models of COPD, N-acetylcysteine (NAC), an antioxidant/mucous modifier, has been shown to modify small airways, which mainly causes lung hyperinflation. Our goal was to examine the effect of 1,200 mg/d of NAC on lung hyperinflation at rest and after exercise in patients with moderate-to-severe COPD. This was a randomized, double-blind, cross-over study that included 24 eligible patients > 40 years of age with a diagnosis of COPD, a FEV(1) < 70% of predicted, FEV(1)/FVC ratio < 0.70, and a functional residual capacity > 120% of predicted normal. Patients were randomized to placebo treatment or NAC treatment twice daily for 6 weeks. This was followed by a 2-week washout period, and then patients were crossed over to alternate therapy for an additional 6 weeks. Evaluation was performed after each 6 weeks of each treatment. IC and FVC were higher especially after exercise after NAC treatment compared with placebo treatment. In addition, the relationship of residual volume to total lung capacity was reduced in a similar pattern. Furthermore, endurance time was longer after NAC treatment compared with placebo treatment. NAC treatment of patients with stable, moderate-to-severe COPD has a beneficial effect on physical performance, probably due to a reduction in air trapping. Clinicaltrials.gov Identifier: NCT00476736.


PhylOTU: a high-throughput procedure quantifies microbial community diversity and resolves novel taxa from metagenomic data.
Microbial diversity is typically characterized by clustering ribosomal RNA (SSU-rRNA) sequences into operational taxonomic units (OTUs). Targeted sequencing of environmental SSU-rRNA markers via PCR may fail to detect OTUs due to biases in priming and amplification. Analysis of shotgun sequenced environmental DNA, known as metagenomics, avoids amplification bias but generates fragmentary, non-overlapping sequence reads that cannot be clustered by existing OTU-finding methods. To circumvent these limitations, we developed PhylOTU, a computational workflow that identifies OTUs from metagenomic SSU-rRNA sequence data through the use of phylogenetic principles and probabilistic sequence profiles. Using simulated metagenomic data, we quantified the accuracy with which PhylOTU clusters reads into OTUs. Comparisons of PCR and shotgun sequenced SSU-rRNA markers derived from the global open ocean revealed that while PCR libraries identify more OTUs per sequenced residue, metagenomic libraries recover a greater taxonomic diversity of OTUs. In addition, we discover novel species, genera and families in the metagenomic libraries, including OTUs from phyla missed by analysis of PCR sequences. Taken together, these results suggest that PhylOTU enables characterization of part of the biosphere currently hidden from PCR-based surveys of diversity?


Characterization of the self-palmitoylation activity of the transport protein particle component Bet3.
Bet3, a transport protein particle component involved in vesicular trafficking, contains a hydrophobic tunnel occupied by a fatty acid linked to cysteine 68. We reported that Bet3 has a unique self-palmitoylating activity. Here we show that mutation of arginine 67 reduced self-palmitoylation of Bet3, but the effect was compensated by increasing the pH. Thus, arginine helps to deprotonate cysteine such that it could function as a nucleophile in the acylation reaction which is supported by the structural analysis of non-acylated Bet3. Using fluorescence spectroscopy we show that long-chain acyl-CoAs bind with micromolar affinity to Bet3, whereas shorter-chain acyl-CoAs do not interact. Mutants with a deleted acylation site or a blocked tunnel bind to Pal-CoA, only the latter with slightly reduced affinity. Bet3 contains three binding sites for Pal-CoA, but their number was reduced to two in the mutant with an obstructed tunnel, indicating that Bet3 contains binding sites on its surface.


Growth curve models of repeated binary response.
Experimental designs that include repeated measures of binary response variables over time and under different conditions are common in biology. In such settings, it is often desirable to characterize the response pattern over time. When response variables are continuous, this characterization can be made in terms of a growth model such as the Potthoff-Roy growth curve model. We illustrate how a similar growth curve modeling strategy can be implemented using weighted least squares (WLS) methods for binary response data. The growth models are constructed in terms of polynomial functions across marginal response. However, when growth models are fit to repeated binary response, the nonsignificant higher-order polynomial functions are dropped from the model, rather than used as covariates. Dropping the nonsignificant polynomials from the model will reduce the number of response functions, and help avoid small-sample problems that can occur when the number of correlated response functions is large and sample sizes are small. The reduced set of response functions are then modeled using WLS methods. We illustrate such models with an example of binary fly oviposition response (accept or reject) exhibited by two populations of flies at four ages to two types of fruit.


The murmur of pulmonic regurgitation in tetralogy of Fallot with absent pulmonic valve.
Absent pulmonic valve (APV) in tetralogy of Fallot produces a pulmonic regurgitation murmur (PRM) which is usually late in onset after A2, low pitched, and of crescendo-decrescendo character. We have seen three adult patients with tetralogy of Fallot with APV and have done intracardiac sound and pressure studies in two. The PRM was loudest in the RV outflow tract (RVOT), where the onset was earlier than the murmur recorded on the chest wall. The crescendo portion of the PRM occurred during an abnormally slow decline in the RVOT pressure pulse after the crossover of PA and RVOT pressures. The RVOT pressure reached its minimum 30 msec after the RV body pressure, resulting in a pressure gradient between the two. The PRM peaked 30 msec later in the RV body than in the RVOT. The delayed precordial onset of the PRM after A2 is likely due to failure of transmission of early vibrations through the chest wall. The morphology of the PRM in tetralogy of Fallot with APV may be related to delayed relaxation with altered diastolic compliance of the RVOT which is subjected to a large regurgitant volume from the massively dilated pulmonary arteries.


