River Water Quality Model no. 1 (RWQM1): I. Modelling approach.
Successful river water quality modelling requires the specification of an appropriate model structure and process formulation. Both must be related to the compartment structure of running water ecosystems including their longitudinal, vertical, and lateral zonation patterns. Furthermore, the temporal variability of abiotic boundary conditions may be important and must be incorporated by an appropriate choice of model parameters. A six-step decision procedure is proposed to achieve these objectives. The steps address the determination of the following model features: (1) temporal representation (dynamic or steady-state); (2) model dimensionality; (3) mixing; (4) advection; (5) reaction terms; and (6) boundary conditions. Numerical criteria based on process time constants and length scales provide a basis for these decisions.


Diagnostic potential and limitation of imaging cancer cells in cytological samples using telomerase-specific replicative adenovirus.
Cytological cancer screening that targets genetic or epigenetic abnormalities may be a viable alternative to morphological screening. Detecting cancer cells by specific genetic markers helps their easy detection in cytological samples. We recently established the telomerase-specific replication-selective adenovirus OBP-401, in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted upstream of the E1 genes, and in which the green fluorescent protein (GFP) gene is driven by the CMV promoter. This virus selectively replicates only in telomerase-positive cells, expressing GFP, and therefore may be a tool for cancer screening. In the present study, we first confirmed that cytological samples can easily be infected with OBP-401, allowing visualization of GFP-positive cells under fluorescent microscopy 24 h after infection. After 32 cytological samples from patients with cervical, endometrial or ovarian cancers were infected with OBP-401, GFP signals were detected in 31 (96%) of the samples. However, some normal endometrial scrapings exhibited GFP-signals, possibly due to endometrial glandular cells with constitutive telomerase activity. The ability of OBP-401 to enrich cancer cells was then tested. Cytological samples containing cervical or endometrial cancer cells were infected with OBP-401, and GFP-positive cells were sorted by flow cytometry; DNA was extracted from the GFP-positive cells. Direct DNA sequencing or methylation-specific PCR identified cancer-derived mutations or hypermethylations of tumor suppressor genes more efficiently than analyses using crude cytological samples. Thus, OBP-401-based sorting of GFP-positive cells successfully enriched cancer cells, allowing efficient detection of genetic or epigenetic abnormalities in cytological samples.


CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions.
Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine model of CD8 T cell-mediated CNS vascular permeability using a variation of the Theiler's murine encephalomyelitis virus system traditionally used to study multiple sclerosis. Previously, we demonstrated that CD8 T cells have the capacity to initiate astrocyte activation, cerebral endothelial cell tight junction protein alterations and CNS vascular permeability through a perforin-dependent process. To address the downstream mechanism by which CD8 T cells promote BBB dysregulation, in this study, we assess the role of vascular endothelial growth factor (VEGF) expression in this model. We demonstrate that neuronal expression of VEGF is significantly upregulated prior to, and coinciding with, CNS vascular permeability. Phosphorylation of fetal liver kinase-1 is significantly increased early in this process indicating activation of this receptor. Specific inhibition of neuropilin-1 significantly reduced CNS vascular permeability and fetal liver kinase-1 activation, and preserved levels of the cerebral endothelial cell tight junction protein occludin. Our data demonstrate that CD8 T cells initiate neuronal expression of VEGF in the CNS under neuroinflammatory conditions, and that VEGF may be a viable therapeutic target in neurologic disease characterized by inflammation-induced BBB disruption.


Sensitivity of a helical diode array dosimeter to Volumetric Modulated Arc Therapy delivery errors.
To study the sensitivity of an ArcCHECK dosimeter in detecting delivery errors during the delivery of Volumetric Modulated Arc Therapy (VMAT). Three types of errors in Multi Leaf Collimator (MLC) position and dose delivery were simulated separately in the delivery of five prostate and five head and neck (H&N) VMAT plans: (i) Gantry independent: a systematic shift in MLC position and variation in output to the whole arc; (ii) Gantry dependent: sag in MLC position and output variation as a function of gantry angle; (iii) Control point specific MLC and output errors introduced to only a specific number of Control Points (CP). The difference in local and global gamma (γ) pass rate between the no-error and error-simulated measurements with 2%/2 mm and 3%/3 mm tolerances was calculated to assess the sensitivity of ArcCHECK. The clinical impact of these errors was also calculated. ArcCHECK was able to detect a minimum 3 mm MLC error and 3% output error for Gantry independent errors using either local or global gamma with 2%/2 mm tolerance. For the Gantry dependent error scenario a minimum 3 mm MLC error and 3% dose error was identifiable by ArcCHECK using either global or local gamma with 2%/2 mm tolerance. In errors introduced to specific CPs a MLC error of 10 mm and dose error of 100% introduced to 4CPs were detected by ArcCHECK. ArcCHECK used with either local or global gamma analysis and 2%/2 mm criteria can be confidently used in the clinic to detect errors above the stated error values.


Comparison of three methods of calculation, experimental and monte carlo simulation in investigation of organ doses (thyroid, sternum, cervical vertebra) in radioiodine therapy.
Radioiodine therapy is an effective method for treating thyroid cancer carcinoma, but it has some affects on normal tissues, hence dosimetry of vital organs is important to weigh the risks and benefits of this method. The aim of this study is to measure the absorbed doses of important organs by Monte Carlo N Particle (MCNP) simulation and comparing the results of different methods of dosimetry by performing a t-paired test. To calculate the absorbed dose of thyroid, sternum, and cervical vertebra using the MCNP code, *F8 tally was used. Organs were simulated by using a neck phantom and Medical Internal Radiation Dosimetry (MIRD) method. Finally, the results of MCNP, MIRD, and Thermoluminescent dosimeter (TLD) measurements were compared by SPSS software. The absorbed dose obtained by Monte Carlo simulations for 100, 150, and 175 mCi administered (131)I was found to be 388.0, 427.9, and 444.8 cGy for thyroid, 208.7, 230.1, and 239.3 cGy for sternum and 272.1, 299.9, and 312.1 cGy for cervical vertebra. The results of paired t-test were 0.24 for comparing TLD dosimetry and MIRD calculation, 0.80 for MCNP simulation and MIRD, and 0.19 for TLD and MCNP. The results showed no significant differences among three methods of Monte Carlo simulations, MIRD calculation and direct experimental dosimetry using TLD.


The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. To evaluate and, as needed, update definitions for sepsis and septic shock. A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.


Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.
A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10-6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15-16·99; p=5·8 × 10-8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19-12·50; p=0·02) and adult COPD (2·41, 1·10-5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97-11·68; p=4·3 × 10-9; and 4·05, 2·00-8·21; p=3·5 × 10-10). Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Department of Health Chair in Pharmacogenetics.


Hospitalization With Major Infection and Incidence of End-Stage Renal Disease: The Atherosclerosis Risk in Communities (ARIC) Study.
To evaluate whether the incidence of infectious diseases increases the long-term risk for incident end-stage renal disease (ESRD) in the general population. In 10,290 participants of the Atherosclerosis Risk in Communities Study who attended visit 4 (1996-1998), we evaluated the association of incident hospitalization with major infections (pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis) with subsequent risk for ESRD through September 30, 2015. Hospitalization with major infection was entered into multivariable Cox models as a time-varying exposure to estimate the hazard ratios. Mean age was 63 years, and of 10,290 individuals, 56% (n=5781) were women, 22% (n=2252) were black, and 7% (n=666) had an estimated glomerular filtration rate less than 60 mL/min/1.73 m2. During a median follow-up of 17.4 years, there were 2642 incident hospitalizations with major infection and 281 cases of ESRD (132 cases after hospitalization with major infection). The risk for ESRD was higher following major infection compared with while free of major infection (crude incidence rate, 10.9 vs 1.0 per 1000 person-years). In multivariable time-varying Cox analysis, hospitalization with major infection was associated with a 3.3-fold increased risk for ESRD (hazard ratio, 3.34; 95% CI, 2.56-4.37). The association was similar across pneumonia, urinary tract infection, bloodstream infection, and cellulitis and osteomyelitis, and remained significant across subgroups of age, sex, race, diabetes, history of cardiovascular disease, and chronic kidney disease. Hospitalization with major infection was independently and robustly associated with subsequent risk for ESRD. Whether preventive approaches against infection have beneficial effects on kidney outcomes may deserve future investigations.


