Modelling wastewater treatment in a submerged anaerobic membrane bioreactor.
Mathematical modelling has been widely applied to membrane bioreactor (MBRs) processes. However, to date, very few studies have reported on the application of the anaerobic digestion model N.1 (ADM1) to anaerobic membrane processes. The aim of this study was to evaluate the applicability of the ADM1 to a submerged anaerobic MBR (SAMBR) treating simulated industrial wastewater composed of cheese whey and sucrose. This study demonstrated that the biological processes involved in SAMBRs can be modelled by using the ADM1. Moreover, the results showed that very few modifications of the parameters describing the ADM1 were required to reasonably fit the experimental data. In particular, adaptation to the specific conditions of the coefficients describing the wastewater characterisation and the reduction of the hydrolysis rate of particulate carbohydrate (khyd,ch) from 0.25 d(-1) (as suggested by the ADM1 for high-rate mesophilic reactors) to 0.13 d(-1) were required to fit the experimental data.


Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells.
Notch is known as a transmembranous receptor family with four homologous forms - Notch 1, Notch 2, Notch 3, and Notch 4 and related to cell fate regulation and angiogenesis. The purpose is to investigate the effect of follicular stimulating hormone (FSH) on the Notch 1 expression and proliferation in ovarian cancer cells. Human ovarian cancer cell line, SK-OV-3 and FSH were used. XTT cell proliferation and cell migration assay were carried out with FSH 100 mIU/mL and Notch 1 siRNA. Western blots and reverse transcriptase-polymerase chain reactions (RT-PCR) were carried out to determine the expression level of the Notch 1 protein and mRNA with FSH treatment in 0, 1, 5, 10, 100, 200, 300 mIU/mL concentrations. Immunofluorescent (IF) stains were performed in SK-OV-3 cell cultures with FSH 100 mIU/mL. Student-t tests were used in statistical analyses. The SK-OV-3 have Notch 1 receptors in their natural status. FSH stimulated SK-OV-3 cells in XTT cell proliferation and cell migration assays and notch 1 siRNA inhibited. The expression level of Notch 1 protein and mRNA were increased in a dose dependent pattern according to FSH concentrations compared to untreated cells. IF stains also showed brighter Notch1 expressions in the FSH treated cells compared to the control cells. FSH enhances proliferation & migration and Notch 1 signaling in SK-OV-3 cells. The Notch signaling probably supports one of the cell proliferating mechanisms of FSH in ovarian cancer cells.


Evidence for degeneration of the Y chromosome in the dioecious plant Silene latifolia.
The human Y--probably because of its nonrecombining nature--has lost 97% of its genes since X and Y chromosomes started to diverge [1, 2]. There are clear signs of degeneration in the Drosophila miranda neoY chromosome (an autosome fused to the Y chromosome), with neoY genes showing faster protein evolution [3-6], accumulation of unpreferred codons [6], more insertions of transposable elements [5, 7], and lower levels of expression [8] than neoX genes. In the many other taxa with sex chromosomes, Y degeneration has hardly been studied. In plants, many genes are expressed in pollen [9], and strong pollen selection may oppose the degeneration of plant Y chromosomes [10]. Silene latifolia is a dioecious plant with young heteromorphic sex chromosomes [11, 12]. Here we test whether the S. latifolia Y chromosome is undergoing genetic degeneration by analyzing seven sex-linked genes. S. latifolia Y-linked genes tend to evolve faster at the protein level than their X-linked homologs, and they have lower expression levels. Several Y gene introns have increased in length, with evidence for transposable-element accumulation. We detect signs of degeneration in most of the Y-linked gene sequences analyzed, similar to those of animal Y-linked and neo-Y chromosome genes.


The impact of ED crowding on early interventions and mortality in patients with severe sepsis.
Critically ill patients require significant time and care coordination in the emergency department (ED). We hypothesized that ED crowding would delay time to intravenous fluids and antibiotics, decrease utilization of protocolized care, and increase mortality for patients with severe sepsis or septic shock. This was a retrospective cohort study of severe sepsis patients admitted to the hospital from the ED between January 2005 and February 2010. Associations between four validated measures of ED crowding (occupancy, waiting patients, admitted patients, and patient-hours) assigned at triage, and time of day, time to antibiotics and fluids, and mortality were tested by analyzing trends across crowding quartiles. During the study period, 2913 severe sepsis patients were admitted to the hospital and 1127 (38.7%) qualified for protocolized care. In-hospital mortality was 14.3% overall and 26% for patients qualifying for protocolized care. Time to IV fluids was delayed as ED occupancy rate increased and as patient hours increased. Time to antibiotics increased as occupancy rates, patient hours, and the number of boarding inpatients increased. Implementation rates of protocolized care decreased from 71.3% to 50.5% (p<0.0001, OR 0.39) as the number of ED inpatient boarders increased; initiation of protocolized care was significantly higher as occupancy increased (OR 1.52). Mortality was unaffected by crowding parameters in all analyses. With increased ED crowding, time to critical severe sepsis therapies significantly increased and protocolized care initiation decreased. As crowding increases, EDs must implement systems that optimize delivery of time-sensitive therapies to critically ill patients.


Aryl hydrocarbon receptor-ligand axis mediates pulmonary fibroblast migration and differentiation through increased arachidonic acid metabolism.
Pulmonary fibroblast migration and differentiation are critical events in fibrogenesis; meanwhile, fibrosis characterizes the pathology of many respiratory diseases. The role of aryl hydrocarbon receptor (AhR), a unique cellular chemical sensor, has been suggested in tissue fibrosis, but the mechanisms through which the AhR-ligand axis influences the fibrotic process remain undefined. In this study, the potential impact of the AhR-ligand axis on pulmonary fibroblast migration and differentiation was analyzed using human primary lung fibroblasts HFL-1 and CCL-202 cells. Boyden chamber-based cell migration assay showed that activated AhR in HFL-1cells significantly enhanced cell migration in response to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), and a known AhR antagonist, CH223191, inhibited its migratory activity. Furthermore, the calcium mobilization and subsequent upregulated expression of arachidonic acid metabolizing enzymes, including cyclooxygenase2 (COX-2) and 5-lipoxygenase (5-LOX), were observed in TCDD-treated HFL-1 cells, concomitant with elevated levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion. Also, significantly increased expression of α-smooth muscle actin α-SMA), a fibroblast differentiation marker, was also noted in TCDD-treated HFL-1 cells (p<0.05), resulting in a dynamic change in cytoskeleton protein levels and an increase in the nuclear translocation of the myocardin-related transcription factor. Moreover, the enhanced levels of α-SMA expression and fibroblast migration induced by TCDD, PGE2 and LTB4 were abrogated by selective inhibitors for COX-2 and 5-LOX. Knockdown of AhR by siRNA completely diminished intracellular calcium uptake and reduced α-SMA protein verified by promoter-reporter assays and chromatin immunoprecipitation. Taken together, our results suggested the importance of the AhR-ligand axis in fibroblast migration and differentiation through its capacity in enhancing arachidonic acid metabolism.


The spectral emissivity of the anode of a carbon arc.
Data in the literature on the spectral emissivity of carbon and graphite show a great divergence, ranging from 0.75 to 0.99 in the visible region. A new determination has been undertaken at a number of wavelengths using an integrating sphere and modulated light. Emissivities ranging from 0.99 in the visible to 0.96 at 0.28 micro and 1.7 micro have been found for several different graphite anodes; the values for lampblack anodes are about 0.005 lower. There is a good agreement with the highest values thus far published. Most of the literature data on the spectral radiance of the anode are consistent with the emissivities found by the present author.


APE1 incision activity at abasic sites in tandem repeat sequences.
Repetitive DNA sequences, such as those present in microsatellites and minisatellites, telomeres, and trinucleotide repeats (linked to fragile X syndrome, Huntington disease, etc.), account for nearly 30% of the human genome. These domains exhibit enhanced susceptibility to oxidative attack to yield base modifications, strand breaks, and abasic sites; have a propensity to adopt non-canonical DNA forms modulated by the positions of the lesions; and, when not properly processed, can contribute to genome instability that underlies aging and disease development. Knowledge on the repair efficiencies of DNA damage within such repetitive sequences is therefore crucial for understanding the impact of such domains on genomic integrity. In the present study, using strategically designed oligonucleotide substrates, we determined the ability of human apurinic/apyrimidinic endonuclease 1 (APE1) to cleave at apurinic/apyrimidinic (AP) sites in a collection of tandem DNA repeat landscapes involving telomeric and CAG/CTG repeat sequences. Our studies reveal the differential influence of domain sequence, conformation, and AP site location/relative positioning on the efficiency of APE1 binding and strand incision. Intriguingly, our data demonstrate that APE1 endonuclease efficiency correlates with the thermodynamic stability of the DNA substrate. We discuss how these results have both predictive and mechanistic consequences for understanding the success and failure of repair protein activity associated with such oxidatively sensitive, conformationally plastic/dynamic repetitive DNA domains.


Depending on My Mood: Mood-Driven Influences on Text Comprehension.
Reading comprehension is a critical component of success in educational settings. To date, research on text processing in educational and cognitive psychological domains has focused predominantly on cognitive influences on comprehension, and in particular, those influences that might be derived from particular tasks or strategies. However, there is growing interest in documenting the influences of emotional factors on the processes and products of text comprehension, because these factors are less likely to be associated with explicit reading strategies. The present study examines this issue by evaluating the degree to which mood can influence readers' processing of text. Participants in control, happy-induced, or sad-induced groups thought aloud while reading expository texts. Happy, sad, and neutral moods influenced the degree to which readers engaged in particular types of coherence-building processes in the service of comprehension. Although reading strategies clearly influence processing, understudied factors that are less explicitly goal-driven, such as mood, can similarly impact comprehension activity. These findings have important implications for the role of mood on reading instruction and evaluation.