EEG electrode caps can reduce SAR induced in the head by GSM900 mobile phones.
This paper investigates the influence of EEG electrode caps on specific absorption rate (SAR) in the head from a GSM900 mobile phone (217-Hz modulation, peak power output 2 W). SAR measurements were recorded in an anthropomorphic phantom using a precision robotic system. Peak 10 g average SAR in the whole head and in just the temporal region was compared for three phantom arrangements; no cap, 64-electrode "Electro-Cap," and 64-electrode "Quick-Cap". Relative to the "no cap" arrangement, the Electro-Cap and Quick-Cap caused a peak SAR (10 g) reduction of 14% and 18% respectively in both the whole head and in the temporal region. Additional computational modeling confirmed that SAR (10 g) is reduced by the presence of electrode leads and that the extent of the effect varies according to the orientation of the leads with respect to the radiofrequency (RF) source. The modeling also indicated that the nonconductive shell between the electrodes and simulated head material does not significantly alter the electrode lead shielding effect. The observed SAR reductions are not likely to be sufficiently large to have accounted for null EEG findings in the past but should nonetheless be noted in studies aiming to measure and report human brain activity under similar exposure conditions.


Randomised, open-label, multicentre trial comparing haemodialysis plus haemoperfusion versus haemodialysis alone in adult patients with end-stage renal disease (HD/HP vs HD): study protocol.
Haemodialysis (HD) is the cornerstone treatment for patients with end-stage renal disease (ESRD). However, highly protein bound or large molecular weight uremic toxins such as phenolic and indolic compounds and homocysteine, which are associated with adverse outcomes such as cardiovascular disease of patients with ESRD, are difficult to remove via HD but can be effectively eliminates by haemoperfusion (HP). The proposed trial (referred to as HD/HP vs HD below) is a randomised, open-label, multicentre trial comparing HD plus HP versus HD alone in adult patients with ESRD. The primary endpoint measure is all-cause mortality. We plan to enrol 1364 maintenance HD patients from 11 medical centres in Shanghai. Participants will be randomised to receive HD plus HP or HD alone at a 1:1 ratio after 1-month run-in period. In both arms, patients will receive low-flux HD at a frequency of two times a week and haemodiafiltration at a frequency of once a week. In the intervention group, subjects also received HP once every 2 weeks. Follow-up is scheduled at 3, 6, 12, 18 and 24 months after randomisation, and will consist the following: routine physical examinations, standard lab panels (blood routine, liver/residual kidney functions, tests of the coagulation system, etc), dialysis adequacy (standard Kt/V), chest X-ray, ECG, echocardiography, heart function rating. Adverse events will be assessed according to the international conference on harmonisation guidelines. The primary outcome is 24-month all-cause mortality. Secondary outcomes will include cardiovascular-related mortality, the occurrence of major cardiovascular events and the quality of life. The study protocol has been approved by the Ethical Committees of all 11 participating centres. Clinical Research Unit of Xin Hua Hospital will oversee the study. The results will be presented at national and international academic meetings, and submitted to peer-reviewed journals for publications. NCT03227770; Pre-results.


Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2; also known as ERBB2), was investigated in combination with chemotherapy for first-line treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer. ToGA (Trastuzumab for Gastric Cancer) was an open-label, international, phase 3, randomised controlled trial undertaken in 122 centres in 24 countries. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation. Participants were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine plus cisplatin or fluorouracil plus cisplatin given every 3 weeks for six cycles or chemotherapy in combination with intravenous trastuzumab. Allocation was by block randomisation stratified by Eastern Cooperative Oncology Group performance status, chemotherapy regimen, extent of disease, primary cancer site, and measurability of disease, implemented with a central interactive voice recognition system. The primary endpoint was overall survival in all randomised patients who received study medication at least once. This trial is registered with ClinicalTrials.gov, number NCT01041404. 594 patients were randomly assigned to study treatment (trastuzumab plus chemotherapy, n=298; chemotherapy alone, n=296), of whom 584 were included in the primary analysis (n=294; n=290). Median follow-up was 18.6 months (IQR 11-25) in the trastuzumab plus chemotherapy group and 17.1 months (9-25) in the chemotherapy alone group. Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 197 [67%] vs chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs 134 [46%]), and neutropenia (157 [53%] vs 165 [57%]). Rates of overall grade 3 or 4 adverse events (201 [68%] vs 198 [68%]) and cardiac adverse events (17 [6%] vs 18 [6%]) did not differ between groups. Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. F Hoffmann-La Roche.


Characterisation of Casein Kinase 1.1 in Leishmania donovani Using the CRISPR Cas9 Toolkit.
The recent adaptation of CRISPR Cas9 genome editing to Leishmania spp. has opened a new era in deciphering Leishmania biology. The method was recently improved using a PCR-based CRISPR Cas9 approach, which eliminated the need for cloning. This new approach, which allows high-throughput gene deletion, was successfully validated in L. mexicana and L. major. In this study, we validated the toolkit in Leishmania donovani targeting the flagellar protein PF16, confirming that the tagged protein localizes to the flagellum and that null mutants lose their motility. We then used the technique to characterise CK1.1, a member of the casein kinase 1 family, which is involved in the regulation of many cellular processes. We showed that CK1.1 is a low-abundance protein present in promastigotes and in amastigotes. We demonstrated that CK1.1 is not essential for promastigote and axenic amastigote survival or for axenic amastigote differentiation, although it may have a role during stationary phase. Altogether, our data validate the use of PCR-based CRISPR Cas9 toolkit in L. donovani, which will be crucial for genetic modification of hamster-derived, disease-relevant parasites.


Optical computing: introduction by the feature editors.
This feature issue of Applied Optics: Information Processing contains 19 papers on Optical Computing. Many of these papers are expanded versions of presentations given at the Optical Society of America's Sixth Topical Meeting on Optical Computing held in Salt Lake City, Utah, in March 1995. This introduction provides a brief historical account of the series of optical computing meetings and a brief review of the papers contained in this special issue.