Establishment of three novel human malignant pleural mesothelioma cell lines: morphological and cytogenetical studies and EGFR mutation status.
The incidence of mesothelioma is estimated to rise sharply worldwide, including Japan, in the next two decades. Molecular and proteomic studies are urgently required to elucidate the pathobiology of malignant mesothelioma. This paper describes the characterization of novel human malignant pleural mesothelioma cell lines representing the sarcomatoid, epithelioid and biphasic subtypes. Established pleural effusion fluid cell lines were observed using phase-contrast microscopy and transmission electron microscopy. The immunoreactivity of the cells was evaluated using immunohistochemistiy, FACS analysis and Western blotting. The expression of SV40 large cell antigen and the EGFR mutation status were also analyzed. The cell lines had different morphological and immunophenotypic characteristics. All cell lines showed immunophenotypic marker expression of vimentin, mesothelin and N-cadherin, but no expression of CEA or E-cadherin. At the electron microscopic level, a cell surface rich in microvilli confirmed mesothelial origin of the cell lines. Karyotype analyses showed complex abnormalities in all cell lines. Neither EGFR mutations relevant to tyrosine kinase inhibitor responsiveness nor the expression of SV40 large cell antigen was detected in any of the cell lines. FACS analysis is more sensitive for evaluating mesothelin expression than immunohistochemistry of cut specimens. Irrespective of the expression of EGFR on FACS analysis, no EGFR mutation was detected. These three cell lines may be useful for studying cellular, molecular and genetic aspects of mesothelioma.


Spatiotemporal visualization of deep brain stimulation-induced effects in the subthalamic nucleus.
Deep brain stimulation (DBS) is a successful surgical therapy used to treat the disabling symptoms of movement disorders such as Parkinson's disease. It involves the chronic stimulation of disorder-specific nuclei. However, the mechanisms that lead to clinical improvements remain unclear. Consequently, this slows the optimization of present-day DBS therapy and hinders its future development and application. We used a computational model to calculate the distribution of electric potential induced by DBS and study the effect of stimulation on the spiking activity of a subthalamic nucleus (STN) projection neuron. We previously showed that such a model can reveal detailed spatial effects of stimulation in the vicinity of the electrode. However, this multi-compartmental STN neuron model can fire in either a burst or tonic mode and, in this study, we hypothesized that the firing mode of the cell will have a major impact on the DBS-induced effects. Our simulations showed that the bursting model exhibits behaviour observed in studies of high-frequency stimulation of STN neurons, such as the presence of a silent period at stimulation offset and frequency-dependent stimulation effects. We validated the model by simulating the clinical parameter settings used for a Parkinsonian patient and showed, in a patient-specific anatomical model, that the region of affected tissue is consistent with clinical observations of the optimal DBS site. Our results demonstrated a method of quantitatively assessing neuronal changes induced by DBS, to maximize therapeutic benefit and minimize unwanted side effects.


Tunneling-induced restoration of the degeneracy and the time-reversal symmetry breaking in optical lattices.
We study the ground-state properties of bosons loaded into the p band of a one-dimensional optical lattice. We show that the phase diagram of the system is substantially affected by the anharmonicity of the lattice potential. In particular, for a certain range of tunneling strength, the full many-body ground state of the system becomes degenerate. In this region, an additional symmetry of the system, namely, the parity of the occupation number of the chosen orbital, is spontaneously broken. The state with a nonvanishing staggered angular momentum, which breaks the time-reversal symmetry, becomes the true ground state of the system.


Analysis of the Rumen Microbiome and Metabolome to Study the Effect of an Antimethanogenic Treatment Applied in Early Life of Kid Goats.
This work aimed to gain insight into the transition from milk to solid feeding at weaning combining genomics and metabolomics on rumen contents from goat kids treated with a methanogenic inhibitor (bromochloromethane, BCM). Sixteen goats giving birth to two kids were used. Eight does were treated (D+) with BCM after giving birth and over 2 months. One kid per doe in both groups was treated with BCM (k+) for 3 months while the other was untreated (k-). Rumen samples were collected from kids at weaning (W) and 1 (W + 1) and 4 (W + 4) months after and from does at weaning and subjected to 16S pyrosequencing and metabolomics analyses combining GC/LC-MS. Results from pyrosequencing showed a clear effect of age of kids, with more diverse bacterial community as solid feed becomes more important after weaning. A number of specific OTUs were significantly different as a result of BCM treatment of the kid at W while at W + 1 and W + 4 less OTUs were significantly changed. At W + 1, Prevotella was increased and Butyrivibrio decreased in BCM treated kids. At W + 4 only the effect of treating mothers resulted in significant changes in the abundance of some OTUs: Ruminococcus, Butyrivibrio and Prevotella. The analysis of the OTUs shared by different treatments revealed that kids at weaning had the largest number of unique OTUs compared with kids at W + 1 (137), W + 4 (238), and does (D) (23). D + k+ kids consistently shared more OTUs with mothers than the other three groups at the three sampling times. The metalobomic study identified 473 different metabolites. In does, lipid super pathway included the highest number of metabolites that were modified by BCM, while in kids all super-pathways were evenly affected. The metabolomic profile of samples from kids at W was different in composition as compared to W + 1 and W + 4, which may be directly ascribed to the process of rumen maturation and changes in the solid diet. This study shows the complexity of the bacterial community and metabolome in the rumen before weaning, which clearly differ from that after weaning and highlight the importance of the dam in transmitting the primary bacterial community after birth.


Feasibility of oxygen sensitive cardiac magnetic resonance of the right ventricle in pulmonary artery hypertension.
Progressive right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) which is contributed by RV ischemia leads to adverse clinical outcomes. Oxygen-sensitive (OS) cardiovascular magnetic resonance (CMR) has been used to determine the in vivo myocardial oxygenation of the left ventricle (LV). The aims of the present study were therefore to determine the feasibility of RV targeted rest/stress OS-CMR imaging in PAH patients and healthy volunteers. We prospectively recruited 20 patients with right heart catheter proven PAH and 9 healthy age matched controls (NC). The CMR examination involved standard functional imaging and OS-CMR imaging. An OS-CMR signal intensity (SI) index (stress/rest SI) was acquired at RV anterior, RV free-wall and RV inferior segments. In the LV, the OS-CMR SI index was acquired globally. Reliable OS SI changes were only obtained from the RV inferior segment. As RV dysfunction in PAH is a global process, hence this segment was used in both patients and NC for further comparison. RV OS-CMR SI change between rest and stress in the NC was 17%±5% (mean ± SD). Nine of 20 (45%) of the PAH patients had a mean OS SI change of less than 9% (or ≥2 SD different from the mean values in NC). Overall, RV OS SI index between the PAH patients and NC was 11%±9% vs. 17%±5% (P=0.045) in the RV inferior segment. In the LV, the global OS-CMR SI index between the PAH patients and NC was 11%±7% vs. 21%±9% (P=0.019). There was a strong correlation between RV Inf OS-CMR SI and LV OS-CMR SI (r=0.86, P<0.001). In this small pilot study, pharmacological induced OS-CMR is a feasible and safe technique to identify and study myocardial oxygenation in the RV of PAH patients.


Structure of the three-way helical junction of the hepatitis C virus IRES element.
The hepatitis C virus internal ribosome entry site (IRES) element contains a three-way junction that is important in the overall RNA conformation, and for its role in the internal initiation of translation. The junction also illustrates some important conformational principles in the folding of three-way helical junctions. It is formally a 3HS(4) junction, with the possibility of two alternative stacking conformers. However, in principle, the junction can also undergo two steps of branch migration that would form 2HS(1)HS(3) and 2HS(2)HS(2) junctions. Comparative gel electrophoresis and ensemble fluorescence resonance energy transfer (FRET) studies show that the junction is induced to fold by the presence of Mg(2+) ions in low micromolar concentrations, and suggest that the structure adopted is based on coaxial stacking of the two helices that do not terminate in a hairpin loop (i.e., helix IIId). Single-molecule FRET studies confirm this conclusion, and indicate that there is no minor conformer present based on an alternative choice of helical stacking partners. Moreover, analysis of single-molecule FRET data at an 8-msec resolution failed to reveal evidence for structural transitions. It seems probable that this junction adopts a single conformation as a unique and stable fold.


A sustainable solution for the activities of the European network for surveillance of congenital anomalies: EUROCAT as part of the EU Platform on Rare Diseases Registration.
The European Commission through its Directorates-General Joint Research Centre (DG JRC) and Health and Food Safety (DG SANTE) is developing the European Platform on Rare Diseases Registration (EU RD Platform) with the objective to set European-level standards for data collection and data sharing. In the field of rare diseases the EU RD Platform will be a source of information on available rare disease patient data with large transnational European coverage. One main function of the EU RD Platform is to enable interoperability for the >600 existing RD registries in Europe. The second function is to offer a sustainable solution for two large European surveillance networks: European Surveillance of Congenital Anomalies (EUROCAT) and Surveillance of Cerebral Palsy in Europe (SCPE). EUROCAT is European network of population-based registries for the epidemiological surveillance of congenital anomalies. It covers about one third of the European birth population. The Central Database contains about 800,000 cases with congenital anomalies among livebirths, stillbirths and terminations of pregnancy, reported using the same standardised classification and coding. These high quality data enables epidemiological surveillance of congenital anomalies, which includes estimating prevalence, prenatal diagnosis and perinatal mortality rates and the detection of teratogenic exposures among others. The network also develops recommendations for primary prevention in the Rare Diseases National Plans for medicinal drugs, food/nutrition, lifestyle, health services, and environmental pollution. The network has received the European Commission's support since its inception. In order to offer a sustainable solution for the continuation of EUROCAT activities, it was agreed that EUROCAT would become part of the EU RD Platform. In 2015, the European level-coordination activities and the Central Database were transferred to the DG JRC, where the JRC-EUROCAT Central Registry is now located. This paper describes the functioning of EUROCAT in the new setting, and gives an overview of the activities and the organisation of the JRC-EUROCAT Central Registry.