DNA repair and aging in basal cell carcinoma: a molecular epidemiology study.
This molecular epidemiology study examines the DNA-repair capacities (DRCs) of basal cell carcinoma (BCC) skin cancer patients (88) and their controls (135) by using a plasmid/host-cell reactivation assay. In this assay UV-damaged expression vector plasmid is transfected into peripheral blood T lymphocytes from the subjects. The host-cellular repair enzymes repair the photochemical damage in the plasmid, and 40 hr later the plasmid-encoded reporter chloramphenicol acetyltransferase is measured. An age-related decline in this DRC, amounting to approximately 0.61% per yr occurred in the controls from 20 to 60 yr of age. Reduced DRC was a particularly important risk factor for young individuals with BCC and for those individuals with a family history of skin cancer. Young individuals with BCC repaired DNA damage poorly when compared with controls. As the BCC patients aged, however, differences between cases and controls gradually disappeared. The normal decline in DNA repair with increased age may account for the increased risk of skin cancer that begins in middle age, suggesting that the occurrence of skin cancer in the young may represent precocious aging. Patients with reduced DRCs and overexposure to sunlight had an estimated risk of BCC > 5-fold greater than the control group. Such a risk was even greater (10-fold) in female subjects.


Interstate migration has fallen less than you think: consequences of hot deck imputation in the current population survey.
We show that much of the recent reported decrease in interstate migration is a statistical artifact. Before 2006, the Census Bureau's imputation procedure for dealing with missing data in the Current Population Survey inflated the estimated interstate migration rate. An undocumented change in the procedure corrected the problem starting in 2006, thus reducing the estimated migration rate. The change in imputation procedures explains 90% of the reported decrease in interstate migration between 2005 and 2006, and 42% of the decrease between 2000 (the recent high-water mark) and 2010. After we remove the effect of the change in procedures, we find that the annual interstate migration rate follows a smooth downward trend from 1996 to 2010. Contrary to popular belief, the 2007-2009 recession is not associated with any additional decrease in interstate migration relative to trend.


Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes.
Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.


Dynamin is required for recombinant adeno-associated virus type 2 infection.
Recombinant adeno-associated virus (rAAV) vectors for gene therapy of inherited disorders have demonstrated considerable potential for molecular medicine. Recent identification of the viral receptor and coreceptors for AAV type 2 (AAV-2) has begun to explain why certain organs may demonstrate higher efficiencies of gene transfer with this vector. However, the mechanisms by which AAV-2 enters cells remain unknown. In the present report, we have examined whether the endocytic pathways of rAAV-2 are dependent on dynamin, a GTPase protein involved in clathrin-mediated internalization of receptors and their ligands from the plasma membrane. Using a recombinant adenovirus expressing a dominant-inhibitory form of dynamin I (K44A), we have demonstrated that rAAV-2 infection is partially dependent on dynamin function. Overexpression of mutant dynamin I significantly inhibited AAV-2 internalization and gene delivery, but not viral binding. Furthermore, colocalization of rAAV and transferrin in the same endosomal compartment provides additional evidence that clathrin-coated pits are the predominant pathway for endocytosis of AAV-2 in HeLa cells.


The role of learning disability nurses in promoting cervical screening uptake in women with intellectual disabilities: A qualitative study.
Research suggests that the uptake of cervical screening by women with intellectual disabilities (commonly known as learning disabilities within UK policy frameworks, practice areas and health services) is poor compared to women without intellectual disabilities. The present study explored learning disability nurses' experiences of supporting women with intellectual disabilities to access cervical screening in order to examine their role in promoting attendance and elucidate potential barriers and facilitators to uptake. Ten participants recruited from a specialist learning disability service completed a semi-structured interview and data were analysed using experiential thematic analysis. Identified individual barriers included limited health literacy, negative attitudes and beliefs and competing demands; barriers attributed to primary care professionals included time pressures, limited exposure to people with intellectual disabilities and lack of appropriate knowledge, attitudes and skills. Attendance at cervical screening was facilitated by prolonged preparation work undertaken by learning disability nurses, helpful clinical behaviours in the primary care context and effective joint working.


An intravoxel incoherent motion diffusion-weighted imaging study of prostate cancer.
The purpose of this study is to investigate whether the intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters are different between prostate cancer, benign prostatic hyperplasia (BPH), and healthy peripheral zone (PZ). Detailed diffusion measurements of 26 patients with histologically proven prostate cancer have been made in this retrospective study. Trace IVIM DWI was performed using 10 b values (0, 10, 20, 30, 50, 80, 100, 200, 400, and 1000 s/mm2). Biexponential fits were applied to diffusion decay curves to calculate molecular diffusion coefficient, perfusion-related diffusion coefficient, and perfusion fraction on the basis of the IVIM model. Decay curves were also fit with monoexponential decay functions, and a statistical comparison between mono- and biexponential fits was performed. Paired t tests were performed to evaluate the statistical significance of the parameters of IVIM DWI and apparent diffusion coefficient (ADC) between prostate cancer, BPH, and PZ. The chi-square values of biexponential fits were smaller than those from monoexponential fits in all cases. Biexponential functions provided statistically improved fits over monoexponential functions in 81% of cases. The ADC, molecular diffusion coefficient, and perfusion fraction in prostate cancer were significantly lower than those found in the PZ; however, perfusion fractions in prostate cancer and BPH were not significantly different. There were no significant differences in the prostate cancer, BPH, and PZ for the perfusion-related diffusion coefficient, which had large SDs. IVIM DWI parameters are significantly different between prostate cancer and PZ. IVIM DWI may offer additional information for tissue characterization in the prostate gland.


A multicentre comparison of quantitative (90)Y PET/CT for dosimetric purposes after radioembolization with resin microspheres : The QUEST Phantom Study.
To investigate and compare the quantitative accuracy of (90)Y imaging across different generation PET/CT scanners, for the purpose of dosimetry after radioembolization with resin microspheres. A strict experimental and imaging protocol was followed by 47 international sites using the NEMA 2007/IEC 2008 PET body phantom with an 8-to-1 sphere-to-background ratio of (90)Y solution. The phantom was imaged over a 7-day period (activity ranging from 0.5 to 3.0 GBq) and all reconstructed data were analysed at a core laboratory for consistent processing. Quantitative accuracy was assessed through measures of total phantom activity, activity concentration in background and hot spheres, misplaced counts in a nonradioactive insert, and background variability. Of the 69 scanners assessed, 37 had both time-of-flight (ToF) and resolution recovery (RR) capability. These current generation scanners from GE, Philips and Siemens could reconstruct background concentration measures to within 10% of true values over the evaluated range, with greater deviations on the Philips systems at low count rates, and demonstrated typical partial volume effects on hot sphere recovery, which dominated spheres of diameter <20 mm. For spheres >20 mm in diameter, activity concentrations were consistently underestimated by about 20%. Non-ToF scanners from GE Healthcare and Siemens were capable of producing accurate measures, but with inferior quantitative recovery compared with ToF systems. Current generation ToF scanners can consistently reconstruct (90)Y activity concentrations, but they underestimate activity concentrations in small structures (≤37 mm diameter) within a warm background due to partial volume effects and constraints of the reconstruction algorithm. At the highest count rates investigated, measures of background concentration (about 300 kBq/ml) could be estimated on average to within 1%, 5% and 2% for GE Healthcare (all-pass filter, RR + ToF), Philips (4i8s ToF) and Siemens (2i21s all-pass filter, RR + ToF) ToF systems, respectively. Over the range of activities investigated, comparable performance between GE Healthcare and Siemens ToF systems suggests suitability for quantitative analysis in a scenario analogous to that of postradioembolization imaging for treatment of liver cancer.


Mathematical models for tumour angiogenesis: numerical simulations and nonlinear wave solutions.
To ensure its sustained growth, a tumour may secrete chemical compounds which cause neighbouring capillaries to form sprouts which then migrate towards it, furnishing the tumour with an increased supply of nutrients. In this paper a mathematical model is presented which describes the migration of capillary sprouts in response to a chemoattractant field set up by a tumour-released angiogenic factor, sometimes termed a tumour angiogenesis factor (TAF). The resulting model admits travelling wave solutions which correspond either to successful neovascularization of the tumour or failure of the tumour to secure a vascular network, and which exhibit many of the characteristic features of angiogenesis. For example, the increasing speed of the vascular front, and the evolution of an increasingly developed vascular network behind the leading capillary tip front (the brush-border effect) are both discernible from the numerical simulations. Through the development and analysis of a simplified caricature model, valuable insight is gained into how the balance between chemotaxis, tip proliferation and tip death affects the tumour's ability to induce a vascular response from neighbouring blood vessels. In particular, it is possible to define the success of angiogenesis in terms of known parameters, thereby providing a potential framework for assessing the viability of tumour neovascularization in terms of measurable quantities.


An enhancer within the divergent promoter of Epstein-Barr virus responds synergistically to the R and Z transactivators.
The EA-R and NotI repeat genes of Epstein-Barr virus (EBV) are oriented head to head and separated by a 1,000-base-pair (bp) divergent promoter region. We have identified functional domains within this divergent promoter which are important for regulation of the rightward EA-R gene. Both the R transactivator (Rta) and the Z transactivator (Zta) increase the abundance of correctly initiated EA-R transcripts. A 258-bp fragment (-114 to -372 from the EA-R cap site) contained the primary Rta and Zta response elements and was capable of transferring Rta and Zta activity to a heterologous promoter in an orientation- and position-independent manner. Rta activated this 258-bp enhancer region in both EBV-positive and EBV-negative cells. However, Zta activity appeared to be dependent on another EBV gene product, since Zta activated the enhancer efficiently (500- to 2,000-fold) in EBV-positive cells but had little or no activity in EBV-negative cells. The combination of Rta and Zta produced a striking synergistic effect on the enhancer in the absence of any additional EBV components, suggesting that the interaction between Zta and Rta accounts for the Zta response observed in EBV-positive cells. An Rta response element was mapped to a domain located 60 bp away from a Zta-binding site within the enhancer. Although Rta activated the enhancer and other early promoters without additional EBV- or B-cell-specific factors, it did not activate the lytic cycle of EBV, in contrast to Zta. Immunofluorescence patterns of Rta and Zta with antipeptide antisera indicated that they have overlapping but different subcellular localizations. Both transactivators were found in the nucleus, but Rta was also found in the cytoplasm.