AADS: Augmented autonomous driving simulation using data-driven algorithms.
Simulation systems have become essential to the development and validation of autonomous driving (AD) technologies. The prevailing state-of-the-art approach for simulation uses game engines or high-fidelity computer graphics (CG) models to create driving scenarios. However, creating CG models and vehicle movements (the assets for simulation) remain manual tasks that can be costly and time consuming. In addition, CG images still lack the richness and authenticity of real-world images, and using CG images for training leads to degraded performance. Here, we present our augmented autonomous driving simulation (AADS). Our formulation augmented real-world pictures with a simulated traffic flow to create photorealistic simulation images and renderings. More specifically, we used LiDAR and cameras to scan street scenes. From the acquired trajectory data, we generated plausible traffic flows for cars and pedestrians and composed them into the background. The composite images could be resynthesized with different viewpoints and sensor models (camera or LiDAR). The resulting images are photorealistic, fully annotated, and ready for training and testing of AD systems from perception to planning. We explain our system design and validate our algorithms with a number of AD tasks from detection to segmentation and predictions. Compared with traditional approaches, our method offers scalability and realism. Scalability is particularly important for AD simulations, and we believe that real-world complexity and diversity cannot be realistically captured in a virtual environment. Our augmented approach combines the flexibility of a virtual environment (e.g., vehicle movements) with the richness of the real world to allow effective simulation.


The clinical diagnosis of acute purulent sinusitis in general practice--a review.
Acute sinusitis is a common illness in primary care. Studies have demonstrated the difficulty of making the differential diagnosis of acute purulent sinusitis based on clinical evaluations alone. This leads to a significant overuse of antibiotics, which in turn may contribute to increased bacterial resistance. In most cases, GPs have to base their differential diagnosis of sinusitis on clinical signs and symptoms and examination of the patient. The aim of this review is to assess which clinical signs and symptoms can predict an acute purulent sinusitis, compared with accepted reference standards. A review of the literature was performed by looking at articles related to the diagnoses of acute sinusitis in general practice. The following search criteria were used: unselected general practice population; objective reference standard; and logistic regression to evaluate symptoms and signs independently associated with the diagnosis. Four studies were identified for further analysis. The following symptoms and signs were associated with acute purulent sinusitis: purulent secretion as a symptom experienced by the patient or as a sign demonstrated in the nasal cavity by the doctor; pain in the teeth; pain at bending forward, and two phases in the illness history. An elevated erythrocyte sedimentation rate and increased C-reactive protein also contributed to the diagnosis. By use of the specified signs and symptoms the GP can increase the probability of correctly diagnosing an acute purulent sinusitis and reserve antibiotic prescription for these patients.


Oxytocin differentially modulates eye gaze to naturalistic social signals of happiness and anger.
A number of previous studies has shown that oxytocin (OT) promotes facial emotion recognition and enhances eye gaze to facial stimuli in humans. Other studies report valence-specific effects of OT, supporting the proposed prosocial role of OT in social interactions. In the present study, we tested the hypothesis whether OT might selectively enhance eye gaze to positive, approach-related, but not to negative, threat-related social cues. In a placebo-controlled, double-blind, between-subject design, we assessed the effects of intranasal OT administration (24 IU) in 62 healthy male volunteers on eye gaze toward the eyes of neutral, positive (happy) and negative (angry) facial expressions compared with placebo. In order to capture the dynamics of facial expressions, we used video sequences showing neutral faces gradually displaying a specific emotion. In line with previous studies, OT increased eye gaze toward neutral facial expressions. Moreover, under OT treatment, eye gaze remained increased when the face showed a happy facial expression, but in contrast decreased when the face displayed an angry expression. These results support the notion that OT differentially modulates visual attention toward social signals of positive approach and threat and thereby contributes to the modulation of non-verbal interpersonal communication.


A Sleeping Beauty DNA transposon-based genetic sensor for functional screening of vitamin D3 analogues.
Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening methods that allow a comparative evaluation of drug properties. As a new tool in functional screening of vitamin D3 analogues, we describe a genomically integratable sensor for sensitive drug detection. This system facilitates assessment of the pharmacokinetic and pharmadynamic properties of vitamin D3 analogues. The tri-cistronic genetic sensor encodes a drug-sensoring protein, a reporter protein expressed from an activated sensor-responsive promoter, and a resistance marker. The three expression cassettes, inserted in a head-to-tail orientation in a Sleeping Beauty DNA transposon vector, are efficiently inserted as a single genetic entity into the genome of cells of interest in a reaction catalyzed by the hyperactive SB100X transposase. The applicability of the sensor for screening purposes is demonstrated by the functional comparison of potent synthetic analogues of vitamin D3 designed for the treatment of psoriasis and cancer. In clones of human keratinocytes carrying from a single to numerous insertions of the vitamin D3 sensor, a sensitive sensor read-out is detected upon exposure to even low concentrations of vitamin D3 analogues. In comparative studies, the sensor unveils superior potency of new candidate drugs in comparison with analogues that are currently in clinical use. Our findings demonstrate the use of the genetic sensor as a tool in first-line evaluation of new vitamin D3 analogues and pave the way for new types of drug delivery studies in sensor-transgenic animals.


Versatile high resolution oligosaccharide microarrays for plant glycobiology and cell wall research.
Microarrays are powerful tools for high throughput analysis, and hundreds or thousands of molecular interactions can be assessed simultaneously using very small amounts of analytes. Nucleotide microarrays are well established in plant research, but carbohydrate microarrays are much less established, and one reason for this is a lack of suitable glycans with which to populate arrays. Polysaccharide microarrays are relatively easy to produce because of the ease of immobilizing large polymers noncovalently onto a variety of microarray surfaces, but they lack analytical resolution because polysaccharides often contain multiple distinct carbohydrate substructures. Microarrays of defined oligosaccharides potentially overcome this problem but are harder to produce because oligosaccharides usually require coupling prior to immobilization. We have assembled a library of well characterized plant oligosaccharides produced either by partial hydrolysis from polysaccharides or by de novo chemical synthesis. Once coupled to protein, these neoglycoconjugates are versatile reagents that can be printed as microarrays onto a variety of slide types and membranes. We show that these microarrays are suitable for the high throughput characterization of the recognition capabilities of monoclonal antibodies, carbohydrate-binding modules, and other oligosaccharide-binding proteins of biological significance and also that they have potential for the characterization of carbohydrate-active enzymes.


Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line.
Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na(+) channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCalpha at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCalpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCbeta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I(TE)). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.


Substituent interference on supramolecular assembly in urea gelators: synthesis, structure prediction and NMR.
Eighteen N-aryl-N'-alkyl urea gelators were synthesised in order to understand the effect of head substituents on gelation performance. Minimum gelation concentration values obtained from gel formation studies were used to rank the compounds and revealed the remarkable performance of 4-methoxyphenyl urea gelator 15 in comparison to 4-nitrophenyl analogue 14, which could not be simply ascribed to substituent effects on the hydrogen bonding capabilities of the urea protons. Crystal structure prediction calculations indicated alternative low energy hydrogen bonding arrangements between the nitro group and urea protons in gelator 14, which were supported experimentally by NMR spectroscopy. As a consequence, it was possible to relate the observed differences to interference of the head substituents with the urea tape motif, disrupting the order of supramolecular packing. The combination of unbiased structure prediction calculations with NMR is proposed as a powerful approach to investigate the supramolecular arrangement in gel fibres and help understand the relationships between molecular structure and gel formation.


Post-Contextual-Bandit Inference.
Contextual bandit algorithms are increasingly replacing non-adaptive A/B tests in e-commerce, healthcare, and policymaking because they can both improve outcomes for study participants and increase the chance of identifying good or even best policies. To support credible inference on novel interventions at the end of the study, nonetheless, we still want to construct valid confidence intervals on average treatment effects, subgroup effects, or value of new policies. The adaptive nature of the data collected by contextual bandit algorithms, however, makes this difficult: standard estimators are no longer asymptotically normally distributed and classic confidence intervals fail to provide correct coverage. While this has been addressed in non-contextual settings by using stabilized estimators, the contextual setting poses unique challenges that we tackle for the first time in this paper. We propose the Contextual Adaptive Doubly Robust (CADR) estimator, the first estimator for policy value that is asymptotically normal under contextual adaptive data collection. The main technical challenge in constructing CADR is designing adaptive and consistent conditional standard deviation estimators for stabilization. Extensive numerical experiments using 57 OpenML datasets demonstrate that confidence intervals based on CADR uniquely provide correct coverage.


Mammalian Metallothionein-3: New Functional and Structural Insights.
Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain of patients affected by a number of metal-linked neurodegenerative disorders, including Alzheimer's disease (AD). In these pathologies, the redox cycling of copper, accompanied by the production of reactive oxygen species (ROS), plays a key role in the neuronal toxicity. Although MT-3 shares the metal-thiolate clusters with the well-characterized MT-1 and MT-2, it shows distinct biological, structural and chemical properties. Owing to its anti-oxidant properties and modulator function not only for Zn, but also for Cu in the extra- and intracellular space, MT-3, but not MT-1/MT-2, protects neuronal cells from the toxicity of various Cu(II)-bound amyloids. In recent years, the roles of zinc dynamics and MT-3 function in neurodegeneration are slowly emerging. This short review focuses on the recent developments regarding the chemistry and biology of MT-3.


The recently introduced Aedes albopictus in Tunisia has the potential to transmit chikungunya, dengue and Zika viruses.
The mosquito Aedes albopictus was detected for the first time in Tunisia in 2018. With its establishment in the capital city of Tunis, local health authorities fear the introduction of new human arboviral diseases, like what happened in Europe with unexpected local cases of chikungunya, dengue and Zika. Even though this mosquito is competent to transmit the arboviruses mentioned above, the transmission level will vary depending on the couple, mosquito population and virus genotype. Here, we assessed the vector competence of Ae. albopictus Tunisia by experimental infections with chikungunya (CHIKV), dengue (DENV), and Zika (ZIKV) viruses. We found that Ae. albopictus Tunisia was highly competent for CHIKV (transmission efficiency of 25% at 21 post-infection) and to a lesser extent, for ZIKV (8.7%) and DENV (8.3%). Virus was detected in mosquito saliva at day 3 (CHIKV), day 10 (ZIKV) and day 21 (DENV) post-infection. These results suggest that the risk of emergence of chikungunya is the highest imposing a more sustained surveillance to limit Ae. albopictus populations in densely populated urban dwellings and at the entry points of travelers returning from CHIKV-endemic regions.


An application of Bradford's law: identification of the core journals of pediatric neurosurgery and a regional comparison of citation density.
Bradford's law describes the number of core journals in a given field or subject and has recently been applied to neurosurgery. The objective of this study was to use currently accepted formulations of Bradford's law to identify core journals of pediatric neurosurgery. An additional analysis was completed to compare regional dependence on citation density among North American and European neurosurgeons. All original research publications from 2009 to 2013 were analyzed for the 25 top publishing pediatric neurosurgeons in North America and Europe, which were sampled to construct regional citation databases of all journal references. Regional differences were compared with each database. Egghe's formulation and the verbal formulation of Bradford's law were applied to create specific citation density zones and identify the core journals. Regional comparison demonstrated a preference for the Journal of Neurosurgery and Child's Nervous System, respectively, but four of the top five journals were common to both groups. Applying the verbal formulation of Bradford's law to the North American citation database, a pattern of citation density was identified across the first three zones. Journals residing in the most highly cited first zone are presented as the core journals. Bradford's law can be applied to identify the core journals of neurosurgical subspecialties. While regional differences exist between the most highly cited and most frequently published in journals among North American and European pediatric neurosurgeons, there is commonality between the top five core journals in both groups.