PVP-coated, negatively charged silver nanoparticles: A multi-center study of their physicochemical characteristics, cell culture and in vivo experiments.
PVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of -20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and the cellular consequences of the exposure of a broad range of biological test systems to this defined type of silver nanoparticles. Silver nanoparticles dissolve in water in the presence of oxygen. In addition, in biological media (i.e., in the presence of proteins) the surface of silver nanoparticles is rapidly coated by a protein corona that influences their physicochemical and biological properties including cellular uptake. Silver nanoparticles are taken up by cell-type specific endocytosis pathways as demonstrated for hMSC, primary T-cells, primary monocytes, and astrocytes. A visualization of particles inside cells is possible by X-ray microscopy, fluorescence microscopy, and combined FIB/SEM analysis. By staining organelles, their localization inside the cell can be additionally determined. While primary brain astrocytes are shown to be fairly tolerant toward silver nanoparticles, silver nanoparticles induce the formation of DNA double-strand-breaks (DSB) and lead to chromosomal aberrations and sister-chromatid exchanges in Chinese hamster fibroblast cell lines (CHO9, K1, V79B). An exposure of rats to silver nanoparticles in vivo induced a moderate pulmonary toxicity, however, only at rather high concentrations. The same was found in precision-cut lung slices of rats in which silver nanoparticles remained mainly at the tissue surface. In a human 3D triple-cell culture model consisting of three cell types (alveolar epithelial cells, macrophages, and dendritic cells), adverse effects were also only found at high silver concentrations. The silver ions that are released from silver nanoparticles may be harmful to skin with disrupted barrier (e.g., wounds) and induce oxidative stress in skin cells (HaCaT). In conclusion, the data obtained on the effects of this well-defined type of silver nanoparticles on various biological systems clearly demonstrate that cell-type specific properties as well as experimental conditions determine the biocompatibility of and the cellular responses to an exposure with silver nanoparticles.


[Current issues in measurement and reporting of urinary albumin excretion].
Urinary excretion of albumin indicates kidney damage and is recognized as a risk factor for progression of kidney disease and cardiovascular disease. The role of urinary albumin measurements has focused attention on the clinical need for accurate and clearly reported results. The National Kidney Disease Education Program and the IFCC convened a conference to assess the current state of preanalytical, analytical, and postanalytical issues affecting urine albumin measurements and to identify areas needing improvement. The chemistry of albumin in urine is incompletely understood. Current guidelines recommend the use of the albumin/creatinine ratio (ACR) as a surrogate for the erro-prone collection of timed urine samples. Although ACR results are affected by patient preparation and time of day of sample collection, neither is standardized. Considerable intermethod differences has been reported for both albumin and creatinine measurement, but trueness is unknown because there are no reference measurement procedures for albumin and no referance materials for either analyte in urine. The recommanded reference intervals for the ACR do not take into account the large intergroup differences in creatinine excretion (e.g., related to differences in age, sex, and ethicity) nor the continuous increase in risk related to albumin excretion. Clinical needs have been identified for standardization of (a) urine collection methodes, (b) urine albumin and creatinine measurements based on a complete reference system, (c) reporting of test results, and (d) reference intervals for the ACR.


Functional network topology associated with posttraumatic stress disorder in veterans.
Posttraumatic stress disorder (PTSD) is a disabling disorder associated with resting state functional connectivity alterations. However, whether specific brain regions are altered in PTSD or whether the whole brain network organization differs remains unclear. PTSD can be treated with trauma-focused therapy, although only half of the patients recover after treatment. In order to better understand PTSD psychopathology our aim was to study resting state networks in PTSD before and after treatment. Resting state functional magnetic resonance images were obtained from veterans with PTSD (n = 50) and controls (combat and civilian controls; n = 54) to explore which network topology properties (degree and clustering coefficient) of which brain regions are associated with PTSD. Then, PTSD-associated brain regions were investigated before and after treatment. PTSD patients were subdivided in persistent (n = 22) and remitted PTSD patients (n = 17), and compared with combat controls (n = 22), who were also reassessed. Prior to treatment associations with PTSD were found for the degree of orbitofrontal, and temporoparietal brain regions, and for the clustering coefficient of the anterior cingulate cortex. No significant effects were found over the course of treatment. Our results are in line with previous resting state studies, showing resting state connectivity alterations in the salience network and default mode network in PTSD, and also highlight the importance of other brain regions. However, network metrics do not seem to change over the course of treatment. This study contributes to a better understanding of the psychopathology of PTSD.


Fibrin encapsulation and vascular endothelial growth factor delivery promotes ovarian graft survival in mice.
Ovarian cryopreservation before chemotherapy and autotransplantation post-treatment can restore fertility to women with premature ovarian failure. Although the majority of primordial follicles survive the cryopreservation cycle, the follicular pool is reduced after transplantation due to ischemic death. Therefore, we engineered a biomaterial-based system to promote angiogenesis in a mouse model of ovarian transplantation. To mimic the clinical situation of sterility, a bilateral ovariectomy was performed 2 weeks before transplantation, during which time serum levels of follicular stimulating hormone rose to menopausal levels. Before transplantation, vitrified/thawed ovarian tissue from 12-day-old C57Bl/6J pups was encapsulated in fibrin modified with heparin-binding peptide (HBP), heparin, and loaded with 0.5 μg vascular endothelial growth factor (VEGF). The group transplanted with fibrin-HBP-VEGF had twice as many surviving primordial follicles and an increased number of blood vessels relative to the no biomaterial control. Transplanted tissue was viable and supported natural conception that led to live and healthy offspring. The timeline of live births with VEGF delivery suggested that primary follicles survived transplantation, and provided the gametes for the first litter. Thus, VEGF delivery from fibrin supported integration of the transplant with the host, promoted angiogenesis, and enhanced engraftment and function of the tissue.


Rectal adenocarcinoma: proposal for a model based on pretreatment prognostic factors.
Currently the choice of chemotherapy regimen in rectal cancer is made prior to surgery in contrast to colon cancer where it is made postoperatively after the pathological stage has been determined. If we could identify which are the important pretreatment prognostic factors in rectal cancer, we could then target those patients with unfavorable features to investigate potentially more effective preoperative chemotherapy regimens aimed at those with unfavorable features. The present study aimed to determine pre-treatment prognostic factors that are associated with an unfavorable outcome. A retrospective review of 99 rectal cancer patients operated at the Auxilio Mutuo Hospital, San Juan, Puerto Rico, and the San Pablo Hospital, Bayamón, Puerto Rico was done. Socio-demographic, clinical and treatment data were collected. Of the 99 cases, 54% were males. The mean age +/- standard deviation was 62.2 +/- 10.4. In age-adjusted Cox model, male gender (HR [95%CI]: 3.32 [1.09-10.13]), mucinous carcinoma (HR [95% CI]: 3.67 [1.25-10.77]), and clinical stages II & III (HR [95%CI]: 8.19 [1.08-62.08]) were predictors of poor prognosis. In the multivariate age-adjusted analysis, a tendency towards a poorer prognosis was observed for male patients (HR: 2.60), carcinoembryonic antigen level > or =5 ng/ml (HR: 2.55), mucinous carcinoma (HR: 2.96), and clinical stages II & III (HR: 4.96), although results were not statistically significant (p > 0.05). Although current therapeutic results are relatively favorable with preoperative 5-fluorouracil and radiotherapy, future clinical trials should address the management of those cases with adverse pretreatment prognostic factors so that they can be treated with potentially more effective albeit more toxic chemotherapy regimens.


Leaving No One Behind: Participatory Technology Appraisal as a Platform for Agenda Setting to Address Disparities in Access to Health Services in Thailand.
This article discusses how participatory technology appraisal as part of the Universal Coverage Scheme (UCS) in Thailand contributes to improving access to essential health services among vulnerable populations. Document review was conducted on health technology appraisal approaches introduced by the UCS. The review involves health benefit proposals advanced by stakeholders and also meeting minutes of relevant working groups and committees published between 2010 and 2015. From the establishment of the UCS participatory technology appraisal mechanism in 2010 until 2015, a total of 133 health interventions have been nominated. Some nominations highlight problems in access to care among vulnerable populations. As policy advocates continue to be involved in the latter stages of coverage decisions, they have opportunities to persuade policy makers and other stakeholders to agree to the rationales of their proposals. Some interventions were rejected because they did not meet value for money, affordability, and feasibility criteria; however, topic nominations from stakeholders as well as relevant deliberation throughout the technology appraisal processes have a potential to improve accessibility of health care among the disadvantaged. Through participation in the UCS policy-making processes, key stakeholders are able to direct the attention of decision makers to significant gaps in access to services among vulnerable citizens, a health system problem rarely brought to discussion by policy elites and experts. The Thai experience reaffirms participatory technology appraisal as a supportive measure to providing universal health coverage.