Differential patterns of mental disorders among the homeless in Madrid (Spain) and Los Angeles (USA).
In this paper we compare rates of mental disorders (major depression, dysthymia, cognitive impairment, and schizophrenia) among homeless people in Madrid and Los Angeles (LA) and examine the ordering of the onset of both conditions (i.e., homelessness and mental disorders). In the Madrid study, 262 homeless persons were interviewed using the CIDI. In the LA study, 1563 homeless persons were interviewed with the DIS. To make an item-by-item comparison, we companied the databases from both studies to submit a single database to statistical analyses. Results showed no significant differences in DSM-III-R life-time prevalence rates of mental disorders between both samples. However, the Madrid sample showed higher 12-month prevalence rates of dysthymia and cognitive impairment as compared to the LA sample. Most subjects across both cities first experienced symptoms of their mental disorders before first becoming homeless. The only significant difference was that all of the depressed adults in Madrid experienced depression prior to first becoming homeless, whereas this was the case for only 59.1% of LA depressed homeless people. We discuss the reasons for these cultural differences and their implications for cross-national public health research and intervention.


Effect of drying methods on hybrid layer thickness.
To evaluate the effect of drying methods used in scanning electron microscopy on the thickness of the hybrid layers created by several different adhesive systems. A total etch dry bonding system, (Photobond), a three-step bonding adhesive system, (Scotchbond Multi-Purpose), a wet-bonding adhesive system (All-Bond 2) and a self-etching primer system (Mac Bond II) were used in this study. To permit measurement of the thickness of the hybrid layer, the resin-dentin interfaces were polished and etched briefly to remove polishing debris followed by immersion in 10% NaOCl for 4 hours. Half of the specimens in each group were subjected to fixation and critical-point drying followed by gold sputter-coating. The remaining specimens were allowed to air dry prior to gold sputter-coating. SEM observations were carried out to determine the structure and thickness of the hybrid layers. The thickness of hybrid layers were affected by the drying methods with the critical-point drying methods producing the thickest hybrid layers (P < 0.05). The thickest hybrid layers were created by Photobond, with Scotchbond Multi-Purpose and All-Bond 2 producing intermediate thickness hybrid layers, among the total etch systems. The thinnest hybrid layer among all of the adhesive systems was produced by the self-etching primer, Mac Bond II.


Bladder Cancer Working Group report.
EPIDEMIOLOGY OF BLADDER CANCER: Bladder cancer is the 7th most common cancer in men and the 17th most common in women in the world. The incidence of bladder cancer varies considerably among countries, with the highest incidence rates seen in Western countries and the lowest rates in Asian countries. In recent years, the mortality rate due to bladder cancer has been stable or decreased gradually. LIFESTYLE AND UROTHELIAL CARCINOMA: Occupational risks, environmental risks, dietary habits and cigarette smoking are lifestyle factors known to influence the development of urothelial carcinoma. Although the relative risk of bladder cancer associated with occupations is small, the public health impact may be significant. The Western pattern of diet is associated with a significant increase in the risk of bladder cancer. It has been found that smoking accounts for more than 50% of bladder cancers in men and 30% in women. Urological patients' awareness of smoking as a risk factor for bladder cancer is lower than their awareness regarding other smoking-related disease entities. Counseling patients regarding the risk of tobacco is a role for urologists. GENETIC SUSCEPTIBILITY TO UROTHELIAL CARCINOMA: Recent single-nucleotide polymorphism genetic studies in relation to bladder carcinogenesis have revealed several associated genetic polymorphisms of detoxification or DNA repair genes, such as NAT2, GST and OGG1. That information is important in relation to environmental risk factors and ethnic differences and will help predict the prognosis of patients with bladder cancer. Further studies are needed to confirm potential gene-gene and gene-environmental interactions leading to bladder carcinogenesis.


Exchange of polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs) between air and a mixed pasture sward.
To improve understanding of air-to-vegetation transfer of persistent organic pollutants (POPs), uptake and depuration of polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs) between grass sward and air was investigated. Pasture swards were placed in fanned (2 m s(-1) wind speed) and unfanned conditions for a period of 20 days and sampled at intervals. Depuration was carried out after a short (4 days) and a long (14 days) exposure period. Prior to contamination, a mixed pasture sward at a semi-rural location contained sigmaPCN concentrations 15-20% of the sigmaPCB concentration. Uptake of both PCBs and PCNs was broadly linear in fanned and unfanned conditions over the 20-day period, i.e., the pasture did not reach equilibrium with the air. Uptake rates (fluxes) were greater under the fanned conditions. The difference in uptake rates between fanned and unfanned conditions increased with degree of chlorination for both PCBs and PCNs, ranging between a factor of 2 for tri-chlorinated PCBs and PCNs and a factor 5 for octa-chlorinated PCBs. Depuration results over the first hours were very scattered, showing an initial period of loss, followed by an increase in concentrations, possibly as a result of re-volatilization of PCBs from the soil in the trays, with consequent recapture by the overlying sward. Rapid clearance was observed over the following days, but depuration of PCBs and PCNs was still incomplete after 14 days, with 20% of the initial concentration of the sigmaPCBs and 10% of the sigmaPCNs retained by the sward. There was no difference in the proportion of POPs retained in the sward between the 4- and 14-day contamination treatments. POP-specific differences in the amount of compound "trapped" in leaves after contamination were observed. The results show that, although changes in the rate of air movement around a pasture have an effect on the uptake rate of POPs into the vegetation, plant-side resistance controls both the air-to-pasture and pasture-to-air exchange of gas-phase PCBs and PCNs; i.e., differences between plant species in cuticle composition and/or structure affecting the permeability of the cuticle are of greater importance than differences in leaf morphology affecting aerodynamic roughness.


Salt, alone or in combination with sucrose, can improve the survival of Escherichia coli O157 (SERL 2) in model acidic sauces.
The commercial production of microbiologically safe and stable sauces containing acetic acid is guided by the Comité des Industries des Mayonnaises et Sauces Condimentaires de la Communauté Economique Européenne's (CIMSCEE) code. The CIMSCEE safety value is calculated using a linear regression equation combining weighted contributions of pH and aqueous-phase concentrations of undissociated acetic acid, NaCl, and sugars. By implication, the CIMSCEE safety equation predicts that increasing concentrations of hurdles will always increase inactivation of the target pathogen. In this study, the time to achieve a 3-log10 reduction of an acid-resistant, acid-adapted, Shiga toxin-producing Escherichia coli (STEC) O157 isolate was determined experimentally for 81 formulations at various pHs and acetic acid, NaCl, and sucrose concentrations in a broth model. The combinations were intended to simulate the aqueous phase of acidic sauces and dressings. Experimental data were fitted to the log logistic model to estimate the time to 3-log10 reduction (t3D). Comparison of fitted t3D estimates with CIMSCEE values showed agreement in predicting safety (as defined by CIMSCEE) for the majority of formulations. However, CIMSCEE safety predictions were "fail dangerous" for 13 of 81 formulations. Among these formulations and others, the observed E. coli t3D initially increased and then decreased with increasing osmolalities (NaCl and sucrose). Relative protection increased with exposure time where the protective effect of NaCl predominated. While commercial acidic sauces are not considered high-risk vehicles for STEC, interactions among hurdles that decrease their combined effectiveness are deserving of further investigation because they may reveal mechanisms of broader relevance in the inactivation of pathogens in foods.


Effects of motivation of the patient on indices of exercise capacity in chronic heart failure.
Measurement of variables of metabolic gas exchange during exercise is widely used to assess the severity of heart failure. The variables derived however, are potentially dependent on motivation of the patient and duration of exercise. The data from exercise tests in 23 patients with exertional breathlessness were analysed to derive the following three common indices of exercise tolerance: anaerobic threshold, extrapolated maximum oxygen consumption, and the ventilation to carbon dioxide production slope. The data were reanalysed with the data points from the first 90% of subsequent exercise, the first 75%, and finally the data up to the point where a respiratory gas exchange ratio of 1 was reached. The mean (SEM) anaerobic threshold was lower when computed from 90% of the data points than from 100% (13.2 (1.0) ml/kg/min v 12.5 (1.0), p < 0.001) and lower still from 75% (11.4 (0.7), p = 0.006 v 90%). Extrapolated maximum oxygen consumption was unchanged when computed from 90% of the data, but higher when computed from 75% (25.4 (2.1) ml/kg/min at 100% v 28.6 (2.1) at 75%, p < 0.001). The slope of the ventilation to carbon dioxide production ratio became progressively shallower measured from 90% and 75% of eventual exercise: 32.3 (1.5) from 100% v 30.0 (1.5) from 90%, p < 0.001; and 28.3 from 75%, p < 0.001 v 90%. At a respiratory gas exchange ratio of 1, extrapolated oxygen consumption was unchanged from the final calculation, anaerobic threshold was lower than at 100% of exercise (11.8 (0.9), p = 0.005) and the ventilation to carbon dioxide production slope was shallower (27.5 (1.4), p < 0.001). Anaerobic threshold tends to overestimate severity of exercise limitation and extrapolated maximum oxygen consumption and the ventilation to carbon dioxide production slope tend to underestimate severity. Extrapolated maximum oxygen consumption is the most reliable of the three measures, and is independent of effort provided that patients are encouraged to exercise to the point where the respiratory gas exchange ratio exceeds 1.