Fucoidan enhances the survival and sustains the number of splenic dendritic cells in mouse endotoxemia.
Fucoidan is a sulfated polysaccharide derived from brown algae that has been reported to perform multiple biological activities, including immunostimulation. In this study, we investigated whether fucoidan has beneficial effects on endotoxemia induced by LPS, a septic model in mice. The focus of this study was on survival rates and spleen function of the mice upon treatment. We found that fucoidan had prophylactic effects on the survival rate of mice with endotoxemia. Flow cytometric analysis using antibodies for subset-specific markers revealed that fucoidan profoundly reversed the depleted population of dendritic cells in mice with endotoxemia. According to Western blot analysis, the spleen cells of LPS/fucoidan-treated mice showed a higher expression of anti-apoptotic molecules compared to those of LPS-treated mice. Also, fucoidan-treated spleen cells were more responsive to mitogens. Taken together, these results demonstrate that fucoidan pre-treatment has beneficial effects on the survival rate and function of the spleen in mice with endotoxemia. This study may broaden the use of fucoidan in clinical fields, especially endotoxemia.


Biological and Functional Changes in Healthy Adult Smokers Who Are Continuously Abstinent From Smoking for One Year: Protocol for a Prospective, Observational, Multicenter Cohort Study.
The harm of smoking results mainly from long-term exposure to harmful and potentially harmful constituents (HPHCs) generated by tobacco combustion. Smoking cessation (SC) engenders favorable changes of clinical signs, pathomechanisms, and metabolic processes that together could reduce the harm of smoking-related diseases to a relative risk level approximating that of never-smokers over time. In most SC studies, the main focus is on the quitting rate of the SC program being tested. As there is limited information in the literature on short to multiple long-term functional or biological changes following SC, more data on short to mid-term favorable impacts of SC are needed. The overall aim of the study was to assess the reversibility of the harm related to smoking over 1 year of continuous smoking abstinence (SA). This has been verified by assessing a set of biomarkers of exposure to HPHCs and a set of biomarkers of effect indicative of multiple pathophysiological pathways underlying the development of smoking-related diseases. This multiregional (United States, Japan, and Europe), multicenter (42 sites) cohort study consisting of a 1-year SA period in an ambulatory setting was conducted from May 2015 to May 2017. A total of 1184 male and female adult healthy smokers, willing to quit smoking, were enrolled in the study. Nicotine replacement therapy (NRT) was provided for up to 3 months upon the subject's request. SC counseling and behavioral support were continuously provided. Biomarkers of exposure to HPHCs and biomarkers of effect were assessed in urine and blood at baseline, Month 3, Month 6, and Month 12. Cardiovascular biomarkers of effect included parameters reflecting inflammation (white blood cell), lipid metabolism (high-density lipoprotein cholesterol), endothelial function (soluble intercellular adhesion molecule-1), platelet function (11-dehydrothromboxane B2), oxidative stress (8-epi-prostaglandin F2 alpha), and carbon monoxide exposure (carboxyhemoglobin). Respiratory biomarkers of effect included lung function parameters and cough symptoms. The biomarkers of effect to evaluate genotoxicity (total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) and xenobiotic metabolism (cytochrome P450 2A6 activity) were also assessed. Continuous SA was verified at each visit following the actual quit date using self-reporting and chemical verification. Safety assessments included adverse events and serious adverse events, body weight, vital signs, spirometry, electrocardiogram, clinical chemistry, hematology and urine analysis safety panel, physical examination, and concomitant medications. In total, 1184 subjects (50.1% male) were enrolled; 30% of them quit smoking successfully for 1 year. Data analyses of the study results are ongoing and will be published after study completion. This study provides insights into biological and functional changes and health effects, after continuous SA over 1 year. Study results will be instrumental in assessing novel alternative products to cigarettes considered for tobacco harm reduction strategies. ClinicalTrials.gov NCT02432729; http://clinicaltrials.gov/ct2/show/NCT02432729 (Archived by WebCite at http://www.webcitation.org/78QxovZrr). DERR1-10.2196/12138.


Disease persistence on temporal contact networks accounting for heterogeneous infectious periods.
The infectious period of a transmissible disease is a key factor for disease spread and persistence. Epidemic models on networks typically assume an identical average infectious period for all individuals, thus allowing an analytical treatment. This simplifying assumption is, however, often unrealistic, as hosts may have different infectious periods, due, for instance, to individual host-pathogen interactions or inhomogeneous access to treatment. While previous work accounted for this heterogeneity in static networks, a full theoretical understanding of the interplay of varying infectious periods and time-evolving contacts is still missing. Here, we consider a susceptible-infectious-susceptible epidemic on a temporal network with host-specific average infectious periods, and develop an analytical framework to estimate the epidemic threshold, i.e. the critical transmissibility for disease spread in the host population. Integrating contact data for transmission with outbreak data and epidemiological estimates, we apply our framework to three real-world case studies exploring different epidemic contexts-the persistence of bovine tuberculosis in southern Italy, the spread of nosocomial infections in a hospital, and the diffusion of pandemic influenza in a school. We find that the homogeneous parametrization may cause important biases in the assessment of the epidemic risk of the host population. Our approach is also able to identify groups of hosts mostly responsible for disease diffusion who may be targeted for prevention and control, aiding public health interventions.