Galantamine administration in chronic post-stroke aphasia.
To investigate the influence of galantamine on linguistic function, any associated factors in patients with chronic post-stroke aphasia were analysed. 45 patients younger than 75 years with chronic aphasia (≥1 year since onset) were prospectively enrolled in the study. Language testing was performed at weeks 0 and 16. Initial galantamine dose was 8 mg/day for 4 weeks, and 16 mg/day for the following 12 weeks. Efficacy was evaluated by the sum of four domains (spontaneous speech, comprehension, repetition and naming) on the aphasia quotient (AQ) of the Western Aphasia Battery from baseline (AQ1) to endpoint (AQ2). Patients were considered as 'responding' if the increase in AQ was ≥20. Mean age was 60.4 years (22-74) and 14 patients were female. Mean duration of aphasia was 2.2±1.5 years. There was a significant increase in the total AQ score in the galantamine group (n=23, 48.5-57.0 percentile; p=0.007) but not in the control group (n=22, 54.3-54.9 percentile; p=0.308). The AQ2 score was independently associated with AQ1, galantamine administration and Mini-Mental State Examination (MMSE) score in multiple linear regression models. With the galantamine group, the good responders (vs poor responders) had a higher level of education (p=0.048), higher baseline MMSE score (p=0.009) and a subcortical dominant pattern (p=0.030). After adjusting for potential variables, subcortical dominant lesion was the independent determinant for galantamine responsiveness (OR 30.3; 95% CI 1.1 to 805.9, p=0.041). Administration of galantamine had a beneficial effect on chronic post-stroke aphasia, and was more prominent in subcortical dominant lesions.


Soluble Angiotensin-Converting Enzyme 2, Cardiac Biomarkers, Structure, and Function, and Cardiovascular Events (from the Atherosclerosis Risk in Communities Study).
Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin-angiotensin-aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels were associated with significantly higher biomarkers of cardiac injury (high-sensitivity cardiac troponin I and T, N-terminal pro-B-type natriuretic peptide), greater left ventricular mass index, and impaired diastolic function in linear regression analyses, and with increased risk for heart failure hospitalization (adjusted hazard ratio per natural log unit increase [HR] 1.32, 95% confidence interval [CI] 1.10 to 1.58), CVD events (HR 1.34, 95% CI 1.13 to 1.60), and all-cause death (HR 1.26, 95% CI 1.01 to 1.57). In an elderly biracial cohort, sACE2 was positively associated with biomarkers reflecting myocardial injury and neurohormonal activation, left ventricular mass index, impaired diastolic function, CVD, events and all-cause death.


Making the case for mastery learning assessments: key issues in validation and justification.
Theoretical and empirical support is increasing for mastery learning, in which learners must demonstrate a minimum level of proficiency before completing a given educational unit. Mastery learning approaches aim for uniform achievement of key objectives by allowing learning time to vary and as such are a course-level analogue to broader competency-based curricular strategies. Sound assessment is the cornerstone of mastery learning systems, yet the nature of assessment validity and justification for mastery learning differs in important ways from standard assessment models. Specific validity issues include (1) the need for careful definition of what is meant by "mastery" in terms of learners' achievement or readiness to proceed, the expected retention of mastery over time, and the completeness of content mastery required in a particular unit; (2) validity threats associated with increased retesting; (3) the need for reliability estimates that account for the specific measurement error at the mastery versus nonmastery cut score; and (4) changes in item- and test-level score variance over retesting, which complicate the analysis of evidence related to reliability, internal structure, and relationships to other variables. The positive and negative consequences for learners, educational systems, and patients resulting from the use of mastery learning assessments must be explored to determine whether a given mastery assessment and pass/fail cut score are valid and justified. In this article, the authors outline key considerations for the validation and justification of mastery learning assessments, with the goal of supporting insightful research and sound practice as the mastery model becomes more widespread.


Single cell cytometry of protein function in RNAi treated cells and in native populations.
High Content Screening has been shown to improve results of RNAi and other perturbations, however significant intra-sample heterogeneity is common and can complicate some analyses. Single cell cytometry can extract important information from subpopulations within these samples. Such approaches are important for immune cells analyzed by flow cytometry, but have not been broadly available for adherent cells that are critical to the study of solid-tumor cancers and other disease models. We have directly quantitated the effect of resolving RNAi treatments at the single cell level in experimental systems for both exogenous and endogenous targets. Analyzing the effect of an siRNA that targets GFP at the single cell level permits a stronger measure of the absolute function of the siRNA by gating to eliminate background levels of GFP intensities. Extending these methods to endogenous proteins, we have shown that well-level results of the knockdown of PTEN results in an increase in phospho-S6 levels, but at the single cell level, the correlation reveals the role of other inputs into the pathway. In a third example, reduction of STAT3 levels by siRNA causes an accumulation of cells in the G1 phase of the cell cycle, but does not induce apoptosis or necrosis when compared to control cells that express the same levels of STAT3. In a final example, the effect of reduced p53 levels on increased adriamycin sensitivity for colon carcinoma cells was demonstrated at the whole-well level using siRNA knockdown and in control and untreated cells at the single cell level. We find that single cell analysis methods are generally applicable to a wide range of experiments in adherent cells using technology that is becoming increasingly available to most laboratories. It is well-suited to emerging models of signaling dysfunction, such as oncogene addition and oncogenic shock. Single cell cytometry can demonstrate effects on cell function for protein levels that differ by as little as 20%. Biological differences that result from changes in protein level or pathway activation state can be modulated directly by RNAi treatment or extracted from the natural variability intrinsic to cells grown under normal culture conditions.


Factors influencing interest in recreational sports participation and its rural-urban disparity.
Recreational sports are important leisure activities. However, most studies investigating barrier factors and motivation for participation in recreational sports have been limited to specific areas (e.g., a city or school) or demographic groups (e.g., adolescents). Therefore, this study set out to gain a more comprehensive understanding of the behavioral and socioeconomic factors influencing interest in recreational sports participation in Taiwan, as well as to evaluate the effect of any urban-rural divide. This study analyzed data collected by the "Taiwan Social Change Survey" (program five, wave 3) "Leisure Life" questionnaire. We used hierarchical linear modeling to assess respondent interest in recreational sports participation and evaluated the influence of behavioral factors, socioeconomic factors, and residence location (urban/rural). Of the 2,146 participants in this study, 50.3% were male, and the average age was 43.9 years. Location of residence (urban/rural) accounted for 35.3% of the variation in interest in recreational sports participation, while the remaining 64.7% came from the individual level. Participants who lived in rural settings were less interested in recreational sports than their urban counterparts. Gender, educational attainment, participation frequency, health-motivated interest, and appearance-motivated interest were also associated with interest in recreational sports participation. Different communication strategies may be needed to effectively reach different demographic groups. We suggest that future public health campaigns aiming to increase recreational sports participation include tailored interventions and messages to effectively encourage leisure physical activities among all, regardless of demographic boundaries.


Adenovirus targeting to HLA-A1/MAGE-A1-positive tumor cells by fusing a single-chain T-cell receptor with minor capsid protein IX.
Adenovirus vectors have great potential in cancer gene therapy. Targeting of cancer-testis (CT) antigens, which are specifically presented at the surface of tumor cells by human leukocyte antigen (HLA) class I molecules, is an attractive option. In this study, a single-chain T-cell receptor (scTCR) directed against the CT antigen melanoma-associated antigen (MAGE)-A1 in complex with the HLA class I molecule of haplotype HLA-A1 is fused with the C terminus of the adenovirus minor capsid protein IX. Propagation of a protein-IX (pIX)-gene-deleted human adenovirus 5 (HAdV-5) vector on cells that constitutively express the pIXscTCR fusion protein yielded viral particles with the pIXscTCR fusion protein incorporated in their capsid. Generated particles specifically transduced melanoma cell lines expressing the HLA-A1/MAGE-A1 target complex with at least 10-fold higher efficiency than control viruses. Whereas loading of HLA-A1-positive cells with MAGE-A1 peptides leads to enhanced transduction of the cells, the efficiency of virus transduction is strongly reduced if the HLA-A1 molecules are not accessible at the target cell. Taken together, these data provide proof of principle that pIXscTCR fusions can be used to target HAdV-5 vectors to tumor cells expressing intracellular CT antigens.