Consequences of chemotactic peptide receptor modulation for leukocyte orientation.
To exhibit chemotaxis, the orientation of locomotion along a chemical gradient cells sense differences in concentrations of a chemotactic factor by detecting some difference in the occupancy of their chemotactic receptors. Thus chemotaxis is sensitive to the number of receptors present and might be used to evaluate the consequences of receptor down-regulation. The ability of rabbit peritoneal polymorphonuclear leukocytes (PMNs) to orient to a standard gradient at various concentrations of N-formylnorleucylleucylphenylalanine (FNLLP) was examined. The observed orientation was compared to that expected if the directional signal were proportional to a difference in the absolute number or the fractional number of receptors occupied. The receptor occupancy in varying gradients was calculated from the binding constant of FNLLP, 2 X 10(-8) M (Zigmond and Sullivan, 1979, J. Cell Biol. 82:517-527), and the receptor number (a) present initially or (b) present after down-regulation (Sullivan and Zigmond, 1980, J. Cell Biol. 85:703-711). The observed concentration dependence of cell orientation is similar to the change in the number of receptors occupied, the receptor number being corrected for down-regulated cells. The net effect of receptor loss appears to be a decreased sensitivity to gradients at high concentrations of peptide.


Porosity in metal-organic framework glasses.
The porosity of a glass formed by melt-quenching a metal-organic framework, has been characterized by positron annihilation lifetime spectroscopy. The results reveal porosity intermediate between the related open and dense crystalline frameworks ZIF-4 and ZIF-zni. A structural model for the glass was constructed using an amorphous polymerization algorithm, providing additional insight into the gas-inaccessible nature of porosity and the possible applications of hybrid glasses.


Validation of the RightLevelpH Detector for Monitoring Gastric pH.
The RightLevelpH indicator is a new device designed to measure the pH of gastric aspirate obtained via a nasogastric tube while minimizing exposure of the operator. To validate the RightLevelpH indicator in vivo and in vitro. With general anesthesia, 20 patients had placement of a nasogastric tube and a gastric pH electrode catheter after endotracheal intubation. Direct intragastric pH was recorded simultaneously with gastric aspirate pH by using the RightLevelpH indicator and by using an external pH electrode. Measurements were made every 30 minutes until removal of the nasogastric tube as indicated clinically. In vitro validation of the RightLevelpH indicator was performed by using standard buffer solutions. The pH of clear buffer solutions was linearly related to pH determined by the RightLevelpH indicator (R(2) = 0.99; P < .001). The pH of gastric aspirate determined with an external pH electrode was linearly related to the gastric aspirate pH determined by using the RightLevelpH indicator (R(2) = 0.92; P < .001). Intragastric pH determined with the catheter electrode was also linearly related but more loosely correlated with gastric aspirate pH determined by using an external pH electrode (R(2) = 0.52; P < .001) and by the RightLevelpH indicator (R(2) = 0.55; P < .001). The RightLevelpH indicator provides accurate measurements of the pH of gastric aspirate in patients.


Paroxysmal Sympathetic Hyperactivity After Acquired Brain Injury: An Integrative Literature Review.
Paroxysmal sympathetic hyperactivity may occur in patients with acute brain injury and is associated with physical disability, poor clinical outcomes, prolonged hospitalization, and higher health care costs. To comprehensively review current literature and provide information about paroxysmal sympathetic hyperactivity for nurses. An integrative literature review was conducted according to Whittemore and Knafl's method. The search was conducted from October 2020 through January 2021. The main targets of the literature search were definition, incidence rate, causes, clinical characteristics, pathophysiology, diagnosis, and treatment of paroxysmal sympathetic hyperactivity in pediatric and adult patients. The results were reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The most characteristic clinical features of paroxysmal sympathetic hyperactivity are hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, and abnormal motor posturing. Reported incidence rates of paroxysmal sympathetic hyperactivity in patients with brain injury range from 8% to 33%. Various diagnostic criteria have been proposed; most are based on clinical symptoms. Ruling out other causes of the signs and symptoms of paroxysmal sympathetic hyperactivity is important because the signs and symptoms are nonspecific. The major goals of paroxysmal sympathetic hyperactivity management are avoidance of stimuli that may trigger a paroxysmal episode, inhibition of sympathetic overactivity, and prevention of damage to other organs. Critical care nurses should be aware of the signs and symptoms of paroxysmal sympathetic hyperactivity in patients with acute brain injury. Early identification is important to ensure timely treatment for patients with paroxysmal sympathetic hyperactivity.


Effects of eugenol on resin bond strengths to root canal dentin.
The purpose of this study was to compare the regional bond strengths of C&B Metabond resin to root canal dentin, with or without treatment using a eugenol-containing endodontic sealer liquid. Eighteen extracted human canines were decoronated at the cementoenamel junction with a slow speed saw. The apical third of the root was removed leaving the cervical and middle dentin. The canal space was then enlarged with files, Gates-Glidden burs, and parapost drills. The teeth were ground on either the mesial or distal sides, permitting direct access to the entire canal. The cervical or middle third dentin was treated with Kerr Root Canal Sealer liquid, alternating between the middle and cervical thirds. Each tooth served as its own control. The adhesive resin was then luted directly to the prepared canal. Specimens, 1 x 1 x 8 mm, were prepared and mounted to a Vitrodyne testing machine enabling microtensile bond strengths to be measured. Data were analyzed using a two-way ANOVA and the least squares means test. The mean microtensile bond strengths for the cervical and middle third dentin treated with eugenol were 13.6 +/- 6.1 MPa (n = 33) and 14.8 +/- 3.9 MPa (n = 29), respectively. Without the eugenol, the mean bond strengths were 18.1 +/- 6.0 MPa (n = 31) and 17.3 +/- 4.6 MPa (n = 31) for the cervical and middle sections. The specimens treated with the eugenol liquid had significantly lower bond strengths than those without eugenol (p < 0.05) only in the cervical third. The region of the tooth tested had no effect on bond strength. That is, bond strength of the cervical third was not significantly different from bond strength on the middle third in either of the two groups (with or without eugenol) tested.


Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control.
Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.


Morphometric analysis of the Korean mandibular ramus for distraction osteogenesis using micro-computed tomography.
When performing distraction osteogenesis, the osteotomy is normally applied to the cortical bone posterior to the mandibular second molar. We measured the topographic thickness of the cortical and trabecular bone of the mandibular ramus and at the mandibular canal (MC) to provide crucial anatomic data aimed at minimizing complications and elucidating the most appropriate site for placing the distractor. Forty sides of the mandibles were prepared from 20 Korean cadavers (10 men and 10 women with a mean age of 68 years). The specimens were scanned and reconstructed into three-dimensional images using a micro-computed tomography system. Coronal and horizontal sectional images of the mandibular ramus were taken at thickness intervals of 2 mm from the reconstructed three-dimensional images. Image analysis software was used to measure the thicknesses of the cortical and trabecular bone and to identify the locations of the MC within the body and the mandibular ramus on each section. The mean thicknesses of the buccal cortical plate, trabecular bone, and lingual cortical plate were 2.9 mm (men, 3.0 mm; women, 2.8 mm), 9.1 mm (men, 9.8 mm; women, 8.5 mm), and 2.2 mm (men, 2.3 mm; women, 2.1 mm), respectively. The distance from the buccal surface of the mandible to the MC increased from 5.3 to 10.0 mm (men, 5.3-10.0 mm; women, 5.3-9.1 mm) when moving progressively anterosuperior from the mandibular angle region. Morphometric analyses of the mandibular ramus can provide crucial data when performing mandibular osteotomy and locating an appropriate placement site for a distractor device during the distraction-osteogenesis procedure.


Retentive Force of Glass-Ceramic Soldered Customized Zirconia Abutment Copings with Prefabricated Titanium Bases.
Two-piece abutments consisting of customized zirconia abutment copings and prefabricated titanium bases are popular due to their biological and esthetic advantages. Glass-ceramic solder (GS) is an alternative biocompatible connective agent. This in vitro study evaluated the retentive force of GS in comparison to classical resin composite cements (RC) after artificial aging and autoclaving. Ninety specimens consisting of prefabricated titanium bases and zirconia abutment copings were fabricated. The two parts of each specimen were fixed either by RC (n = 30) or GS with a luting space of either 30 µm (n = 30) or 100 µm (n = 30). Ten specimens of each group underwent autoclaving before artificial aging (water storage, thermocycling). Twenty specimens (including the 10 autoclaved specimens) of each group were exposed to a mechanical load. The retentive force between the zirconia and titanium in all specimens was determined. A fractographic analysis was performed to analyze the fracture surfaces of the GS specimens. The RC- and GS-connected two-piece abutments showed no relevant differences, independent of the luting space. RC appears to be more vulnerable to the thermal and mechanical loads than GS. Thus, GS may be an appropriate alternative to RC for two-piece abutments, especially for patients with enhanced biocompatibility requirements.