Identifying priority technical and context-specific issues in improving the conduct, reporting and use of health economic evaluation in low- and middle-income countries.
The use of economic evaluation in healthcare policies and decision-making, which is limited in low- and middle-income countries (LMICs), might be promoted through the improvement of the conduct and reporting of studies. Although the literature indicates that there are many issues affecting the conduct, reporting and use of this evidence, it is unclear which factors should be prioritised in finding solutions. This study aims to identify the top priority issues that impede the conduct, reporting and use of economic evaluation as well as potential solutions as an input for future research topics by the international Decision Support Initiative and other movements. A survey on issues regarding the conduct, reporting and use of economic evaluation as well as on potential solutions was conducted using an online questionnaire among researchers who have experience in conducting economic evaluations in LMICs. The respondents were requested to consider the list of issues provided, rank the most important ones and propose solutions. A scoring system was applied to derive the ranking of difficulties according to researchers' responses. Issues were grouped into technical and context-specific difficulties and analysed separately as a whole and by region. Researchers considered the lack of quality local clinical data, poor reporting and insufficient data to conduct the analysis from the chosen perspective as the most important technical difficulties. On the other hand, the non-integration of economic evaluations into decision-making was considered the most important context-specific issue. Finally, context-specific issues were considered the larger barrier to the use of economic evaluation. The technical issues that were considered most important were closely linked with the lack of an appropriately functioning information system as well as the capacity to generate essential contextual information (e.g. data and locally relevant utility values), especially when the methodology is complex. To overcome this, simpler approaches to collect data that yields information of comparable quality to more rigorous methods should be developed. The international community can play a major role through research on methodologies feasible for LMIC settings as well as in building research capacity in countries. Context-specific issues, which were recognised as larger barriers, should be improved in parallel.


Differential gender response to respiratory infections and to the protective effect of breast milk in preterm infants.
The protective role of breastfeeding against severe acute lung disease in infants is well established, but its mechanism is unclear. Most hypotheses assume that breastfeeding confers similar passive protection to every infant; however, a few observations have suggested that the benefits of breast milk against severe lung disease may differ according to gender. The objective of this study was to determine whether the effect of breastfeeding on susceptibility to severe acute lung disease among infants at high risk is different for girls and boys. A cohort was analyzed prospectively by use of 2 different strategies: (1) predictors of first episode of rehospitalization by univariate and multivariate analyses using robust Poisson regression and (2) mean number of rehospitalizations between groups using multiple regression negative binomial models. A total of 119 high-risk, very low birth weight infants were enrolled. Breast milk protected girls but not boys against severe acute lung disease. The interaction between breastfeeding and gender was clinically and statistically significant, even after adjustment for variables that can affect severity of acute lung disease. Disease was most severe in formula-fed girls (versus formula-fed boys). Breastfeeding decreased the risk for severe acute lung disease in girls but not in boys. These findings suggest that breast milk protection is not universally conferred by passive transfer of humoral immunity (which should be gender indifferent), show that respiratory symptoms may be amenable to nonspecific modulation, and identify nonbreastfed preterm infant girls as an at-risk group for severe acute lung disease.


Challenges in Internet Addiction Disorder: Is a Diagnosis Feasible or Not?
An important international discussion began because of some pioneer studies carried out by Young (a) on the internet addiction disorder (IAD). In the fifth and most recent version of the Diagnostic, and Statistical Manual of Mental Disorders (DSM) there is no mention of this disorder and among researchers there are basically two opposite positions. Those who are in favor of a specific diagnosis and those who are claiming the importance of specific criteria characterizing this behavior and the precise role it has in the patient's life. The aim of the present paper is to answer the question whether it is possible or not to formulate diagnoses of internet-related disorders. We revised literature on the history of diagnostic criteria, on neurocognitive evidence, on the topic debate and on IAD instrumental measures. We found that the disorder was not univocally defined and that the construct was somehow too broad and generic to be explicative for a diagnosis. Indeed, the models are borrowed from other addiction pathologies and they are often formulated before the development of internet as intended in current society. In conclusion, we think we need a more innovative, integrated and comprehensive model for an IAD diagnosis.


Ultrastrong and Bioactive Nanostructured Bio-Based Composites.
Nature's design of functional materials relies on smart combinations of simple components to achieve desired properties. Silk and cellulose are two clever examples from nature-spider silk being tough due to high extensibility, whereas cellulose possesses unparalleled strength and stiffness among natural materials. Unfortunately, silk proteins cannot be obtained in large quantities from spiders, and recombinant production processes are so far rather expensive. We have therefore combined small amounts of functionalized recombinant spider silk proteins with the most abundant structural component on Earth (cellulose nanofibrils (CNFs)) to fabricate isotropic as well as anisotropic hierarchical structures. Our approach for the fabrication of bio-based anisotropic fibers results in previously unreached but highly desirable mechanical performance with a stiffness of ∼55 GPa, strength at break of ∼1015 MPa, and toughness of ∼55 MJ m-3. We also show that addition of small amounts of silk fusion proteins to CNF results in materials with advanced biofunctionalities, which cannot be anticipated for the wood-based CNF alone. These findings suggest that bio-based materials provide abundant opportunities to design composites with high strength and functionalities and bring down our dependence on fossil-based resources.


Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians.
To investigate whether the neuropeptide Y receptor 5 gene (NPY5R) is associated with obesity in humans. The NPY5R gene was screened for polymorphisms by direct sequencing in two groups of Pima Indians, selected for extremes of body mass index (BMI). Genotype frequencies were analyzed for association with BMI extreme. Full-heritage Pima Indians, non-diabetic and not first degree relatives. Obese group: 19 M/24 F, BMI = 49+/-7 kg/m2 (mean+/-s.d.) age = 24+/-2 y, lean group: 16 M/16 F, BMI = 23+/-2 kg/m2, age = 27+/-3 y. Initially, the entire gene (proximal promoter, exon 1A, coding sequence, 5' and 3' UTRs) was sequenced in a subset of 20 individuals. No variants were found in the coding sequence, however three novel single nucleotide polymorphisms were detected in the non-coding regions: (1) a C-->T transition located within the promoter 28 bp upstream of the exon 1A transcription start site; (2) a T-->C transition 94 bp downstream of the stop codon; and (3) a G-->A transition 432 bp downstream of the stop codon. The polymorphisms were then screened in all 75 subjects. The polymorphisms had mean heterozygosities of 0.34-0.50 and were in strong linkage disequilibrium (P<0.001). Genotype frequencies differed significantly in lean and obese Pimas for P2 (P=0.04) and for a triple haplotype (P=0.02, Bonferroni corrected). Considering the importance of this gene in regulation of body weight, the association of these polymorphisms with extremes of BMI in Pima Indians indicates that NPY5R, or a locus nearby, may contribute to susceptibility to obesity in this population.