Concurrent use of prescription drugs and herbal medicinal products in older adults: a systematic review protocol.
There has been a global increase in the use of herbal medicinal products (HMPs). About a quarter of UK adults use HMPs, bought over the counter by self-prescription and often not disclosed to healthcare professionals. Potential herb-drug interaction is a clinical concern, with older people at greater risk because of co-morbidities and slower clearance of pharmacologically active compounds. While there is a good understanding of general herbal medicine use by older people, less is known about the extent and implications of concurrent use with prescription medicines. The aim of this systematic review is to assess the prevalence, patterns, safety issues and other factors associated with concurrent prescription and herbal medicines use among older adults. Systematic electronic searches of MEDLINE, PsychINFO, Excerpta Medica dataBASE (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), Web of Science and Cochrane from inception till present for studies reporting the concurrent use of prescription medicines with HMPs in older adults (≥65 years). Lateral searching via related citation (PubMed) and checking reference lists of identified studies will be performed. Two reviewers will independently screen studies, extract data and appraise methodological quality using the Joanna Briggs Institute checklist for prevalence data and the Critical Appraisal Skills Programme (CASP) checklist. Qualitative and quantitative studies from all settings will be included. Non-empirical papers, in vitro experiments and animal studies will be excluded. Primary outcomes are prevalence and patterns of concurrent use, number and types of prescription and HMPs and adverse reactions reported. Secondary outcomes are disclosure of HMP use to healthcare professionals and cost of HMPs. A narrative synthesis of included studies will be performed to summarise the evidence. This review will synthesise and critically appraise current knowledge on the concurrent use of drugs and HMPs by older adults and thus provide a better understanding of the issue. It will also identify any gaps in knowledge. By establishing safety issues associated with concurrent use, it will also inform strategies that can help practitioners to identify and manage older people at potential risk of herb-drug interactions. PROSPERO CRD42014009091.


Arresting inflammation: contributions of plasma membrane and endosomal signalling to neuropeptide-driven inflammatory disease.
GPCR (G-protein-coupled receptor) signalling at the plasma membrane is under tight control. In the case of neuropeptides such as SP (substance P), plasma membrane signalling is regulated by cell-surface endopeptidases (e.g. neprilysin) that degrade extracellular neuropeptides, and receptor interaction with β-arrestins, which uncouple receptors from heterotrimeric G-proteins and mediate receptor endocytosis. By recruiting GPCRs, kinases and phosphatases to endocytosed GPCRs, β-arrestins assemble signalosomes that can mediate a second wave of signalling by internalized receptors. Endosomal peptidases, such as ECE-1 (endothelin-converting enzyme-1), can degrade SP in acidified endosomes, which destabilizes signalosomes and allows receptors, freed from β-arrestins, to recycle and resensitize. By disassembling signalosomes, ECE-1 terminates β-arrestin-mediated endosomal signalling. These mechanisms have been studied in model cell systems, and the relative importance of plasma membrane and endosomal signalling to complex pathophysiological processes, such as inflammation, pain and proliferation, is unclear. However, deletion or inhibition of metalloendopeptidases that control neuropeptide signalling at the plasma membrane and in endosomes has marked effects on inflammation. Neprilysin deletion exacerbates inflammation because of diminished degradation of pro-inflammatory SP. Conversely, inhibition of ECE-1 attenuates inflammation by preventing receptor recycling/resensitization, which is required for sustained pro-inflammatory signals from the plasma membrane. β-Arrestin deletion also affects inflammation because of the involvement of β-arrestins in pro-inflammatory signalling and migration of inflammatory cells. Knowledge of GPCR signalling in specific subcellular locations provides insights into pathophysiological processes, and can provide new opportunities for therapy. Selective targeting of β-arrestin-mediated endosomal signalling or of mechanisms of receptor recycling/resensitization may offer more effective and selective treatments than global targeting of cell-surface signalling.


Cardiovascular responses to elevation of intra-abdominal hydrostatic pressure.
Intra-abdominal fluid volume and hydrostatic pressure were elevated by positive pressure infusion of Tyrode solution into the peritoneal cavity of anesthetized dogs. The compliance of the peritoneal cavity fell from 10.8 to 0.56 ml X mmHg-1 X kg-1 of body wt as intra-abdominal pressure increased from 0 to 40 mmHg. Intrathoracic pressure also increased as elevated peritoneal pressure caused diaphragmatic bulging. Cardiac output and stroke volume were reduced by 36% after an intra-abdominal pressure rise of 40 mmHg; in contrast, heart rate did not change. Flow in the celiac, superior mesenteric, and renal arteries was reduced by 42, 61, and 70%, respectively. Pressure in the femoral vein increased to 46 mmHg, while flow in the femoral artery decreased by 65%. Whole-body O2 consumption, pH, and arterial PO2 decreased as intra-abdominal pressure rose. The peritoneal cavity, with its high initial compliance, affords the body an ideal location for the temporary accumulation of small to moderate volumes of fluid during episodes of increased vascular pressure or permeability. The marked alterations in the hemodynamic properties of the cardiovascular system are indicative of the physiological changes that occur when intra-abdominal fluid accumulation becomes excessive and peritoneal pressure rises to high levels.


Titanium coordination compounds: from discrete metal complexes to metal-organic frameworks.
Owing to their promise in photocatalysis and optoelectronics, titanium based metal-organic frameworks (MOFs) are one of the most appealing classes of MOFs reported to date. Nevertheless, Ti-MOFs are still very scarce because of their challenging synthesis associated with a poor degree of control of their chemistry and crystallization. This review aims at giving an overview of the recent progress in this field focusing on the most relevant existing titanium coordination compounds as well as their promising photoredox properties. Not only Ti-MOFs but also Ti-oxo-clusters will be discussed and particular interest will be dedicated to highlight the different successful synthetic strategies allowing to overcome the still "unpredictable" reactivity of titanium ions, particularly to afford crystalline porous coordination polymers.


Direct regulation of ENaC by bradykinin in the distal nephron. Implications for renal sodium handling.
Locally produced peptide hormones kinins, such as bradykinin, are thought to oppose many of the prohypertensive actions of the renin-angiotensin-aldosterone system. In the kidney, bradykinin, via stimulation of B2 receptors (B2R), favors natriuresis mostly due to the inhibition of tubular Na reabsorption. Recent experimental evidence identifies the epithelial Na channel (ENaC) as a key end effector of bradykinin actions in the distal tubular segments. The focus of this review is the physiological relevance and molecular details of the bradykinin signal to ENaC. The recent epidemiological GenSalt study demonstrated that genetic variants of the gene encoding B2R show significant associations with the salt sensitivity of blood pressure. Bradykinin was shown to have an inhibitory effect on the distal nephron sodium transport via stimulation of B2 receptor-phospholipase C (B2R-PLC) cascade to decrease ENaC open probability. Genetic ablation of bradykinin receptors in mice led to an augmented ENaC function, particularly during elevated sodium intake, likely contributing to the salt-sensitive hypertensive phenotype. Furthermore, augmentation of bradykinin signaling in the distal nephron was demonstrated to be an important component of the natriuretic and antihypertensive effects of angiotensin converting enzyme inhibition. Salt-sensitive inhibition of ENaC activity by bradykinin greatly advances our understanding of the molecular mechanisms that are responsible for shutting down distal tubule sodium reabsorption during volume expanded conditions to avoid salt-sensitive hypertension.


Postnatal and non-invasive prenatal detection of β-thalassemia mutations based on Taqman genotyping assays.
The β-thalassemias are genetic disorder caused by more than 200 mutations in the β-globin gene, resulting in a total (β0) or partial (β+) deficit of the globin chain synthesis. The most frequent Mediterranean mutations for β-thalassemia are: β039, β+IVSI-110, β+IVSI-6 and β0IVSI-1. Several molecular techniques for the detection of point mutations have been developed based on the amplification of the DNA target by polymerase chain reaction (PCR), but they could be labor-intensive and technically demanding. On the contrary, TaqMan® genotyping assays are a simple, sensitive and versatile method suitable for the single nucleotide polymorphism (SNP) genotyping affecting the human β-globin gene. Four TaqMan® genotyping assays for the most common β-thalassemia mutations present in the Mediterranean area were designed and validated for the genotype characterization of genomic DNA extracted from 94 subjects comprising 25 healthy donors, 33 healthy carriers and 36 β-thalassemia patients. In addition, 15 specimens at late gestation (21-39 gestational weeks) and 11 at early gestation (5-18 gestational weeks) were collected from pregnant women, and circulating cell-free fetal DNAs were extracted and analyzed with these four genotyping assays. We developed four simple, inexpensive and versatile genotyping assays for the postnatal and prenatal identification of the thalassemia mutations β039, β+IVSI-110, β+IVSI-6, β0IVSI-1. These genotyping assays are able to detect paternally inherited point mutations in the fetus and could be efficiently employed for non-invasive prenatal diagnosis of β-globin gene mutations, starting from the 9th gestational week.


Enhanced bone marrow stromal cell adhesion and growth on segmented poly(ether ester)s based on poly(ethylene oxide) and poly(butylene terephthalate).
In previous studies in rats and goats, hydrophilic compositions of the PEOT/PBT block copolymer family have shown in vivo calcification and bone bonding. These copolymers are therefore interesting candidates as scaffolding materials in bone tissue engineering applications. Model studies using goat bone marrow stromal cells, however, showed that it was not possible to culture bone marrow stromal cells in vitro on these hydrophilic copolymers. In this paper two ways of surface modifying these materials to improve in vitro bone marrow stromal cell attachment and growth are discussed. Two different approaches are described: (1) blending of hydroxyapatite (HA) followed by CO(2) gas plasma etching; (2) surface modification using CO(2) gas plasma treatments. It was observed that not only HA but also the CO(2) plasma treatment by itself has a positive effect on bone marrow stromal cell attachment and growth. Gas plasma treatment appeared to be the most successful approach, resulting in a large increase in the amount of bone marrow stromal cells present on the surface (determined by a DNA assay). The amount of DNA present on the plasma-treated copolymer 1000/70/30 PEOT/PBT, based on poly(ethylene oxide, M(w) = 1000, 70 m% soft segment), was comparable to the amount present on PDLLA and significantly higher than the amount present on PCL after 7 days of cell culturing. The fact that after gas plasma treatment bone marrow stromal cells do attach to PEOT/PBT copolymers, enables in vitro bone marrow stromal cell culturing, making bone tissue engineering applications of these materials possible.


6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.
Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. UK National Institute for Health Research, Health Technology Assessment Programme.


Perspectives of Final Year Students and Newly Qualified Doctors of the Teaching of Preclinical Courses at the College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria.
It is established that there is a strong relationship between perception and outcome of learners' satisfaction, achievement, and success and that a positive learning environment well received by learners is necessary for positive learning outcomes. This study is a first step in providing an answer to the question "how do learners perceive preclinical medical education in Ife" with the aim of obtaining information which can serve as basis for the review of teaching methods and improvement of learning environment. A questionnaire adopted from two validated questionnaires (Dundee Ready Education Environment Measure questionnaire from Dundee and another from a study carried out in Bangladesh) was administered to 187 respondents comprising 106 final year students and 81 newly qualified doctors to obtain the information about their perception of teaching and learning of the three major preclinical participants. Items were rated using the 5-point Likert scale, and each item was scored 4-0. Data were analyzed using the descriptive and inferential statistics. Values were expressed as the mean of scores. The mean gross scores for the 19 items rated for anatomy, biochemistry, and physiology were 28.92, 35.76, and 45.06 (out of 76), respectively. Physiology had the highest score in all the subdomains examined, with 62% of the respondents rating their overall quality of learning experience in the subject "very good." Scores for perception of learning environment were generally low (7.54 ± 0.43, 10.44 ± 0.42, and 12.51 ± 0.47, out of a total of 28 for anatomy, biochemistry, and physiology, respectively). The opinion of learners in this study emphasizes the need for the improvement of teaching methods and learning environment.


Resource distribution and internal factors interact to govern movement of a freshwater snail.
Movement enables mobile organisms to respond to local environmental conditions and is driven by a combination of external and internal factors operating at multiple scales. Here, we explored how resource distribution interacted with the internal state of organisms to drive patterns of movement. Specifically, we tracked snail movements on experimental landscapes where resource (algal biofilm) distribution varied from 0 to 100% coverage and quantified how that movement changed over a 24 h period. Resource distribution strongly affected snail movement. Trajectories were tortuous (i.e. Brownian-like) within resource patches but straighter (i.e. Lévy) in resource-free (bare) patches. The average snail speed was slower in resource patches, where snails spent most of their time. Different patterns of movement between resource and bare patches explained movement at larger spatial scales; movement was ballistic-like Lévy in resource-free landscapes, Lévy in landscapes with intermediate resource coverage and approximated Brownian in landscapes covered in resources. Our temporal analysis revealed that movement patterns changed predictably for snails that satiated their hunger and then performed other behaviours. These changes in movement patterns through time were similar across all treatments that contained resources. Thus, external and internal factors interacted to shape the inherently flexible movement of these snails.


PyNCS: a microkernel for high-level definition and configuration of neuromorphic electronic systems.
Neuromorphic hardware offers an electronic substrate for the realization of asynchronous event-based sensory-motor systems and large-scale spiking neural network architectures. In order to characterize these systems, configure them, and carry out modeling experiments, it is often necessary to interface them to workstations. The software used for this purpose typically consists of a large monolithic block of code which is highly specific to the hardware setup used. While this approach can lead to highly integrated hardware/software systems, it hampers the development of modular and reconfigurable infrastructures thus preventing a rapid evolution of such systems. To alleviate this problem, we propose PyNCS, an open-source front-end for the definition of neural network models that is interfaced to the hardware through a set of Python Application Programming Interfaces (APIs). The design of PyNCS promotes modularity, portability and expandability and separates implementation from hardware description. The high-level front-end that comes with PyNCS includes tools to define neural network models as well as to create, monitor and analyze spiking data. Here we report the design philosophy behind the PyNCS framework and describe its implementation. We demonstrate its functionality with two representative case studies, one using an event-based neuromorphic vision sensor, and one using a set of multi-neuron devices for carrying out a cognitive decision-making task involving state-dependent computation. PyNCS, already applicable to a wide range of existing spike-based neuromorphic setups, will accelerate the development of hybrid software/hardware neuromorphic systems, thanks to its code flexibility. The code is open-source and available online at https://github.com/inincs/pyNCS.


STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism.
We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.


The value of endocervical curettage after conization for cervical intraepithelial neoplasia.
The objective of this study is to assess the value of postcone endocervical curettage, after conization of cervical intraepithelial neoplasia or carcinoma as a predictive tool for residual lesions. This is a retrospective observational study. All data were obtained by the University Hospital of Zurich, Department of Gynaecology. One hundred fifty patients underwent hysterectomy within 12 months after conization and endocervical curettage from 1993 to 2006. To analyze the sensitivity, specificity, and the positive predictive value (PPV) and negative predictive value (NPV) of the endocervical curettage after conization, we used the Fisher exact test and χ(2) test. The main outcome measures are the sensitivity and specificity as well as the PPV and NPV of the postconization endocervical curettage. The endocervical curettage exhibited a sensitivity of 0.38, a specificity of 0.85, a PPV of 0.56, and an NPV of 0.73. Comparing patients younger than 50 years to women 50 years or older, endocervical curettage had a sensitivity of 0.35 and 0.44, a specificity of 0.83 and 0.94, a PPV of 0.46 and 0.88, and an NPV of 0.76 and 0.63, respectively. The endocervical curettage after conization of cervical intraepithelial neoplasia does not generally improve the prediction of residual lesions. However, in women 50 years or older, a higher specificity and PPV, 0.94 and 0.88, respectively, was observed. Therefore, this subgroup of patients may benefit from an endocervical curettage.


The role of exogenous growth-promoting factors and their receptors in organogenesis.
The mechanisms involved in the regulation of early embryonic development are poorly understood. Certain growth promoting molecules are known to be produced within the embryo itself. It is clear, however, that at the early stages of embryonic development, many additional growth promoting factors have to be provided by the maternal system. Since the levels of factors such as epidermal growth factor and insulin in the maternal circulation are not linked with gestational age of the offspring, it is likely that regulation of receptors in the embryonic tissues may provide the key to the regulation of development. The expression of any receptor may depend on its synthetic rate, turnover or its distribution between the cell surface and intracellular pools. The study of the role of exogenous growth promoting molecules and receptor distribution and regulation for such growth factors, in particular insulin, insulin-like growth factor-I and epidermal growth factor, in embryos has been addressed using whole embryo culture, supported by anembryonic yolk sac culture and intravitelline injection of rat embryos.


Habitual versus goal-directed action control in Parkinson disease.
This study presents the first direct investigation of the hypothesis that dopamine depletion of the dorsal striatum in mild Parkinson disease leads to impaired stimulus-response habit formation, thereby rendering behavior slow and effortful. However, using an instrumental conflict task, we show that patients are able to rely on direct stimulus-response associations when a goal-directed strategy causes response conflict, suggesting that habit formation is not impaired. If anything our results suggest a disease severity-dependent deficit in goal-directed behavior. These results are discussed in the context of Parkinson disease and the neurobiology of habitual and goal-directed behavior.


Psychosocial problems in children of women entering substance use disorder treatment: A longitudinal study.
While parental substance use disorder (SUD) has been recognized as a risk factor for child outcomes, past research seldom focused specifically on children whose mothers suffer from alcohol and drug use disorders. Are these children at risk for elevated psychosocial problems, and would such risk be reduced if maternal substance use was reduced? Children of substance-abusing mothers (COSAM, N=130) were compared to a demographically matched comparison sample, and examined soon after their mothers entered SUD treatment and in the 18months after treatment entry. We expected to observe elevated symptomatology among COSAM at baseline assessment, followed by a decreasing trend after maternal treatment in general, and remission in particular. Children's psychosocial problems were assessed through maternal reports on the Pediatric Symptom Checklist. Soon after their mothers entered SUD treatment, COSAM exhibited significantly greater overall and clinical-level psychosocial problems than the children from the matched comparison sample. However, at the end of the 18-months study period, these two groups no longer differed in terms of problems. Results from the longitudinal growth models revealed reductions in COSAM's overall and clinical-level problems following their mothers' SUD treatment. However, these reductions were similar for all COSAM, regardless of whether their mothers relapsed or remitted. Psychosocial problems were significantly reduced in COSAM following maternal SUD treatment, such that COSAM did not significantly differ from children from the matched comparison sample by the end of the 18-month study period.


Patellar component resection in revision and reimplantation total knee arthroplasty.
Between 1979 and 1995, 34 knees in 31 patients had a revision or reimplantation total knee arthroplasty in which the patellar component could not be reinserted. The patellar bone stock in each of those cases was compromised markedly and precluded adequate prosthetic fixation. The mean followup after the revision operation was 3.5 years (range, 2-14 years). The Knee Society knee score improved from a mean of 59 points preoperatively to a mean of 75 points postoperatively. The function score improved from a mean of 46 points preoperatively to a mean of 69 points postoperatively. Complications occurred in five patients: one patient sustained a patellar fracture that required no additional treatment; one experienced intermittent episodes of patellar subluxation; one had a recurvatum deformity develop and was treated with a brace; one had persistent knee stiffness and had four manipulations; and one patient had an extensor lag of 30 degrees develop. Twenty-six patients were satisfied with the results of their revision operations and five were dissatisfied. Ten patients had persistent knee symptoms referable to the patellofemoral articulation: mild pain in three; moderate pain in six; and severe pain in one. This study suggests that resection of the patellar component during revision or reimplantation total knee arthroplasty may be a reasonable approach for patients with markedly compromised patellar bone stock; however, mild or moderate anterior knee pain can be expected to persist in as much as 1/3 of these patients.


To live close to a person with cancer--experiences of family caregivers.
The purpose of this study was to obtain a deeper understanding of the experiences of Family Caregivers (FC) living close to a patient with cancer. This article reports on the findings from individual interviews with 15 FCs of patients with cancer. The interview transcripts were analyzed using qualitative hermeneutic analysis. This study revealed that living close to a cancer patient over the course of his or her illness affected many aspects of FCs lives in significant ways. Their experiences can be summarized with two major themes: (1) living in an ever changing life world and (2) balancing between conflicting interests and dilemmas. This study contributed to deeper insights into FC's experiences than previously reported in the literature.


A comprehensive analysis of mortality-related health metrics associated with mental disorders: a nationwide, register-based cohort study.
Systematic reviews have consistently shown that individuals with mental disorders have an increased risk of premature mortality. Traditionally, this evidence has been based on relative risks or crude estimates of reduced life expectancy. The aim of this study was to compile a comprehensive analysis of mortality-related health metrics associated with mental disorders, including sex-specific and age-specific mortality rate ratios (MRRs) and life-years lost (LYLs), a measure that takes into account age of onset of the disorder. In this population-based cohort study, we included all people younger than 95 years of age who lived in Denmark at some point between Jan 1, 1995, and Dec 31, 2015. Information on mental disorders was obtained from the Danish Psychiatric Central Research Register and the date and cause of death was obtained from the Danish Register of Causes of Death. We classified mental disorders into ten groups and causes of death into 11 groups, which were further categorised into natural causes (deaths from diseases and medical conditions) and external causes (suicide, homicide, and accidents). For each specific mental disorder, we estimated MRRs using Poisson regression models, adjusting for sex, age, and calendar time, and excess LYLs (ie, difference in LYLs between people with a mental disorder and the general population) for all-cause mortality and for each specific cause of death. 7 369 926 people were included in our analysis. We found that mortality rates were higher for people with a diagnosis of a mental disorder than for the general Danish population (28·70 deaths [95% CI 28·57-28·82] vs 12·95 deaths [12·93-12·98] per 1000 person-years). Additionally, all types of disorders were associated with higher mortality rates, with MRRs ranging from 1·92 (95% CI 1·91-1·94) for mood disorders to 3·91 (3·87-3·94) for substance use disorders. All types of mental disorders were associated with shorter life expectancies, with excess LYLs ranging from 5·42 years (95% CI 5·36-5·48) for organic disorders in females to 14·84 years (14·70-14·99) for substance use disorders in males. When we examined specific causes of death, we found that males with any type of mental disorder lost fewer years due to neoplasm-related deaths compared with the general population, although their cancer mortality rates were higher. Mental disorders are associated with premature mortality. We provide a comprehensive analysis of mortality by different types of disorders, presenting both MRRs and premature mortality based on LYLs, displayed by age, sex, and cause of death. By providing accurate estimates of premature mortality, we reveal previously underappreciated features related to competing risks and specific causes of death. Danish National Research Foundation.


Central Venous Catheter Adverse Events Are not Associated with Crowding Indicators.
Crowding in the emergency department (ED) impacts a number of important quality and safety metrics. We studied ED crowding measures associated with adverse events (AE) resulting from central venous catheters (CVC) inserted in the ED, as well as the relationship between crowding and the frequency of CVC insertions in an ED cohort admitted to the intensive care unit (ICU). We conducted a retrospective observational study from 2008-2010 in an academic tertiary care center. Participants undergoing CVC in the ED or admitted to an ICU were categorized by quartile based on the following: National Emergency Department Overcrowding Scale (NEDOCS); waiting room patients (WR); ED patients awaiting inpatient beds (boarders); and ED occupancy (EDO). Main outcomes were the occurrence of an AE during CVC insertion in the ED, and deferred procedures assessed by frequency of CVC insertions in ED patients admitted to the ICU. Of 2,284 ED patients who had a CVC inserted, 293 (13%) suffered an AE. There was no association between AEs from ED CVCs and crowding scales when comparing the highest crowding level or quartile to all other quartiles: NEDOCS (dangerous crowding [13.1%] vs other levels [13.0%], P = 0.98); number of WR patients (14.0% vs 12.7%, P = 0.81); EDO (13.0% vs 12.9%, P = 0.99); and number of boarding patients (12.0% vs 13.3%), P = 0.21). In a cohort of ED patients admitted to the ICU, there was no association between CVC placement rates in the ED and crowding scales comparing the highest vs all other quartiles: NEDOCS (dangerous crowding 16% vs all others 16%, P = 0.97); WR patients (16% vs 16%, P = 0.82), EDO (15% vs. 17%, P = 0.15); and number of boarding patients (17% vs 16%, P = 0.08). In a large, academic tertiary-care center, frequency of CVC insertion in the ED and related AEs were not associated with measures of crowding. These findings add to the evidence that the negative effects of crowding, which impact all ED patients and measures of ED performance, are less likely to impair the delivery of prioritized time-critical interventions.


Venous morbidity after superficial femoral-popliteal vein harvest.
The superficial femoral-popliteal vein (SFPV) is a reliable conduit for aortoiliac, infrainguinal, and venous reconstructions. In this prospective study, we characterized the anatomic and physiologic changes in SFPV harvest limbs and their relationship to the development of late venous complications. Since 1990, we have studied 61 patients after harvest of 86 SFPVs at 6-month intervals with clinical examinations, lower-extremity venous duplex, and venous function tests. The CEAP system was used as a means of categorizing clinical changes. Mean (+/- SEM) follow-up was 37 +/- 3 months. Less than one third of harvest limbs had edema without skin changes (C3). No patient had major chronic venous changes (C4 to C6) or venous claudication. There were no significant differences in limb measurements between harvest and non-harvest limbs, except in a subgroup of patients with unilateral harvest in which there was a small but significant (P =.046) increase in harvest limb thigh and calf circumference, compared with the opposite non-harvest limb. These clinical results were not affected by the presence or absence of an intact greater saphenous vein (GSV). Large, direct collaterals (4 to 6 mm in diameter) between the popliteal vein stump and profunda femoris vein (PFV) were seen by means of duplex ultrasonography in 29 harvest limbs (34%). The remainder appeared to have smaller, less direct collaterals to the PFV. Mild venous reflux with rapid cuff deflation was present at the popliteal or posterior tibial vein in nine of 79 harvest limbs (11%). Six of these nine limbs (67%) with reflux were clinical class C3, compared with only 19 of the 70 limbs without reflux (27%; P =.02). Ambulatory venous pressure (AVP) with exercise was significantly increased in harvest limbs (60 +/- 4.7 mm Hg), compared with non-harvest limbs (47.8 +/- 5.2 mm Hg; P =.049). The AVP recovery time of harvest limbs (14.0 +/- 1.0 seconds) was reduced, compared with non-harvest limbs (23.5 +/- 4.5 seconds; P =.02). AVPs (exercise) remained stable or decreased in six of 10 harvest limbs measured serially. Venous refill time in harvest limbs (15.1 +/- 1.1 seconds) was shortened, compared with non-harvest limbs (22.3 +/- 2. 1 seconds)(P =.002). Venous outflow obstruction measured by means of plethysmography was present in 93% of harvest limbs, compared with 36% of non-harvest limbs (P =.001). SFPV harvest results in minimal mid-term to late-term lower-extremity venous morbidity despite outflow obstruction. The most likely mechanisms preserving clinical status include the low incidence of mild reflux, the presence of collateral venous channels, and the lack of progression in abnormal harvest limb physiology. The absence of the ipsilateral GSV does not adversely affect clinical outcome.


Cotargeting tumor and stroma in a novel chimeric tumor model involving the growth of both human prostate cancer and bone stromal cells.
Stromal-epithelial interaction contributes to local prostate tumor growth, androgen-independent progression and distant metastasis. We have established in vitro coculture and in vivo chimeric tumor models to evaluate the roles of stromal cells isolated from either osteosarcoma or normal bone, a site where prostate cancer cells frequently metastasize, in contributing to the growth and survival of human prostate cancer cells. We have evaluated extensively the effects of toxic gene therapy using luciferase-tagged chimeric human prostate cancer models both in vitro and in vivo. In the in vitro cocultured cell model, we assessed cancer cell growth and residual cellular proteins after targeting either prostate cancer epithelial cells alone or both prostate cancer and bone stromal cells. In the in vivo animal model, we measured tumor volume and serum prostate-specific antigen (PSA) in mice bearing chimeric prostate tumors comprised of human prostate tumor cells and normal bone stromal cells. Our results demonstrated that: (1) The rate of human prostate cancer cell growth in vitro is accelerated by coculturing with human and rat osteosarcoma or normal mouse bone marrow stromal cell lines. No growth stimulation was noted when cocultured with a human prostate epithelial cell line. (2) Disabling the growth of normal bone stromal cells using transgenic targeting with a bystander gene, herpes simplex virus thymidine kinase (hsv-TK), plus the pro-drug ganciclovir (GCV) or acyclovir markedly depressed the growth of cocultured human prostate cancer cells in vitro and human prostate cancer-mouse normal bone stroma chimeric tumors in vivo. (3) By cotargeting both human prostate cancer and normal mouse bone stromal cells in vitro with an adenoviral construct, Ad-hOC-TK (a replication-defective Ad5 vector with the bystander transgene hsv-TK under the control of a human osteocalcin (hOC) promoter) plus GCV4, we observed greater inhibition of tumor cell growth than by targeting a single cell compartment with Ad-PSA-TK (a vector construct similar to Ad-hOC-TK except that the transgene expression is under regulation by a full-length human PSA promoter). These results, taken together, established a basic principle that cotargeting both tumor and its supporting stroma is more efficacious than targeting a single cell compartment in the treatment of human prostate cancer bone metastasis. This principle can be applied to other clinical conditions of cancer growth where stroma contribute to the overall growth and survival potential of the cancer.


Healthy aging: The ultimate preventative medicine.
Age is the greatest risk factor for nearly every major cause of mortality in developed nations. Despite this, most biomedical research focuses on individual disease processes without much consideration for the relationships between aging and disease. Recent discoveries in the field of geroscience, which aims to explain biological mechanisms of aging, have provided insights into molecular processes that underlie biological aging and, perhaps more importantly, potential interventions to delay aging and promote healthy longevity. Here we describe some of these advances, along with efforts to move geroscience from the bench to the clinic. We also propose that greater emphasis should be placed on research into basic aging processes, because interventions that slow aging will have a greater effect on quality of life compared with disease-specific approaches.


Sense of place among Atlanta public housing residents.
For almost two decades now, cities around the country have been demolishing traditional public housing and relocating residents to subsidized private market rental housing. In this paper, we examine sense of place, consisting of both community and place attachment, among a sample of Atlanta public housing residents prior to relocation (N = 290). We find that 41% of the residents express place attachment, and a large percentage express some level of community attachment, though residents of senior public housing are far more attached than residents of family public housing. Positive neighborhood characteristics, such as collective efficacy and social support, are associated with community attachment, and social support is also associated with place attachment. Negative neighborhood characteristics, such as social disorder and fear of crime, are not consistently associated with sense of place. We argue that embodied in current public housing relocation initiatives is a real sense of loss among the residents. Policy makers may also want to consider the possibilities of drawing upon residents' sense of place as a resource for renovating and revitalizing public housing communities rather than continuing to demolish them and relocating residents to other neighborhoods.


Spontaneous activity in default-mode network predicts ascription of self-relatedness to stimuli.
Spontaneous activity levels prior to stimulus presentation can determine how that stimulus will be perceived. It has also been proposed that such spontaneous activity, particularly in the default-mode network (DMN), is involved in self-related processing. We therefore hypothesised that pre-stimulus activity levels in the DMN predict whether a stimulus is judged as self-related or not. Participants were presented in the MRI scanner with a white noise stimulus that they were instructed contained their name or another. They then had to respond with which name they thought they heard. Regions where there was an activity level difference between self and other response trials 2 s prior to the stimulus being presented were identified. Pre-stimulus activity levels were higher in the right temporoparietal junction, the right temporal pole and the left superior temporal gyrus in trials where the participant responded that they heard their own name than trials where they responded that they heard another. Pre-stimulus spontaneous activity levels in particular brain regions, largely overlapping with the DMN, predict the subsequent judgement of stimuli as self-related. This extends our current knowledge of self-related processing and its apparent relationship with intrinsic brain activity in what can be termed a rest-self overlap.


Vitamin C protects against lysophosphatidylcholine-induced expression of monocyte chemoattractant protein-1 in cultured human umbilical vein endothelial cells.
It is well documented that oxidized low-density lipoproteins (LDLs) can stimulate human vascular endothelial cells to produce monocyte chemoattractant protein-1 (MCP-1). Vitamin C is known to be an important antioxidant for vasodilatation. The purpose of this study was to determine whether pretreatment with vitamin C could protect against oxidized-LDL-induced expression of MCP-1 in cultured human umbilical vein endothelial cells (HUVECs). Cultured HUVECs were used for desired experiments before passage 4. Lysophosphatidylcholine (lysoPC), an oxidized component of LDL, was designated as the stimulator for MCP-1 synthesis from cultured HUVECs. MCP-1 concentrations in the cultured media were determined by enzyme-linked immunosorbent assay. MCP-1 RNA was evaluated by a semi-quantitative reverse transcriptase-polymerase chain reaction. HUVECs secreted MCP-1 within 30 minutes after exposure to 50 microM lysoPC. Compared with samples treated with lysoPC alone, pretreatment with vitamin C in concentrations of 50, 100, 150, and 200 microM, reduced levels of MCP-1 in the culture medium by 44%, 51%, 60%, and 67%, respectively, while levels of MCP-1 mRNA decreased by 15%, 18%, 80%, and 82%, respectively. Our findings imply that pretreatment with vitamin C can suppress lysoPC-induced expression and secretion of MCP-1 in cultured HUVECs. Therefore, vitamin C is protective against lysoPC-mediated inflammatory insults to the vascular endothelium in vitro.


Animation Plans for Before-and-After Satellite Images.
Before-and-after image pairs show how entities in a given region have evolved over a specific period of time. Satellite images are a major source of such data, that capture how natural phenomena or human activity impact a geographical area. These images are used both for data analysis and to illustrate the resulting findings to diverse audiences. The simple techniques used to display them, including juxtaposing, swapping and monolithic blending, often fail to convey the underlying phenomenon in a meaningful manner. We introduce Baia, a framework to create advanced animated transitions, called animation plans, between before-and-after images. Baia relies on a pixel-based transition model that gives authors much expressive power, while keeping animations for common types of changes easy to create thanks to predefined animation primitives. We describe our model, the associated animation editor, and report on two user studies. In the first study, advanced transitions enabled by Baia were compared to monolithic blending, and perceived as more realistic and better at focusing viewer's attention on a region of interest than the latter. The second study aimed at gathering feedback about the usability of Baia's animation editor.


Hyperbaric oxygen therapy for painful bladder syndrome/interstitial cystitis resistant to conventional treatments: long-term results of a case series in Japan.
There is no confirmed strategy for treating painful bladder syndrome/interstitial cystitis (PBS/IC) with unclear etiology. Therefore, a pilot study was carried out to evaluate the efficacy and safety of hyperbaric oxygen (HBO) therapy in treatment-resistant PBS/IC patients. HBO treatment (2.0 ATA for 60 minutes/day × 5 days/week for 2 or 4 weeks) was performed on 11 patients with severe symptoms that had not been improved by previous therapy regimens between December 2004 and July 2009. Seven of the 11 patients demonstrated persistent improvement in symptoms during the 12 months after HBO treatment. These responders demonstrated a decrease in the pelvic pain scale and urgency scale from 7.7 ± 1.0 and, 6.6 ± 0.9 to 3.4 ± 2.5 and 4.3 ± 2.4 after 12 months, respectively (p < 0.05). The total score of the interstitial cystitis symptom index and 24-hour urinary frequency demonstrated a significant sustained decrease from the baseline. Two responders, who received an additional course of HBO 12 and 13 months after initial treatment, respectively, did not suffer impairment for more than two years. There was one case of transient eustachian tube dysfunction and three cases of reversible exudative otitis media as a consequence of HBO treatment. HBO is a potent treatment for PBS/IC patients resistant to conventional therapy. It was well tolerated and provided maintained amelioration of pain, urgency and urinary frequency for at least 12 months.