First Report of Vinca Blight Caused by Phytophthora nicotianae in Northwestern Mexico.
Vinca (Catharantus roseus (L.) G. Don) is a common ornamental landscape plant. From July to September 2012, blighted and wilted vinca plants were found in retail stores, commercial nurseries, and urban landscape areas of Culiacan, Sinaloa, in northwestern Mexico. In several commercial nurseries and a retail store, incidence of the unknown disease on vinca plants ranged from 20 to 50%, resulting in significant economic losses. Symptoms of the disease started with a foliar blight, and if warm and wet conditions were present, the disease progressed, causing plant wilting and death. Surface-sterilized (0.5% NaOCl 1 min) diseased plant tissue was plated on V8 agar medium, and after 72 h of incubation at 25°C, white colonies of coenocytic mycelium were developed from the plated tissues. Isolates produced cottony colonies on V8 agar medium, grew well between 7 and 30°C (optimum of 25°C), and produced spherical, intercalary, and terminal chlamydospores (17 to 30 μm) and non caducous, papillate, spherical to ovoid sporangia of 30 to 39 × 21 to 31 μm. Based on these morphological characteristics, Phytophthora isolates were identified as Phytophthora nicotianae Breda de Haan (1,3). The identity of two representative isolates OV4 and OV11 was confirmed by sequence analysis of the rDNA internal transcribed spacers (ITS; GenBank Accession Nos. KC248202 and KC248201), and of the β-tubulin (β-tub; KC248404 and KC248403) and translation elongation factor 1-α (EF1-α; KC248206 and KC248205) genes. Comparative sequence analysis against the NCBI nucleotide database showed a high degree of identity with reference sequences of P. nicotianae (ITS, 99%; β-tub, 99%; EF1-α, 100%) (2). A pathogenicity test with a representative isolate of P. nicotianae was performed on 10-week-old healthy vinca seedlings (n = 10). An aliquot of 10 ml of a zoosporic suspension (104 zoospores/ml) was sprayed onto the seedlings' leaves. An equal number of non-inoculated control seedlings were sprayed with sterile distilled water. Seedlings were maintained in a moist chamber at 25°C with 80 to 90% relative humidity and watered as needed with sterile water. Inoculated plants showed initial symptoms of foliar blight after 4 days, whereas control plants remained healthy. Ten days after inoculation, inoculated plants showed severe wilting. P. nicotianae was reisolated only from inoculated plants, thus fulfilling Koch's postulates. To our knowledge, this is the first report of P. nicotianae attacking annual vinca in northwestern Mexico. References: (1) D. C. Erwin and O. K. Ribeiro. Phytophthora Diseases Worldwide. The American Phytopathological Society, St. Paul, MN, 1996. (2) L. P. Kroon et al. Fungal Genet Biol. 41:766, 2004. (3) F. N. Martin et al. Plant Dis. 96:1080, 2013.


Exposure to high levels of fumarate and succinate leads to apoptotic cytotoxicity and altered global DNA methylation profiles in vitro.
In the Krebs cycle, succinate is oxidized to fumarate by succinate dehydrogenase (SDH), followed by the conversion of fumarate to malate by fumarate hydratase (FH). In cells with defective SDH and FH, the Krebs cycle is congested, respiration impaired and fumarate and succinate accumulates. Several studies have indicated that the accumulation of these substrates are associated with cytotoxicity and oncogenesis. High levels of succinate and fumarate induce hypoxia inducible factor (HIF1A) hydroxylases, leading to the activation of oncogenic HIF pathways. However, the role of HIF as primary inducer of oncogenic change has been questioned, as other non-enzymatic mechanisms have been shown to interfere with cellular metabolism, cell signalling as well as disrupting protein function. Owing to the essential roles that SDH and FH play in cellular energy metabolism, and their associated tumor suppressor capacity, it is vital to understand the biochemical effects resulting from the accumulation of their associated metabolites. Therefore, in this study, we investigated the effect of high concentrations of succinate and fumarate exposure on cell viability, genome integrity and global DNA methylation using a human hepatocellular carcinoma (HepG2) cell culture model. It was found that relatively high concentrations of succinate and fumarate cause a loss of cell viability, which seems to be orchestrated through an apoptotic pathway. Cells exposed to high levels of succinate also presented with elevated caspase 3 and/or caspase 7 levels. In addition, elevated levels of fumarate lead to extensive DNA fragmentation, which may contribute pathophysiologically by inducing chromosomal instability, while succinate demonstrated lower genotoxicity. Furthermore, both succinate and fumarate altered the global DNA methylation patterns via significant DNA hypermethylation. Since numerous studies have reported correlations between aberrant DNA methylation and oncogenesis, hypermethylation may contribute to the oncogenesis observed in cells exposed to high concentrations of these metabolites.


Orexin-A modulates glutamatergic NMDA-dependent spinal reflex potentiation via inhibition of NR2B subunit.
Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (OxA) as well as orexin-B (OxB) and send their axons to the spinal dorsal horn, which predominantly expresses orexin receptor-1 (OX-1), showing a higher sensitivity to OxA. The purpose of the present study was to assess the effects of OxA on the induction of a novel form of activity-dependent reflex potentiation, spinal reflex potentiation (SRP), in the pelvic-urethral reflex activity. External urethra sphincter electromyogram in response to pelvic afferent nerve test stimulation (TS; 1/30 Hz) or repetitive stimulation (RS; 1 Hz) was recorded in anesthetized rats. TS evoked a baseline reflex activity, whereas RS produced SRP, which was abolished by intrathecal OxA (30 nM, 10 mul). Intrathecal SB-408124 (10 muM, 10 mul), an OX-1 antagonist, reversed the abolition on SRP caused by OxA. Although there is, so far, no NR2A- and NR2B-specific agonist available, N-methyl-d-aspartate (NMDA) reversed the abolition on the RS-induced SRP caused by the co-administration of OxA and Co-101244 (30 nM, 10 mul; an NMDA NR2B subunit antagonist), but it did not reverse the abolition by the co-administration of OxA and PPPA (300 nM, 10 mul; an NMDA NR2A subunit antagonist). In conclusion, the activation of descending orexinergic fibers may inhibit the repetitive afferent input-induced central sensitization of pelvic-urethral reflex activity and urethra hyperactivity, indicating that spinal orexinergic neural transmission may be a novel target for the treatment of patients with neuropathetic or postinflammatory pain of pelvic origin.


Point-of-care Ultrasound for Nonangulated Distal Forearm Fractures in Children: Test Performance Characteristics and Patient-centered Outcomes.
Distal forearm fractures are the most common fracture type in children. Point-of-care-ultrasound (POCUS) is increasingly being used, and preliminary studies suggest that it offers an accurate approach to diagnosis. However, outcomes such as pain, satisfaction, and procedure duration have not been explored but may be salient to the widespread acceptance of this technology by caregivers and children. Our objectives were to examine the test performance characteristics of POCUS for nonangulated distal forearm injuries in children and compare POCUS to x-ray with respect to pain, caregiver satisfaction, and procedure duration. We conducted a cross-sectional study involving children aged 4-17 years with a suspected nonangulated distal forearm fracture. Participants underwent both x-ray and POCUS assessment. The primary outcome was sensitivity between POCUS and x-ray, the reference standard. Secondary outcomes included self-reported pain using the Faces Pain Scale-Revised, caregiver satisfaction using a five-item Likert scale, and procedure duration. POCUS was performed in 169 children of whom 76 were diagnosed with a fracture including 61 buckle fractures. Sensitivity of POCUS for distal forearm fractures was 94.7% (95% confidence interval [CI] = 89.7-99.8) and specificity was 93.5% (95% CI = 88.6-98.5). POCUS was associated with a significantly lower median (interquartile range [IQR]) pain score compared to x-ray: 1 (0-2) versus 2 (1-3), respectively (median difference = 0.5; 95% CI = 0.5-1; p < 0.001) and no significant difference in median (IQR) caregiver satisfaction score: 5 (0) versus 5 (4-5), respectively (median difference = 0, 95% CI = 0, p = 1.0). POCUS was associated with a significantly lower median (IQR) procedure duration versus x-ray: 1.5 (0.8-2.2) minutes versus 27 (15-58) minutes, respectively (median difference = 34.1, 95% CI = 26.8-41.5, p < 0.001). Our findings suggest that POCUS assessment of distal forearm injuries in children is accurate, timely, and associated with low levels of pain and high caregiver satisfaction.


Are we failing our teenagers? Value of a family planning service for teenagers within the sexually transmitted disease clinic.
Out of 100 teenage girls attending a sexually transmitted disease clinic for the first time, 77 were found to be using a reliable method of contraception and had similar characteristics to teenage girls attending a family planning clinic. The 23 girls not using any reliable contraception exhibited a different pattern of sexual behaviour and were at high risk of unplanned pregnancy. Subsequently, another group of 23 girls not using contraception when seen at the sexually transmitted disease clinic were actively encouraged to attend a family planning clinic. Their risk of unplanned pregnancy was much reduced, although their pattern of sexual activity was unchanged. Ready availability of contraceptive advice for unprotected teenagers in sexually transmitted disease clinics would reduce their high risk of unplanned pregnancy.


Burden of illness and treatment patterns for patients with fibromyalgia.
This study was designed to describe burden of illness and treatment patterns, and to examine the patient, physician, and care factors associated with the treatment choices of individuals receiving new prescriptions for fibromyalgia (FM). This is a baseline assessment of the Real-World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments (REFLECTIONS), a prospective observational study. Baseline data (including a physician survey, a patient visit form, and computer-assisted telephone interviews) were collected from July 2008 through May 2010 in 58 care settings in the United States, including Puerto Rico. Patients (N = 1,700) were mostly female (94.6%) and white (82.9%). Mean age was 50.4 years and mean duration of illness was 5.6 years. Mean Fibromyalgia Impact Questionnaire total score was 54.4 (range 0-80), and Brief Pain Inventory average pain severity level was 5.5 (range 0-10). Patients reported high annual health care use and numerous work limitations related to FM. Patients were taking 182 unique types of medications prescribed for FM, including duloxetine (26.8%), nonsteroidal anti-inflammatory drugs (26.6%), pregabalin (24.5%), opioids (24.2%), tramadol (15.3%), benzodiazepines (15.2%), cyclobenzaprine (12.9%), milnacipran (8.9%), and others. Most patients took more than one medication concurrently (77.8%). Type of current medications used was most strongly associated with medication history and physician specialty. Burden of illness was high for patients with FM, and treatment patterns were highly variable. Importantly, the treatments with the most evidence to support their use were not always the most frequently chosen.