Physical Activity and Alzheimer's Disease: A Narrative Review.
Although age is a dominant risk factor for Alzheimer's disease (AD), epidemiological studies have shown that physical activity may significantly decrease age-related risks for AD, and indeed mitigate the impact in existing diagnosis. The aim of this study was to perform a narrative review on the preventative, and mitigating, effects of physical activity on AD onset, including genetic factors, mechanism of action and physical activity typology. In this article, we conducted a narrative review of the influence physical activity and exercise have on AD, utilising key terms related to AD, physical activity, mechanism and prevention, searching the online databases; Web of Science, PubMed and Google Scholar, and, subsequently, discuss possible mechanisms of this action. On the basis of this review, it is evident that physical activity and exercise may be incorporated in AD, notwithstanding, a greater number of high-quality randomised controlled trials are needed, moreover, physical activity typology must be acutely considered, primarily due to a dearth of research on the efficacy of physical activity types other than aerobic.


Decoding antibacterial and antibiofilm properties of cinnamon and cardamom essential oils: a combined molecular docking and experimental study.
This study sets out to compare the antibacterial and antibiofilm profiles of Ci/Ca EOs alone and in combination together against infectious bacterial strains. MIC assay was carried out to survey the effectiveness of prepared EOs by two-fold serial dilution method and MTT evaluation. Synergic antibacterial properties of EOs against target strains were studied by using checkerboard titration method. Biofilm growth and development were evaluated using CV and XTT reduction assays. Antibacterial activity was observed for EOs against both bacterial strains with stronger activity for CiEO against both bacteria. The synergistic antibacterial effect was observed only against B. subtilis. Based on the FIC index, combinations could not inhibit the growth of E. coli. The pure EOs and their combination inhibited cell attachment for both studied bacteria with stronger effect on E. coli. CV and XTT reduction assays results showed that Ci EO and its combination with CaEO had the highest antibiofilm activity at lowest MIC value 0.08% and 0.04/0.02% against biofilm formed by E. coli and B. subtilis respectively, indicating a high antibiofilm potential. Computational docking analyses also postulated that the active constituents of evaluated EOs have the potential to interact with different bacterial targets, suggested binding mode of action of EOs metabolites. By and large, synergistic anti-biofilm properties of EOs may provide further options for developing novel formula to inhibit a variety of infectious clinical and industrial strains without (or less) toxicity effects on human body.


Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial.
PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (-1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. Pfizer.


How do Dutch general practitioners diagnose children's urinary tract infections?
To study which tests general practitioners used to diagnose a urinary tract infection (UTI) in children and which patient characteristics were associated with test choice. Retrospective chart review on the diagnosis of UTIs in children in Dutch general practices who were diagnosed as having a UTI. A total of 49 general practices participated in the study, and provided information on 148 children aged 0-12 years old. The nitrite test, which is recommended as first step, was performed in 87% of the children during the first contact. Less than 30% of the children had a dipslide and 37% a cultured urine. About half of all children with a UTI diagnosis had a follow-up contact in general practice, and an average of 83% of these children had their urine tested. The recommended test, a dipslide, was performed in 26% of the children with a follow-up contact. Patient age and UTI history were associated with choice of test. The diagnostic procedures for UTIs in children in general practices could be improved, with focus on the importance of an accurate UTI diagnosis in all children, and explaining which tests should be performed and what the test results mean.


Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3.
Skeletal muscle atrophy is a debilitating condition associated with weakness, fatigue, and reduced functional capacity. Nuclear factor-kappaB (NF-κB) transcription factors play a critical role in atrophy. Knockout of genes encoding p50 or the NF-κB co-transactivator, Bcl-3, abolish disuse atrophy and thus they are NF-κB factors required for disuse atrophy. We do not know however, the genes targeted by NF-κB that produce the atrophied phenotype. Here we identify the genes required to produce disuse atrophy using gene expression profiling in wild type compared to Nfkb1 (gene encodes p50) and Bcl-3 deficient mice. There were 185 and 240 genes upregulated in wild type mice due to unloading, that were not upregulated in Nfkb1⁻/⁻ and Bcl-3⁻/⁻ mice, respectively, and so these genes were considered direct or indirect targets of p50 and Bcl-3. All of the p50 gene targets were contained in the Bcl-3 gene target list. Most genes were involved with protein degradation, signaling, translation, transcription, and transport. To identify direct targets of p50 and Bcl-3 we performed chromatin immunoprecipitation of selected genes previously shown to have roles in atrophy. Trim63 (MuRF1), Fbxo32 (MAFbx), Ubc, Ctsl, Runx1, Tnfrsf12a (Tweak receptor), and Cxcl10 (IP-10) showed increased Bcl-3 binding to κB sites in unloaded muscle and thus were direct targets of Bcl-3. p50 binding to the same sites on these genes either did not change or increased, supporting the idea of p50:Bcl-3 binding complexes. p65 binding to κB sites showed decreased or no binding to these genes with unloading. Fbxo9, Psma6, Psmc4, Psmg4, Foxo3, Ankrd1 (CARP), and Eif4ebp1 did not show changes in p65, p50, or Bcl-3 binding to κB sites, and so were considered indirect targets of p50 and Bcl-3. This work represents the first study to use a global approach to identify genes required to produce the atrophied phenotype with disuse.