Formation and spread of aircraft-induced holes in clouds.
Hole-punch and canal clouds have been observed for more than 50 years, but the mechanisms of formation, development, duration, and thus the extent of their effect have largely been ignored. The holes have been associated with inadvertent seeding of clouds with ice particles generated by aircraft, produced through spontaneous freezing of cloud droplets in air cooled as it flows around aircraft propeller tips or over jet aircraft wings. Model simulations indicate that the growth of the ice particles can induce vertical motions with a duration of 1 hour or more, a process that expands the holes and canals in clouds. Global effects are minimal, but regionally near major airports, additional precipitation can be induced.


Metabolic specialization of denitrifiers in permeable sediments controls N2 O emissions.
Coastal oceans receive large amounts of anthropogenic fixed nitrogen (N), most of which is denitrified in the sediment before reaching the open ocean. Sandy sediments, which are common in coastal regions, seem to play an important role in catalysing this N-loss. Permeable sediments are characterized by advective porewater transport, which supplies high fluxes of organic matter into the sediment, but also leads to fluctuations in oxygen and nitrate concentrations. Little is known about how the denitrifying communities in these sediments are adapted to such fluctuations. Our combined results indicate that denitrification in eutrophied sandy sediments from the world's largest tidal flat system, the Wadden Sea, is carried out by different groups of microorganisms. This segregation leads to the formation of N2 O which is advectively transported to the overlying waters and thereby emitted to the atmosphere. At the same time, the production of N2 O within the sediment supports a subset of Flavobacteriia which appear to be specialized on N2 O reduction. If the mechanisms shown here are active in other coastal zones, then denitrification in eutrophied sandy sediments may substantially contribute to current marine N2 O emissions.


Influence of obesity and physical workload on disability benefits among construction workers followed up for 37 years.
The objectives of this study are to investigate the relation between obesity and labour force exit via diagnosis-specific disability benefits, and whether physical workload modifies this association. A longitudinal analysis was performed among 3 28 743 Swedish construction workers in the age of 15-65 years. Body weight and height were measured at a health examination and enriched with register information on disability benefits up to 37 years later. Diagnoses of disability benefits were categorised into cardiovascular diseases (CVDs), musculoskeletal diseases (MSDs), mental disorders and others. A job exposure matrix, based on self-reported lifting of heavy loads and working in bent forward or twisted position, was applied as a measure of physical workload. Cox proportional hazards regression analyses were performed, and the relative excess risk due to interaction (RERI) between obesity and physical workload was calculated. Obese construction workers were at increased risk of receiving disability benefits (HR 1.70, 95% CI 1.65 to 2.76), mainly through CVD (HR 2.30) and MSD (HR 1.71). Construction workers with a high physical workload were also more likely to receive a disability benefit (HR 2.28, 95% CI 2.21 to 2.34), particularly via MSD (HR 3.02). Obesity in combination with a higher physical workload increased the risk of disability benefits (RERI 0.28) more than the sum of the risks of obesity and higher physical workload, particularly for MSD (RERI 0.44). Obesity and a high physical workload are risk factors for disability benefit. Furthermore, these factors are synergistic risk factors for labour force exit via disability benefit through MSD. Comprehensive programmes that target health promotion to prevent obesity and ergonomic interventions to reduce physical workload are important to facilitate sustained employment.


Government As Innovation Catalyst: Lessons From The Early Center For Medicare And Medicaid Innovation Models.
Congress established the Center for Medicare and Medicaid Innovation (CMMI) to design, test, and spread innovative payment and service delivery models that either reduce spending without reducing the quality of care or improve the quality of care without increasing spending. CMMI sought to leverage these models to foster market innovation and accelerate the transformation of payment and care delivery to achieve the Triple Aim of better health, better care, and lower cost. This article provides a perspective on the design and execution of CMMI's five initial models, the resulting outcomes and lessons, and how their core concepts evolved within and spread beyond CMMI. This experience yields three key insights that could inform future efforts by CMMI and public and private payers, including model designs and policy decisions. These insights center on the need for iterative testing and learning guided by market feedback, more realistic time frames to demonstrate impact on cost and quality, and greater integration of models.


Molecular evaluation of five cardiac genes in Doberman Pinschers with dilated cardiomyopathy.
To sequence the exonic and splice site regions of 5 cardiac genes associated with the human form of familial dilated cardiomyopathy (DCM) in Doberman Pinschers with DCM and to identify a causative mutation. 5 unrelated Doberman Pinschers with DCM and 2 unaffected Labrador Retrievers (control dogs). Exonic and splice site regions of the 5 genes encoding the cardiac proteins troponin C, lamin A/C, cysteine- and glycine-rich protein 3, cardiac troponin T, and the beta-myosin heavy chain were sequenced. Sequences were compared for nucleotide changes between affected dogs and the published canine sequences and 2 control dogs. Base pair changes were considered to be causative for DCM if they were present in an affected dog but not in the control dogs or published sequences and if they involved a conserved amino acid and changed that amino acid to a different polarity, acid-base status, or structure. A causative mutation for DCM in Doberman Pinschers was not identified, although single nucleotide polymorphisms were detected in some dogs in the cysteine- and glycine-rich protein 3, beta-myosin heavy chain, and troponin T genes. Mutations in 5 of the cardiac genes associated with the development of DCM in humans did not appear to be causative for DCM in Doberman Pinschers. Continued evaluation of additional candidate genes or a focused approach with an association analysis is warranted to elucidate the molecular cause of this important cardiac disease in Doberman Pinschers.


Physiological bone responses in the fingers after more than 10 years of high-level sport climbing: analysis of cortical parameters.
Sports activity can induce bone modeling processes with apposition of new bone and changes in bone morphology. Sport climbing places extreme forces and stress on the hands, especially on the bones of the fingers. This study examines sports-induced physiological adaptations of the finger bones of climbers. In this cohort study, the radiographs of 31 high-level (Union Internationale des Associations d'Alpinisme [UIAA] metric scale range 8.33 to 11.33), experienced (median 20 years climbing time) adult climbers were compared with those of a control group of 67 patients. Cortical dimensions and variables were measured and analyzed in a total of 330 fingers. An association analysis of climbing-related variables was also performed. The climber's bones showed a 25% higher cortical proportion than those of the control group. On average, the outer cortical width of the climbers' bones was 6% larger and the medullary canal was 20% narrower than in the control group (P < .05). The differences between groups were more pronounced in the sagittal plane and more pronounced distally in the fingers. No associations were found between age, climbing experience, climbing level, and the cortical hypertrophy. Differences in bone morphology can be observed in the finger bones of adult climbers when compared with controls. Because the differences are more pronounced at the palmar and dorsal cortices, the analysis of the sagittal plane should always be included in future investigations. To evaluate climbing-related factors influencing these adaptive morphologic differences, further studies with larger, more specific study cohorts are needed.


Intrathecal urokinase as a treatment for intraventricular hemorrhage in the preterm infant.
Despite improvements in the care of preterm infants, intraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus (PHH) continue to be frequent occurrences in this patient population. Shunt procedures in these children are frequently complicated by obstruction and/or infection. As the hydrocephalus is usually caused by an obliterative arachnoiditis due to contact of the blood with the basilar meninges, it was postulated that infusion of urokinase into the ventricles of infants who have sustained an IVH would clear the blood, mitigate the arachnoiditis, and prevent the progression of PHH. Accordingly, 18 preterm infants who had sustained IVH and subsequently developed PHH were treated with intraventricular urokinase instilled via a surgically implanted subcutaneous reservoir. There were no complications associated with the urokinase. Infants were divided into two dosage groups: low dose (110,000-140,000 IU total) and high dose (280,000 IU total). One infant in the low-dose group died at 1 month of life of respiratory complications. In the low-dose group, 3 of 8 (37%) infants required shunt placement; in the high-dose group, all 9 required shunt placement. For the total group, the shunt rate was 71%. This compares to a historical control group shunt rate of 92%. While the difference between the treatment group as a whole and control group approaches, but does not reach, statistical significance (p = 0.068), there was a significant reduction in the shunt rate when the low-dose group was considered separately (p < 0.002). For those infants that required shunt placement, there were fewer shunt revisions performed in the treatment group than in the control group during the first 24 months following shunt placement: 0.67 versus 1.5 shunt revisions/shunted child. Initial experience with intraventricular urokinase following IVH and PHH in preterm infants suggests a beneficial effect in reducing the shunt revision rate in both high- and low-dose groups. Reduction in shunt placement rate is seen only in the low-dose group.


Bleeding disorders in adolescents with heavy menstrual bleeding in a multicenter prospective US cohort.
Heavy menstrual bleeding is common in adolescents. The frequency and predictors of bleeding disorders in adolescents, especially with anovulatory bleeding, are unknown. Adolescents referred for heavy menstrual bleeding underwent an evaluation of menstrual bleeding patterns, and bleeding disorders determined a priori The primary outcome was the diagnosis of a bleeding disorder. Two groups were compared: anovulatory and ovulatory bleeding. Multivariable logistic regression analysis of baseline characteristics and predictors was performed. Kaplan Meier curves were constructed for the time from the first bleed to bleeding disorder diagnosis. In 200 adolescents, a bleeding disorder was diagnosed in 33% (n=67): low von Willebrand factor levels in 16%, von Willebrand disease in 11%, and qualitative platelet dysfunction in 4.5%. The prevalence of bleeding disorder was similar between ovulatory and anovulatory groups (31% vs 36%; P=0.45). Predictors of bleeding disorder included: younger age at first bleed (OR: 0.83; 95%CI: 0.73, 0.96), Hispanic ethnicity (OR: 2.48; 95%CI: 1.13, 5.05), non-presentation to emergency department for heavy bleeding (OR: 0.14; 95%CI: 0.05, 0.38), and International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool score ≥4 (OR: 8.27; 95%CI: 2.60, 26.44). Time from onset of the first bleed to diagnosis was two years in the anovulatory, and six years in the ovulatory cohort (log-rank test, P<0.001). There is a high prevalence of bleeding disorders in adolescents with heavy periods, irrespective of the bleeding pattern. Among bleeding disorders, the prevalence of qualitative platelet dysfunction is lower than previously reported.


Ab initio molecular dynamics study of the aqueous HOO(-) ion.
The properties of the hydroperoxide anion, HOO(-), in water play a key role in many biological systems and industrial processes. However the dynamics of HOO(-) and its solvation shell are largely unknown. We have undertaken an ab initio molecular dynamics study of aqueous HOO(-) at ambient temperature in liquid water. Two solvation structures for the hydroperoxide anion account for 90% or more of the configurations in a 25 ps NVT run at 300 K: these have four hydrogen bond donors to the terminal oxygen atom of HOO(-) and either one or two hydrogen bond donors to its middle oxygen atom. The H of HOO(-) is essentially always a donor in an H-bond to a water molecule. Two structures with three donors to the terminal O and either one or two at the middle O are also important. A set of five NVE runs totaling 74 ps found considerable variability in the proportions of time spent in each type of solvation pattern. Mean lifetimes of these patterns ranged from 54 to 109 fs, after which the complexes were observed to transform into different, sometimes less favorable structures. Analysis of the electronic structure associated with different solvation patterns indicates that a traditional Lewis-type picture of hydrogen bonding at the middle oxygen and non-Lewis behavior at the terminal oxygen coexist in aqueous HOO(-). The non-Lewis character of the terminal oxygen is compared to similar observations of the oxygen in the hydrated hydroxide ion from previous ab initio molecular dynamics of OH(-)(aq).


Antimicrobial evaluation of indole-containing hydrazone derivatives.
There has been an increasing importance of drug-resistant pathogens in clinical microbiological and antibacterial research. Indoles and hydrazone-type compounds constitute important classes of compounds in the search for effective agents against multidrug-resistant microbial infections. In this study a series of 1-methylindole-3-carboxaldehyde hydrazone derivatives were evaluated for their in vitro antimicrobial activities using the two-fold serial dilution technique against Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-resistant S. aureus isolate, Escherichia coli, Bacillus subtilis, and Candida albicans. The minimum inhibitory concentration (MIC) of the test compounds and the reference standards sultamicillin, ampicillin, fluconazole, and ciprofloxacin was determined. All compounds possessed a broad spectrum of activity having MIC values of 6.25-100 microg/ml against the tested microorganisms. Aromaticity and disubstitution of the phenyl ring with especially fluorine and chlorine atoms were found to be significant for the antimicrobial activity


An evaluation of fitness for practice curricula: self-efficacy, support and self-reported competence in preregistration student nurses and midwives.
This element of the larger Scottish evaluation aimed to explore differences between access routes, cohorts and higher education institutes (HEI) (universities and colleges) in levels of self-efficacy, student support and self-reported competence in a nationally representative sample of student nurses and midwives. This paper reports findings from the National Review of Pre-Registration Nursing and Midwifery Programmes in Scotland. Fitness for practice curricula have been the heart of many recent developments in nurse and midwifery education. Fitness for practice set out to map out the future direction of preregistration nursing and midwifery education with the aim of ensuring fitness for practice based on healthcare need. There have been no national evaluations of the effectiveness of this strategic objective. Previous major evaluations in the 1990s suggested that students may not have had the skills needed to be fit for practice. The study design was a cross-sectional survey of a stratified random sample of student nurses and midwives (n = 777). Data collected included demographic information, generalised perceived self-efficacy, student support and self-reported competency. Students reported high levels of self-reported competency. There were no significant differences between two cohorts or between students with different access routes. Students rated support from family and friends highest and support from HEI lowest. There was a significant difference in support levels between HEI. Self-efficacy scores were similar to other population means and showed small-moderate correlations with self-report competence. Similarly, self-reported competency appears to be at the higher end of the spectrum, although older students may have a more realistic perception of their competence. However, support from HEI was seen as less satisfactory and varied from one institution to another. This study portrays a relatively positive picture of preregistration fitness for practice curricula. Questions are raised about the relative value students place on support from educationalists and mentors and whether support from family and friends and from peers needs to feature more prominently in curricula. The study provides modest support for social cognitive theory. The major drivers for changes in preregistration curricula stemmed from fears about the competence of students. This study did not provide support for this viewpoint, and students' self-reports suggest that curricula are, in this respect, meeting their objectives. Nevertheless support from mentors and from educational institutes may need to be improved.


National outbreak of Salmonella serotype saintpaul infections: importance of Texas restaurant investigations in implicating jalapeño peppers.
In May 2008, PulseNet detected a multistate outbreak of Salmonella enterica serotype Saintpaul infections. Initial investigations identified an epidemiologic association between illness and consumption of raw tomatoes, yet cases continued. In mid-June, we investigated two clusters of outbreak strain infections in Texas among patrons of Restaurant A and two establishments of Restaurant Chain B to determine the outbreak's source. We conducted independent case-control studies of Restaurant A and B patrons. Patients were matched to well controls by meal date. We conducted restaurant environmental investigations and traced the origin of implicated products. Forty-seven case-patients and 40 controls were enrolled in the Restaurant A study. Thirty case-patients and 31 controls were enrolled in the Restaurant Chain B study. In both studies, illness was independently associated with only one menu item, fresh salsa (Restaurant A: matched odds ratio [mOR], 37; 95% confidence interval [CI], 7.2-386; Restaurant B: mOR, 13; 95% CI 1.3-infinity). The only ingredient in common between the two salsas was raw jalapeño peppers. Cultures of jalapeño peppers collected from an importer that supplied Restaurant Chain B and serrano peppers and irrigation water from a Mexican farm that supplied that importer with jalapeño and serrano peppers grew the outbreak strain. Jalapeño peppers, contaminated before arrival at the restaurants and served in uncooked fresh salsas, were the source of these infections. Our investigations, critical in understanding the broader multistate outbreak, exemplify an effective approach to investigating large foodborne outbreaks. Additional measures are needed to reduce produce contamination.


Wearing the wolf skin: psychiatry and the phenomenon of the berserker in medieval Scandinavia.
This paper examines the berserker, a frenzied warrior attested to in both the written and material sources of medieval Scandinavia, and elucidates the characteristics that define him. It critiques explanations for the phenomenon offered in the existing historiography and whether this can be explained as a psychiatric diagnosis. It concludes that the berserker cannot be simply defined as a culturally bound or other psychiatric syndrome, or accounted for by psychogenic drugs alone. Instead, it proposes that berserk frenzy constituted a transitory dissociative state shared among a small warband steeped in religious/spiritual ideology. In entering this state, the psyche of the berserker was reconstituted in an almost archetypal pattern. Further research is required into this phenomenon in other contexts, including modern conflicts.


Trends in the prevalence of obesity and overweight in English adults by age and birth cohort, 1991-2006.
To describe trends in the prevalence of obesity and overweight in English adults. Analysis of nationally representative cross-sectional population surveys. Sociodemographic information was gathered by an interviewer-administered questionnaire and measurements of height and weight were used to calculate the prevalence of obesity and overweight. A total of 61 515 men and 69 733 women aged 16-65 years participating in the annual Health Survey for England between 1991 and 2006. When the 4-year periods 1991/94 and 2003/06 were compared, male and female obesity had risen by 8.2 % and 6.0 %, and male and female overweight had risen by 8.8 % and 7.4 %. However, the rate of increase appears to be slowing down: the increases between 1995/98 and 1999/02 were greater than those between 1999/02 and 2003/06. There was relatively little variation across the age range in the average changes in obesity or overweight prevalence between time periods, except that the increase in male obesity between periods was significantly greater for older than younger males. When the subjects were divided into 10-year pseudo birth cohorts, it was seen that the prevalence of obesity and overweight was consistently higher at a given average age for pseudo cohorts born more recently. This agreed with data from two British cohort studies. Obesity and overweight continued to rise over the study period, but there are signs that the rate of increase is slowing down, even though the prevalence is consistently higher for a given age in cohorts born more recently.


WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations.
Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.


Platinum-based metallomesogens bearing a Pt(4,6-dfppy)(acac) skeleton: synthesis, photophysical properties and polarised phosphorescence application.
Polarised phosphorescence has a bright future in backlighting for conventional liquid crystal displays due to its theoretical 100% internal quantum efficiency and low cost. However, there are scarce reports on polarised phosphorescence from metallomesogens. In this contribution, a platinum-based metallomesogen containing a mesogenic biphenyl (Pt1) was prepared and characterised. To further explore the effect of the substituent on mesophase and emission properties, a related complex Pt2 containing a tetraphenylethene (TPE) moiety was also synthesised. Both complexes melt at elevated temperatures but thereafter do not appear to crystallise on cooling. Complex Pt1 shows an enantiotropic nematic phase from which a broad emission can be seen when spread as a film; in solution, an intense, sky-blue emission is observed. For Pt2, which shows a monotropic SmA phase, the emission in the condensed phase is suppressed and there is only weak emission in solution. Polarisation-dependent photoluminescence with a polarised ratio of 5.4 was obtained for the aligned film of a Pt1:polyimide mixture. Using Pt1 as an emissive layer, non-doped, polarised organic light-emitting diodes presented a broad emission spectrum in the range of 450-900 nm with a polarised ratio of 1.33 and the highest external quantum efficiency of 1.1%. This research has an important significance for achieving broad-based polarised phosphorescence from platinum complex-based metallomesogens.


A genetic determinant in Streptococcus gordonii Challis encodes a peptide with activity similar to that of enterococcal sex pheromone cAM373, which facilitates intergeneric DNA transfer.
Enterococcus faecalis strains secrete multiple peptides representing different sex pheromones that induce mating responses by bacteria carrying specific conjugative plasmids. The pheromone cAM373, which induces a response by the enterococcal plasmid pAM373, has been of interest because a similar activity is also secreted by Streptococcus gordonii and Staphylococcus aureus. The potential to facilitate intergeneric DNA transfer from E. faecalis is of concern because of extensive multiple antibiotic resistance, including vancomycin resistance, that has emerged among enterococci in recent years. Here, we characterize the related pheromone determinant in S. gordonii and show that the peptide it encodes, gordonii-cAM373, does indeed induce transfer of plasmid DNA from E. faecalis into S. gordonii. The streptococcal determinant camG encodes a lipoprotein with a leader sequence, the last 7 residues of which represent the gordonii-cAM373 heptapeptide SVFILAA. Synthetic forms of the peptide had activity similar to that of the enterococcal cAM373 AIFILAS. The lipoprotein moiety bore no resemblance to the lipoprotein encoded by E. faecalis. We also identified determinants in S. gordonii encoding a signal peptidase and an Eep-like zinc metalloprotease (lspA and eep, respectively) similar to those involved in processing certain pheromone precursors in E. faecalis. Mutations generated in camG, lspA, and eep each resulted in the ablation of gordonii-cAM373 activity in culture supernatants. This is the first genetic analysis of a potential sex pheromone system in a commensal oral streptococcal species, which may have implications for intergeneric gene acquisition in oral biofilms.


Combination chemoprophylaxis and immunoprophylaxis in reducing the incidence of leprosy.
Leprosy is a complex infectious disease caused by Mycobacterium leprae that is a leading cause of nontraumatic peripheral neuropathy. Current control strategies, with a goal of early diagnosis and treatment in the form of multidrug therapy, have maintained new case reports at ~225,000 per year. Diagnostic capabilities are limited and even with revisions to multidrug therapy regimen, treatment can still require up to a year of daily drug intake. Although alternate chemotherapies or adjunct immune therapies that could provide shorter or simpler treatment regimen appear possible, only a limited number of trials have been conducted. More proactive strategies appear necessary in the drive to elimination. As a prevention strategy, most chemoprophylaxis campaigns to date have provided about a 2-year protective window. Vaccination, in the form of a single bacillus Calmette-Guérin (BCG) immunization, generally provides ~50% reduction in leprosy cases. Adapting control strategies to provide both chemoprophylaxis and immunoprophylaxis has distinct appeal, with chemoprophylaxis theoretically buttressed by vaccination to generate immediate protection that can be sustained in the long term. We also discuss simple assays measuring biomarkers as surrogates for disease development or replacements for invasive, but not particularly sensitive, direct measures of M. leprae infection. Such assays could facilitate the clinical trials required to develop these new chemoprophylaxis, immunoprophylaxis strategies, and transition into wider use.


Efficacy and long-term follow-up of IL-1R inhibitor anakinra in adults with Still's disease: a case-series study.
To assess the efficacy and safety of the interleukin-1 receptor (IL-1R) inhibitor anakinra in adult patients with refractory Still's disease. Twenty-five patients (13 males and 12 females, median age 32 years, median disease duration seven months) with Still's disease were treated with subcutaneous injections of anakinra (100 mg/day). Treatment was given as adjunct therapy in 16 patients and as standalone in 9 patients for a median time of 15 months (range 1.5-71). The clinical and laboratory parameters during follow-up were recorded. In 84% of patients the clinical activity resolved completely within a few days (median time 0.2 months), and response was maintained until the last visit in all but one patient. A complete response of all disease-related symptoms (clinical and laboratory) occurred subsequently within a median time of three months in 80% of patients. A partial clinical and laboratory improvement was shown in 12% and 16% of patients, respectively. The Visualized Analogue Scale and Health Assessment Questionnaire scores significantly decreased during treatment. The proportion of patients achieving the American College of Rheumatology 20 (ACR20) score (20% improvement) was 82% at one month and improved to 100% at one year. The mean oral corticosteroid dose was significantly reduced at each visit. Anakinra was discontinued due to unresponsiveness in one patient and due to relapsing disease in another. Treatment was also withdrawn in three patients with severe skin reactions (urticaria). Seven patients experienced an infection during follow-up. The rapid and sustained response in the majority of our patients encourages the use of anakinra in adults with Still's disease.


Evidence that mast cells are not required for healing of splinted cutaneous excisional wounds in mice.
Wound healing is a complex biological process involving the interaction of many cell types to replace lost or damaged tissue. Although the biology of wound healing has been extensively investigated, few studies have focused on the role of mast cells. In this study, we investigated the possible role of mast cells in wound healing by analyzing aspects of cutaneous excisional wound healing in three types of genetically mast cell-deficient mice. We found that C57BL/6-Kit(W-sh/W-sh), WBB6F1-Kit(W/W-v), and Cpa3-Cre; Mcl-1(fl/fl) mice re-epithelialized splinted excisional skin wounds at rates very similar to those in the corresponding wild type or control mice. Furthermore, at the time of closure, scars were similar in the genetically mast cell-deficient mice and the corresponding wild type or control mice in both quantity of collagen deposition and maturity of collagen fibers, as evaluated by Masson's Trichrome and Picro-Sirius red staining. These data indicate that mast cells do not play a significant non-redundant role in these features of the healing of splinted full thickness excisional cutaneous wounds in mice.


Phospholipid membranes decorated by cholesterol-based oligonucleotides as soft hybrid nanostructures.
DNA monomers and oligomers are currently showing great promise as building blocks for supramolecular arrays that can self-assemble in a fashion preprogrammed by the base pairing code. The design and build-up of hybrid DNA/amphiphilic self-assemblies can expand the range of possible architectures and enhance the selectivity toward a well-specified geometry. We report on the self-assembly properties in aqueous solution of a cholesteryl-tetraethylenglycol single stranded 18-mer oligonucleotide (ON 1TEG-Chol) and on its spontaneous insertion in fluid phospholipid membranes. Up to 500 units of these lipophilic ss-oligonucleotides can be incorporated in the outer leaflet of 350 A radius POPC vesicle. The insertion and hybridization with the complementary oligonucleotide are monitored through light scattering as an increase of hydrodynamic thickness, which is interpreted in terms of average distance between anchoring sites. The conformation of the ss-oligonucleotidic portion is strongly dependent on surface coverage, passing from a quasi-random coil to a more rigid configuration, as concentration increases. Interestingly, conformational details affect in a straightforward fashion the hybridization kinetics. Liposomes with single- and double-strand decorations remain stable within the experimental time window (about one week). The structure represents an example of successful and stable amphiphile/DNA supramolecular hybrid, where a DNA guest is held in a membrane by hydrophobic interactions. The lipophilic oligonucleotide under investigation is therefore a suitable building block that can effectively serve as a hydrophobic anchor in the fluid bilayer to assemble supramolecular constructs based on the DNA digital code.


SUVmax after (18)fluoro-deoxyglucose positron emission tomography/computed tomography: A tool to define treatment strategies in pancreatic cancer.
(18)fluoro-deoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) might be a useful tool in the management of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to analyze maximum standard uptake value (SUVmax) after 18FDG-PET/CT as predictor of survival outcomes and method to determine treatment strategies. A consecutive series of patients who underwent preoperative 18FDG-PET/CT and subsequent resection for PDAC were retrospectively reviewed. Patients who underwent neoadjuvant chemotherapy were excluded. 46 patients were included in the analysis. Median follow-up was 27 months (4-67). Patients who recurred within 12 months showed a significantly higher preoperative median SUVmax (8.1 vs 6.1, p=0.039). Receiver operating characteristics (ROC) curves for disease-free survival (DFS) and disease-specific survival (DSS) identified SUVmax of 6.0 as optimal cut-off. Multivariate analysis showed that SUVmax ≥ 6.0 was an independent predictor of poor DFS (HR 2.288, p=0.024) and DSS (HR 4.875, p<0.001). The combination of SUVmax ≥6.0 with CA19.9 ≥200U/ml was significantly associated with survival outcomes in comparison to patients without concordantly elevated values. SUVmax ≥6.0 is an independent predictor of DFS and DSS in resected PDAC. 18FDG-PET/CT might be considered in the preoperative evaluation of patients with pancreatic cancer.


Cytoskeletal protein degradation in brain death donor kidneys associates with adverse posttransplant outcomes.
In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys adversely impacting the quality of grafts. Here, we hypothesized that donation after brain death (DBD) kidneys undergo proteolytic processes that may deem grafts susceptible to posttransplant dysfunction. Using mass spectrometry and immunoblotting, we mapped degradation profiles of cytoskeletal proteins in deceased and living donor kidney biopsies. We found that key cytoskeletal proteins in DBD kidneys were proteolytically cleaved, generating peptide fragments, predominantly in grafts with suboptimal posttransplant function. Interestingly, α-actinin-4 and talin-1 proteolytic fragments were detected in brain death but not in circulatory death or living donor kidneys with similar donor characteristics. As talin-1 is a specific proteolytic target of calpain-1, we investigated a potential trigger of calpain activation and talin-1 degradation using human ex vivo precision-cut kidney slices and in vitro podocytes. Notably, we showed that activation of calpain-1 by transforming growth factor-β generated proteolytic fragments of talin-1 that matched the degradation fragments detected in DBD preimplantation kidneys, also causing dysregulation of the actin cytoskeleton in human podocytes; events that were reversed by calpain-1 inhibition. Our data provide initial evidence that brain death donor kidneys are more susceptible to cytoskeletal protein degradation. Correlation to posttransplant outcomes may be established by future studies.