Coccidioidomycosis in patients with hematologic malignancies.
An endemic fungal infection of the desert southwestern United States, coccidioidomycosis is generally a self-limited illness in healthy persons. Immunosuppressed persons who contract coccidioidomycosis, however, are at increased risk for disseminated infection. We conducted a retrospective review of patients with coccidioidomycosis and hematologic malignancy or bone marrow disease. Fifty-five patients were identified. The most common underlying malignancies were non-Hodgkin lymphoma and chronic lymphocytic leukemia. Extrathoracic (or disseminated) infection was observed in 12 patients (22%). Fifteen patients (27%) died with active coccidioidomycosis. Treatment of the hematologic disease with corticosteroids or antineoplastic chemotherapy increased the risk of death. To date, this is the largest case series of patients with hematologic malignancy and coccidioidomycosis. In persons with hematologic malignancy, coccidioidomycosis can be a severe illness with a high risk for disseminated infection and death.


[Epidemiologic surveillance of measles and rubella in Campinas (SP), Brazil: the reliability of the data].
To evaluate and validate the information concerning measles and rubella from the Brazilian National Disease Notification System (BNDNS) (Sistema Nacional de Informação de Agravos de Notificação, or SINAN) for Campinas, a large city in the state of São Paulo, Brazil, using as a reference the data from a control system, the Syndromic Surveillance System for Fever and Exanthem (SSSFE) (Sistema de Vigilância Sindrômica de Febre e Exantema, or VigiFEx), which operated from May 2003 through June 2004. In our study we compared: (1) annual data from BNDNS for the years 1999 through 2003 and (2) data from BNDNS and data from SSSFE for the period of June 2003 through May 2004. We analyzed the rate of completion for key fields (record number, date of notification, and city of notification) as well as for name of disease, date of first symptoms, name of patient, birth date and age, sex, city of residence, date of investigation, immunization history, presence of exanthem, date at start of exanthem, presence of fever, suspected cases among pregnant women, signs and symptoms, date of collection of first sample, results with the sample, virus isolation, final classification, criteria for confirmation/exclusion of cases, diagnosis of excluded patients, development of the case, and date of closure. The level of agreement between the recorded cases in the two data banks was also analyzed. From June 2003 through May 2004, 211 suspected cases of measles or rubella were identified in SSSFE and 275 in BNDNS. All the records had complete information concerning the three key fields. The rate of completion was also 100% for patient name, disease, and city of residence. The completion rate was higher than 95% for date of investigation, measles vaccine, measles and rubella vaccine, and rubella vaccine. A lower completion rate was found for other vaccination variables (number of doses and date of last dose) and for exanthem, fever, and date of start of exanthem. The two information systems were not completely consistent, particularly in terms of variables related to epidemiologic background, clinical data, and case closure. The quality of the SSSFE data was higher. Epidemiologic surveillance, immunization, and laboratory information systems need to undergo routine evaluation to ensure that the data are reliable and can support the planning of public health efforts.


Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial.
Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates. Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant. In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding. URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872.


Recent updates in renal cell carcinoma.
The review will examine the recent advances in our understanding of the genetic and molecular events that shape this cancer, and overview the emerging targeted therapies that have altered the landscape for renal cell carcinoma (RCC) patients. The incidence of RCC continues to rise, making it the 7th and 8th most common cancer among men and women in the US, respectively. Von Hippel-Lindau (VHL) gene loss is an important factor in the development of clear cell RCC, however: loss of VHL can result in tumors which express both HIF1 and HIF2, or HIF2 alone, correlating with distinct pathway activities. Invasive tumors demonstrating loss of VHL consistently demonstrate additional genetic changes, which appear to be essential for tumor progression. Targeted therapies have demonstrated improvements in overall survival. New ways to radiographically measure the tumor response to these treatments may provide additional information about a drug's activity in an individual patient. Vascular endothelial growth factor receptor tyrosine kinase inhibitors are still being investigated in the adjuvant setting. The field of RCC biology continues to rapidly change. As new targeted strategies to control this cancer evolve, so do both the clinical strategies, and the strategies to measure response and predict outcome.


Genome-wide analysis of the spatiotemporal regulation of firing and dormant replication origins in human cells.
In metazoan cells, only a limited number of mini chromosome maintenance (MCM) complexes are fired during S phase, while the majority remain dormant. Several methods have been used to map replication origins, but such methods cannot identify dormant origins. Herein, we determined MCM7-binding sites in human cells using ChIP-Seq, classified them into firing and dormant origins using origin data and analysed their association with various chromatin signatures. Firing origins, but not dormant origins, were well correlated with open chromatin regions and were enriched upstream of transcription start sites (TSSs) of transcribed genes. Aggregation plots of MCM7 signals revealed minimal difference in the efficacy of MCM loading between firing and dormant origins. We also analysed common fragile sites (CFSs) and found a low density of origins at these sites. Nevertheless, firing origins were enriched upstream of the TSSs. Based on the results, we propose a model in which excessive MCMs are actively loaded in a genome-wide manner, irrespective of chromatin status, but only a fraction are passively fired in chromatin areas with an accessible open structure, such as regions upstream of TSSs of transcribed genes. This plasticity in the specification of replication origins may minimize collisions between replication and transcription.


Elasticity of human embryonic stem cells as determined by atomic force microscopy.
The expansive growth and differentiation potential of human embryonic stem cells (hESCs) make them a promising source of cells for regenerative medicine. However, this promise is off set by the propensity for spontaneous or uncontrolled differentiation to result in heterogeneous cell populations. Cell elasticity has recently been shown to characterize particular cell phenotypes, with undifferentiated and differentiated cells sometimes showing significant differences in their elasticities. In this study, we determined the Young's modulus of hESCs by atomic force microscopy using a pyramidal tip. Using this method we are able to take point measurements of elasticity at multiple locations on a single cell, allowing local variations due to cell structure to be identified. We found considerable differences in the elasticity of the analyzed hESCs, reflected by a broad range of Young's modulus (0.05-10 kPa). This surprisingly high variation suggests that elasticity could serve as the basis of a simple and efficient large scale purification/separation technique to discriminate subpopulations of hESCs.


A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma.
Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment. We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients. 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes. The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy.