Noise in laser speckle correlation and imaging techniques.
We study the noise of the intensity variance and of the intensity correlation and structure functions measured in light scattering from a random medium in the case when these quantities are obtained by averaging over a finite number N of pixels of a digital camera. We show that the noise scales as 1/N in all cases and that it is sensitive to correlations of signals corresponding to adjacent pixels as well as to the effective time averaging (due to the finite integration time) and spatial averaging (due to the finite pixel size). Our results provide a guide to estimation of noise levels in such applications as multi-speckle dynamic light scattering, time-resolved correlation spectroscopy, speckle visibility spectroscopy, laser speckle imaging etc.


Bordetella adenylate cyclase is a virulence associated factor and an immunoprotective antigen.
Bordetella pertussis and Bordetella parapertussis are both causative agents of whooping cough outbreaks. Although not expressing the pertussis toxin, B. parapertussis induces, in a murine model, an acute hemorrhagic edematous alveolitis, similar to that observed with B. pertussis. These data suggest that the pertussis toxin may only play an accessory role in the acute pulmonary syndrome observed during Bordetella infection. Both with B. pertussis and B. parapertussis, the ability to induce lethal pulmonary lesions is associated with enhanced in vitro adenylate cyclase expression and activity. We also demonstrate that passive immunization with specific anti-B. pertussis adenylate cyclase antibodies or active immunization with purified B. pertussis secreted adenylate cyclase protect mice against a lethal respiratory challenge with B. pertussis or B. parapertussis. Our results suggest that adenylate cyclase might be the primary cytotoxin responsible for mouse pulmonary lesions during respiratory tract infection with B. pertussis or with the related species B. parapertussis and is a protective antigen of B. pertussis.


EULAR points to consider for conducting clinical trials in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex multi-organ disease, characterised by relapses and remissions. ng a high-quality randomised controlled trial poses many challenges. We have developed evidenced-based recommendations for points to consider in conducting clinical trials in patients with SLE. The EULAR Task Force on SLE comprised 19 specialists and a clinical epidemiologist. Initially, the evidence for clinical trial end-points in SLE was evaluated and this has been reported separately. A consensus approach was developed by the SLE Task Force in formulating recommendations for points to consider when conducting clinical trials in SLE. The literature review revealed that most outcome measures used in phase 2/3 trials in SLE have not actually been validated in clinical trials, although other forms of validation have been undertaken. The final recommendations for points to consider for conducting clinical trials in SLE address the following areas: study design, eligibility criteria, outcome measures including adverse events, concomitant therapies for SLE and its complications. Recommendations for points to consider when conducting clinical trials in SLE were developed using an evidence-based approach followed by expert consensus. The recommendations should be disseminated, implemented and then reviewed in detail and revised using an evidence-based approach in about 5 years, by which time there will be further evidence to consider from current clinical trials.


In vitro and in vivo studies for assessing the immune response and protection-inducing ability conferred by Fasciola hepatica-derived synthetic peptides containing B- and T-cell epitopes.
Fasciolosis is considered the most widespread trematode disease affecting grazing animals around the world; it is currently recognised by the World Health Organisation as an emergent human pathogen. Triclabendazole is still the most effective drug against this disease; however, resistant strains have appeared and developing an effective vaccine against this disease has increasingly become a priority. Several bioinformatics tools were here used for predicting B- and T-cell epitopes according to the available data for Fasciola hepatica protein amino acid sequences. BALB/c mice were immunised with the synthetic peptides by using the ADAD vaccination system and several immune response parameters were measured (antibody titres, cytokine levels, T-cell populations) to evaluate their ability to elicit an immune response. Based on the immunogenicity results so obtained, seven peptides were selected to assess their protection-inducing ability against experimental infection with F. hepatica metacercariae. Twenty-four B- or T-epitope-containing peptides were predicted and chemically synthesised. Immunisation of mice with peptides so-called B1, B2, B5, B6, T14, T15 and T16 induced high levels of total IgG, IgG1 and IgG2a (p<0.05) and a mixed Th1/Th2/Th17/Treg immune response, according to IFN-γ, IL-4, IL-17 and IL-10 levels, accompanied by increased CD62L+ T-cell populations. A high level of protection was obtained in mice vaccinated with peptides B2, B5, B6 and T15 formulated in the ADAD vaccination system with the AA0029 immunomodulator. The bioinformatics approach used in the present study led to the identification of seven peptides as vaccine candidates against the infection caused by Fasciola hepatica (a liver-fluke trematode). However, vaccine efficacy must be evaluated in other host species, including those having veterinary importance.


Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).


Prevalence and Risk Factors of Women's Past-Year Physical IPV Perpetration and Victimization in Tanzania.
Recent studies of intimate partner violence (IPV) in high-resource countries suggest that men and women may perpetrate similar rates of violence against their partners, yet the prevalence and etiology of female-perpetrated IPV, especially in comparison with IPV victimization among females, remains largely understudied in low-resource, high-prevalence countries, particularly in sub-Saharan Africa. Using multivariate logistic regression models, the current study examines the prevalence of and risk factors associated with past 12-month experiences of isolated physical IPV perpetration (i.e., violence perpetrated against an intimate partner not in self-defense) and physical IPV victimization among a nationally representative sample of women of reproductive age (15-49 years) from Tanzania who completed the Tanzanian Demographic and Health Survey Domestic Violence Module (n = 5,372). Approximately 1.5% reported perpetrating violence in the past 12 months, whereas 35% reported victimization in the same time period. Risk factors of past 12-month IPV perpetration included past 12-month IPV victimization, making cash or in-kind earnings, having autonomy in decision making, and acceptance of justifications for wife beating. Women much younger than their partners had lower odds of IPV perpetration. Risk factors of past 12-month IPV victimization included past 12-month IPV perpetration, educational attainment, having children, partner's alcohol consumption, partner's decision making, acceptance of justifications for wife beating, and exposure to parental IPV. Making cash or in-kind earnings was the only protective factor against victimization. Findings suggest that female IPV perpetration and victimization may result from a combination of factors including power differentials between partners and attitudes about the acceptability of using violence. Future research directions and implications for policy and prevention efforts to reduce IPV in Tanzania are discussed.


Highly efficient all-optical beam modulation utilizing thermo-optic effects.
Suspensions of plasmonic nanoparticles can diffract optical beams due to the combination of thermal lensing and self-phase modulation. Here, we demonstrate extremely efficient optical continuous wave (CW) beam switching across the visible range in optimized suspensions of 5-nm Au and Ag nanoparticles in non-polar solvents, such as hexane and decane. On-axis modulation of greater than 30 dB is achieved at incident beam intensities as low as 100 W/cm2 with response times under 200 μs, at initial solution transparency above 70%. No evidence of laser-induced degradation is observed for the highest intensities used. Numerical modeling of experimental data reveals thermo-optic coefficients of up to -1.3 × 10-3 /K, which, to our knowledge, is the highest observed to date in such nanoparticle suspensions.


Transduction of biologically active motifs of the small heat shock-related protein HSP20 leads to relaxation of vascular smooth muscle.
Activation of cyclic nucleotide-dependent signaling pathways leads to phosphorylation of the small heat shock-related protein, HSP20, on serine 16, and relaxation of vascular smooth muscle. In this study, we used an enhanced protein transduction domain (PTD) sequence to deliver HSP20 phosphopeptide analogs into porcine coronary artery. The transduction of phosphoHSP20 analogs led to dose-dependent relaxation of coronary artery smooth muscle. Peptides containing the protein transduction domain coupled to a random orientation of the same amino acids did not. Direct fluorescence microscopy of arterial rings incubated with fluorescein isothiocyanate (FITC)-PTD or FITC-PTD-HSP20 peptides showed a diffuse peptide uptake. Mass spectrometric immunoassays (MSIAs) of smooth muscle homogenates were used to determine whether the phosphopeptide analogs affected the phosphorylation of endogenous HSP20. Treatment with the phosphodiesterase inhibitor papaverine led to a mass shift of 80 Da. However, there was no mass shift of HSP20 in muscles treated with phosphoHSP20 analogs. This suggests that the PTD-phosphoHSP20 peptide alone is sufficient to inhibit force maintenance and likely has a direct effect on the target of phosphorylated HSP20. These results suggest that transduction of phosphopeptide analogs of HSP20 directly alters physiological responses of intact muscles. The data also support a direct role for phosphorylated HSP20 in mediating vasorelaxation.


Sonographic evaluation of intravascular volume status: Can internal jugular or femoral vein collapsibility be used in the absence of IVC visualization?
Inferior vena cava collapsibility index (IVC-CI) has been shown to correlate with both clinical and invasive assessment of intravascular volume status, but has important limitations such as the requirement for advanced sonographic skills, the degree of difficulty in obtaining those skills, and often challenging visualization of the IVC in the postoperative patient. The current study aims to explore the potential for using femoral (FV) or internal jugular (IJV) vein collapsibility as alternative sonographic options in the absence of adequate IVC visualization. A prospective, observational study comparing IVC-CI and Fem- and/or IJV-CI was performed in two intensive care units (ICU) between January 2012 and April 2014. Concurrent M-mode measurements of IVC-CI and FV- and/or IJV-CI were collected during each sonographic session. Measurements of IVC were obtained using standard technique. IJV-CI and FV-CI were measured using high-frequency, linear array ultrasound probe placed in the corresponding anatomic areas. Paired data were analyzed using coefficient of correlation/determination and Bland-Altman determination of measurement bias. We performed paired ultrasound examination of IVC-IJV (n = 39) and IVC-FV (n = 22), in 40 patients (mean age 54.1; 40% women). Both FV-CI and IJV-CI scans took less time to complete than IVC-CI scans (both, P < 0.02). Correlations between IVC-CI/FV-CI (R(2) = 0.41) and IVC-CI/IJV-CI (R(2) = 0.38) were weak. There was a mean -3.5% measurement bias between IVC-CI and IJV-CI, with trend toward overestimation for IJV-CI with increasing collapsibility. In contrast, FV-CI underestimated collapsibility by approximately 3.8% across the measured collapsibility range. Despite small measurement biases, correlations between IVC-CI and FV-/IJV-CI are weak. These results indicate that IJ-CI and FV-CI should not be used as a primary intravascular volume assessment tool for clinical decision support in the ICU. The authors propose that IJV-CI and FV-CI be reserved for clinical scenarios where sonographic acquisition of both IVC-CI or subclavian collapsibility are not feasible, especially when trended over time. Sonographers should be aware that IJV-CI tends to overestimate collapsibility when compared to IVC-CI, and FV-CI tends to underestimates collapsibility relative to IVC-CI.


Metacognitive beliefs and rumination as predictors of anger: A prospective study.
The metacognitive approach conceptualizes the relationship between anger and rumination as driven by metacognitive beliefs, which are information individuals hold about their own cognition and about coping strategies that impact on it. The present study aimed to test the prospective predictive impact of metacognitive beliefs and rumination on anger in a community sample. Seventy-six participants were recruited and engaged in a 2-week anger, rumination, and metacognitive beliefs monitoring protocol. A multi-wave panel design was employed to test whether metacognitive beliefs and rumination have a prospective impact on anger. Metacognitive beliefs and rumination were found to have a significant prospective impact on anger that was independent from the number of triggering events. Metacognitive beliefs about the need to control thoughts were shown to have a direct impact on subsequent anger, independently from rumination. These findings provide support for the potential value for applying metacognitive theory and therapy to anger-related problems. Aggr. Behav. 43:421-429, 2017. © 2017 Wiley Periodicals, Inc.


The effect of single dose ivermectin alone or in combination with albendazole on Wuchereria bancrofti infection in primary school children in Tanzania.
Examination of 1829 children from 6 primary schools in coastal Tanzania revealed overall Wuchereria bancrofti microfilaria (mf) and circulating filarial antigen (CFA) prevalences of 17.3% and 43.7%, respectively. A randomized double-blind field trial with a single dose of ivermectin (150-200 microg/kg body weight) alone or in combination with albendazole (400 mg) was subsequently carried out among these children. Both treatment regimens resulted in a considerable decrease in mean mf intensities, with overall reductions being slightly but statistically significantly higher for the combination than for ivermectin alone. The difference in effect between the two treatment regimens was most pronounced at 6 months, whereas it was minor at 12 months after treatment. The relative effect of treatment on mean CFA units was less pronounced than on mf. For both treatment regimens, reductions in CFA intensity appeared to be higher in children who were both CFA and mf positive before treatment, which may suggest that treatment mainly affected the survival and/or production of mf, rather than the survival of adult worms. New cases of infection appeared after treatment with both regimens among the pre-treatment mf and CFA negative children. Adverse reactions were few and mild in both groups, and mainly reported from pre-treatment mf and CFA positive children. The alarmingly high prevalence of W. bancrofti infection in primary school children highlights the importance of also determining the reversibility of already acquired early lesions, and the development of new measures and strategies to specifically protect children from later developing clinical disease.


Comparison between topical honey and mafenide acetate in treatment of auricular burn.
The auricle is a frequently injured part of the head and neck during thermal injury leading to ear deformity. The burned ear represents one of the most difficult problems for reconstructive surgeons. Mafenide acetate is a topical agent used routinely for these patients, but it has some disadvantages including painful application and allergic rash. Some authors have reported the healing effect and antibacterial activity of honey. The study reported here was undertaken to compare the effect of honey and mafenide acetate on auricular burn in rabbit. In our study, although the pathologic score of the honey group was better than that of the mafenide group both on 14 and 21 days after burning, it was not statistically significant. In the mafenide acetate group, deep complication of burn (chondritis) was significantly lower than that of the honey group. In conclusion, in contrast to healing and antibiotic activity reported for honey, it may have failure in preventing deep bacterial complications of wound (like chondritis). So in deep wounds, the use of honey as dressing is not recommended.


Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.
We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 x 10(-5)), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p = 1.7 x 10(-5)), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.


Evolution of the EGFR pathway in Metazoa and its diversification in the planarian Schmidtea mediterranea.
The EGFR pathway is an essential signaling system in animals, whose core components are the epidermal growth factors (EGF ligands) and their trans-membrane tyrosine kinase receptors (EGFRs). Despite extensive knowledge in classical model organisms, little is known of the composition and function of the EGFR pathway in most animal lineages. Here, we have performed an extensive search for the presence of EGFRs and EGF ligands in representative species of most major animal clades, with special focus on the planarian Schmidtea mediterranea. With the exception of placozoans and cnidarians, we found that the EGFR pathway is potentially present in all other analyzed animal groups, and has experienced frequent independent expansions. We further characterized the expression domains of the EGFR/EGF identified in S. mediterranea, revealing a wide variety of patterns and localization in almost all planarian tissues. Finally, functional experiments suggest an interaction between one of the previously described receptors, Smed-egfr-5, and the newly found ligand Smed-egf-6. Our findings provide the most comprehensive overview to date of the EGFR pathway, and indicate that the last common metazoan ancestor had an initial complement of one EGFR and one putative EGF ligand, which was often expanded or lost during animal evolution.


Viral replication under combination antiretroviral therapy: a comparison of four different regimens.
A mathematical model of the interaction among CD4+ T-cells, HIV-1, and antiretroviral drugs was fitted to the viral load decline following initiation of combination therapy to estimate differences in the residual reproductive capacity of virus (R(0)) in the average patient in each group. Four regimens were studied: 12 patients on 5-drug nucleoside reverse transcriptase inhibitor (NRTIs), nonnucleoside reverse transcriptase inhibitor (NNRTIs) and protease inhibitor (PI)-containing combination therapy, 11 patients on PI-containing triple therapy, 10 patients on double NRTI therapy, and 10 patients on NNRTI-containing triple therapy. Model fits were used to estimate R(0). The NNRTI-containing triple therapy and the 5-drug regimen blocked viral replication to the greatest extent (R(0) = 0.85; 95% confidence interval [CI], 0.79-0.91; and 0.90, 95% CI, 0.82-0.98, respectively), with the former being significantly better than the PI-containing triple regimen (R(0) = 0.98; 95% CI, 0.92-1.03; p =.007). Both the NNRTI-containing and the 5-drug regimen, as well as the PI-containing triple therapy, were significantly better at blocking viral replication than the double NRTI therapy (R(0) = 1.04; 95% CI, 1.0-1.07). Measurement of viral load after approximately 7 days provided the most accurate measure of the degree of viral suppression induced by a given drug regimen.


Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.


Red wine and component flavonoids inhibit UGT2B17 in vitro.
The metabolism and excretion of the anabolic steroid testosterone occurs by glucuronidation to the conjugate testosterone glucuronide which is then excreted in urine. Alterations in UGT glucuronidation enzyme activity could alter the rate of testosterone excretion and thus its bioavailability. The aim of this study is to investigate if red wine, a common dietary substance, has an inhibitory effect on UGT2B17. Testosterone glucuronidation was assayed using human UGT2B17 supersomes with quantification of unglucuronidated testosterone over time using HPLC with DAD detection. The selected red wine was analyzed using HPLC; and the inhibitory effects of the wine and phenolic components were tested independently in a screening assay. Further analyses were conducted for the strongest inhibitors at physiologically relevant concentrations. Control experiments were conducted to determine the effects of the ethanol on UGT2B17. Over the concentration range of 2 to 8%, the red wine sample inhibited the glucuronidation of testosterone by up to 70% over 2 hours. The ethanol content had no significant effect. Three red wine phenolics, identified by HPLC analyses, also inhibited the enzyme by varying amounts in the order of quercetin (72%), caffeic acid (22%) and gallic acid (9%); using a ratio of phenolic:testosterone of 1:2.5. In contrast p-coumaric acid and chlorogenic acid had no effect on the UGT2B17. The most active phenolic was selected for a detailed study at physiologically relevant concentrations, and quercetin maintained inhibitory activity of 20% at 2 μM despite a ten-fold excess of testosterone. This study reports that in an in vitro supersome-based assay, the key steroid-metabolizing enzyme UGT2B17 is inhibited by a number of phenolic dietary substances and therefore may reduce the rate of testosterone glucuronidation in vivo. These results highlight the potential interactions of a number of common dietary compounds on testosterone metabolism. Considering the variety of foodstuffs that contain flavonoids, it is feasible that diet can elevate levels of circulating testosterone through reduction in urinary excretion. These results warrant further investigation and extension to a human trial to delineate the health implications.


Cross-sectional structural parameters from densitometry.
Bone densitometry has previously been used to obtain cross-sectional properties of bone from a single X-ray projection across the bone width. Using three unique projections, we have extended the method to obtain the principal area moments of inertia and orientations of the principal axes at each scan cross-section along the length of the scan. Various aluminum phantoms were used to examine scanner characteristics to develop the highest accuracy possible for in vitro non-invasive analysis of cross-sectional properties. Factors considered included X-ray photon energy, initial scan orientation, the angle spanned by the three scans (included angle), and I(min)/I(max) ratios. Principal moments of inertia were accurate to within +/-3.1% and principal angles were within +/-1 degrees of the expected value for phantoms scanned with included angles of 60 degrees and 90 degrees at the higher X-ray photon energy (140 kVp). Low standard deviations in the error (0.68-1.84%) also indicate high precision of calculated measurements with these included angles. Accuracy and precision decreased slightly when the included angle was reduced to 30 degrees. The method was then successfully applied to a pair of excised cadaveric tibiae. The accuracy and insensitivity of the algorithms to cross-sectional shape and changing isotropy (I(min)/I(max)) values when various included angles are used make this technique viable for future in vivo studies.


A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus.
A quantitative three-dimensional analysis of nuclear components involved in precursor messenger RNA metabolism was performed with a combination of fluorescence hybridization, immunofluorescence, and digital imaging microscopy. Polyadenylate [poly(A)] RNA-rich transcript domains were discrete, internal nuclear regions that formed a ventrally positioned horizontal array in monolayer cells. A dimmer, sometimes strand-like, poly(A) RNA signal was dispersed throughout the nucleoplasm. Spliceosome assembly factor SC-35 localized within the center of individual domains. These data support a nuclear model in which there is a specific topological arrangement of noncontiguous centers involved in precursor messenger RNA metabolism, from which RNA transport toward the nuclear envelope radiates.


Frequent p16INK4A/CDKN2A alterations in chemically induced Syrian golden hamster pancreatic tumors.
The p16INK4A/CDKN2A (p16) tumor suppressor gene is known to be inactivated in up to 98% of human pancreatic cancer specimens. Chemically induced pancreatic tumors in Syrian golden hamsters have been demonstrated to share many morphological and biological similarities with human pancreatic tumors and represent a potentially suitable model for the evaluation of therapies targeting p16. The purpose of this study was to evaluate primary hamster pancreatic tumor specimens for potentially inactivating p16 alterations. Tumors were induced with N-nitroso-bis-(2-oxopropyl) amine, followed by two cycles of augmentation pressure, and were harvested on day 100. Foci of tumor cells were identified by light microscopy after staining with hematoxylin and eosin, and corresponding tumor tissues were excised for DNA extraction. The techniques of multiplex real-time PCR, direct sequencing and methylation-specific PCR were used to evaluate 30 tumor specimens for homozygous deletions, mutations and aberrant methylation of 5' CpG islands, respectively. Homozygous deletions were identified in 11 of 30 (36.7%) specimens, mutations were identified in four of 30 (13.3%) specimens, and aberrant methylation of 5' CpG islands was found in 14 of 30 (46.7%) specimens. The overall frequency of p16 alterations was 93.3% (28 of 30 specimens) and the majority of changes (83.3%) were noted to be secondary to methylation or homozygous deletion. The four mutations significantly impaired cyclin-dependent kinase 4 inhibitory activity, and two resulted in perturbation of the global structure of P16 protein. These findings indicate that p16 inactivation is a common event in chemically induced hamster tumors, and that this animal model is appropriate for comparative studies evaluating pancreatic cancer therapeutic strategies targeting p16.


Classifying thoracolumbar fractures: role of quantitative imaging.
This article describes different types of vertebral fractures that affect the thoracolumbar spine and the most relevant contributions of the different classification systems to vertebral fracture management. The vertebral fractures types are based on the three columns model of Denis that includes compression, burst, flexion-distraction and fracture-dislocation types. The most recent classifications systems of these types of fractures are reviewed, including the Thoracolumbar Injury Classification and Severity score (TLICS) and the Arbeitsgemeinschaft für Osteosynthesefragen Spine Thoracolumbar Injury Classification and Severity score (AOSpine-TLICS). Correct classification requires a quantitative imaging approach in which several measurements determine TLICS or AOSpine-TLICS grade. If the TLICS score is greater than 4, or the AOSpine-TLICS is greater than 5, surgical management is indicated. In this review, the most important imaging findings and measurements on radiography, multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) are described. These include degree of vertebral wedging and percentage of vertebral height loss in compression fractures, degree of interpedicular distance widening and spinal canal stenosis in burst fractures, and the degree of vertebral translation or interspinous widening in more severe fractures types, such as flexion-distraction and fracture-dislocation. These findings and measurements are illustrated with schemes and cases of our archives in a didactic way.


Histidine is selectively required for the growth of Myc-dependent dedifferentiation tumours in the Drosophila CNS.
Rewired metabolism of glutamine in cancer has been well documented, but less is known about other amino acids such as histidine. Here, we use Drosophila cancer models to show that decreasing the concentration of histidine in the diet strongly inhibits the growth of mutant clones induced by loss of Nerfin-1 or gain of Notch activity. In contrast, changes in dietary histidine have much less effect on the growth of wildtype neural stem cells and Prospero neural tumours. The reliance of tumours on dietary histidine and also on histidine decarboxylase (Hdc) depends upon their growth requirement for Myc. We demonstrate that Myc overexpression in nerfin-1 tumours is sufficient to switch their mode of growth from histidine/Hdc sensitive to resistant. This study suggests that perturbations in histidine metabolism selectively target neural tumours that grow via a dedifferentiation process involving large cell size increases driven by Myc.


Reinfection after treatment of first cerebrospinal fluid shunt infection: a prospective observational cohort study.
OBJECTIVE CSF shunt infection requires both surgical and antibiotic treatment. Surgical treatment includes either total shunt removal with external ventricular drain (EVD) placement followed by new shunt insertion, or distal shunt externalization followed by new shunt insertion once the CSF is sterile. Antibiotic treatment includes the administration of intravenous antibiotics. The Hydrocephalus Clinical Research Network (HCRN) registry provides a unique opportunity to understand reinfection following treatment for CSF shunt infection. This study examines the association of surgical and antibiotic decisions in the treatment of first CSF shunt infection with reinfection. METHODS A prospective cohort study of children undergoing treatment for first CSF infection at 7 HCRN hospitals from April 2008 to December 2012 was performed. The HCRN consensus definition was used to define CSF shunt infection and reinfection. The key surgical predictor variable was surgical approach to treatment for CSF shunt infection, and the key antibiotic treatment predictor variable was intravenous antibiotic selection and duration. Cox proportional hazards models were constructed to address the time-varying nature of the characteristics associated with shunt surgeries. RESULTS Of 233 children in the HCRN registry with an initial CSF shunt infection during the study period, 38 patients (16%) developed reinfection over a median time of 44 days (interquartile range [IQR] 19-437). The majority of initial CSF shunt infections were treated with total shunt removal and EVD placement (175 patients; 75%). The median time between infection surgeries was 15 days (IQR 10-22). For the subset of 172 infections diagnosed by CSF culture, the mean ± SD duration of antibiotic treatment was 18.7 ± 12.8 days. In all Cox proportional hazards models, neither surgical approach to infection treatment nor overall intravenous antibiotic duration was independently associated with reinfection. The only treatment decision independently associated with decreased infection risk was the use of rifampin. While this finding did not achieve statistical significance, in all 5 Cox proportional hazards models both surgical approach (other than total shunt removal at initial CSF shunt infection) and nonventriculoperitoneal shunt location were consistently associated with a higher hazard of reinfection, while the use of ultrasound was consistently associated with a lower hazard of reinfection. CONCLUSIONS Neither surgical approach to treatment nor antibiotic duration was associated with reinfection risk. While these findings did not achieve statistical significance, surgical approach other than total removal at initial CSF shunt infection was consistently associated with a higher hazard of reinfection in this study and suggests the feasibility of controlling and standardizing the surgical approach (shunt removal with EVD placement). Considerably more variation and equipoise exists in the duration and selection of intravenous antibiotic treatment. Further consideration should be given to the use of rifampin in the treatment of CSF shunt infection. High-quality studies of the optimal duration of antibiotic treatment are critical to the creation of evidence-based guidelines for CSF shunt infection treatment.


Mechanism of anteroposterior axis specification in vertebrates. Lessons from the amphibians.
Interest in the problem of anteroposterior specification has quickened because of our near understanding of the mechanism in Drosophila and because of the homology of Antennapedia-like homeobox gene expression patterns in Drosophila and vertebrates. But vertebrates differ from Drosophila because of morphogenetic movements and interactions between tissue layers, both intimately associated with anteroposterior specification. The purpose of this article is to review classical findings and to enquire how far these have been confirmed, refuted or extended by modern work. The "pre-molecular" work suggests that there are several steps to the process: (i) Formation of anteroposterior pattern in mesoderm during gastrulation with posterior dominance. (ii) Regional specific induction of ectoderm to form neural plate. (iii) Reciprocal interactions from neural plate to mesoderm. (iv) Interactions within neural plate with posterior dominance. Unfortunately, almost all the observable markers are in the CNS rather than in the mesoderm where the initial specification is thought to occur. This has meant that the specification of the mesoderm has been assayed indirectly by transplantation methods such as the Einsteckung. New molecular markers now supplement morphological ones but they are still mainly in the CNS and not the mesoderm. A particular interest attaches to the genes of the Antp-like HOX clusters since these may not only be markers but actual coding factors for anteroposterior levels. We have a new understanding of mesoderm induction based on the discovery of activins and fibroblast growth factors (FGFs) as candidate inducing factors. These factors have later consequences for anteroposterior pattern with activin tending to induce anterior, and FGF posterior structures. Recent work on neural induction has implicated cAMP and protein kinase C (PKC) as elements of the signal transduction pathway and has provided new evidence for the importance of tangential neural induction. The regional specificity of neural induction has been reinvestigated using molecular markers and provides conclusions rather similar to the classical work. Defects in the axial pattern may be produced by retinoic acid but it remains unclear whether its effects are truly coordinate ones or are concentrated in certain regions of high sensitivity. In general the molecular studies have supported and reinforced the "pre-molecular ones". Important questions still remain: (i) How much pattern is there in the mesoderm (how many states?) (ii) How is this pattern generated by the invaginating organizer? (iii) Is there one-to-one transmission of codings to the neural plate? (iv) What is the nature of the interactions within the neural plate? (v) Are the HOX cluster genes really the anteroposterior codings?


Effect of Intravenous Acetaminophen vs Placebo Combined With Propofol or Dexmedetomidine on Postoperative Delirium Among Older Patients Following Cardiac Surgery: The DEXACET Randomized Clinical Trial.
Postoperative delirium is common following cardiac surgery and may be affected by choice of analgesic and sedative. To evaluate the effect of postoperative intravenous (IV) acetaminophen (paracetamol) vs placebo combined with IV propofol vs dexmedetomidine on postoperative delirium among older patients undergoing cardiac surgery. Randomized, placebo-controlled, factorial clinical trial among 120 patients aged 60 years or older undergoing on-pump coronary artery bypass graft (CABG) surgery or combined CABG/valve surgeries at a US center. Enrollment was September 2015 to April 2018, with follow-up ending in April 2019. Patients were randomized to 1 of 4 groups receiving postoperative analgesia with IV acetaminophen or placebo every 6 hours for 48 hours and postoperative sedation with dexmedetomidine or propofol starting at chest closure and continued for up to 6 hours (acetaminophen and dexmedetomidine: n = 29; placebo and dexmedetomidine: n = 30; acetaminophen and propofol: n = 31; placebo and propofol: n = 30). The primary outcome was incidence of postoperative in-hospital delirium by the Confusion Assessment Method. Secondary outcomes included delirium duration, cognitive decline, breakthrough analgesia within the first 48 hours, and ICU and hospital length of stay. Among 121 patients randomized (median age, 69 years; 19 women [15.8%]), 120 completed the trial. Patients treated with IV acetaminophen had a significant reduction in delirium (10% vs 28% placebo; difference, -18% [95% CI, -32% to -5%]; P = .01; HR, 2.8 [95% CI, 1.1-7.8]). Patients receiving dexmedetomidine vs propofol had no significant difference in delirium (17% vs 21%; difference, -4% [95% CI, -18% to 10%]; P = .54; HR, 0.8 [95% CI, 0.4-1.9]). There were significant differences favoring acetaminophen vs placebo for 3 prespecified secondary outcomes: delirium duration (median, 1 vs 2 days; difference, -1 [95% CI, -2 to 0]), ICU length of stay (median, 29.5 vs 46.7 hours; difference, -16.7 [95% CI, -20.3 to -0.8]), and breakthrough analgesia (median, 322.5 vs 405.3 µg morphine equivalents; difference, -83 [95% CI, -154 to -14]). For dexmedetomidine vs propofol, only breakthrough analgesia was significantly different (median, 328.8 vs 397.5 µg; difference, -69 [95% CI, -155 to -4]; P = .04). Fourteen patients in both the placebo-dexmedetomidine and acetaminophen-propofol groups (46% and 45%) and 7 in the acetaminophen-dexmedetomidine and placebo-propofol groups (24% and 23%) had hypotension. Among older patients undergoing cardiac surgery, postoperative scheduled IV acetaminophen, combined with IV propofol or dexmedetomidine, reduced in-hospital delirium vs placebo. Additional research, including comparison of IV vs oral acetaminophen and other potentially opioid-sparing analgesics, on the incidence of postoperative delirium is warranted. ClinicalTrials.gov Identifier: NCT02546765.


A simple plasmid-based transient gene expression method using High Five cells.
The High Five (H5) cell line, derived from the lepidopteran Trichoplusia ni, is one of the major insect cell hosts for the production of recombinant proteins using the baculovirus expression vector system (BEVS). Here, we describe a simple polyethylenimine (PEI)-based transient gene expression (TGE) process for the rapid production of recombinant proteins from suspension-adapted H5 cells. The method was optimized using two model proteins, enhanced green fluorescent protein (EGFP) and human tumor necrosis factor receptor-Fc fusion protein (TNFR-Fc). After screening several promoter and enhancer combinations for high levels of TNFR:Fc production, an expression vector containing the Autographa californica multicapsid nucleopolyhedrovirus immediate early 1 (ie1) promoter and homologous region 5 (hr5) enhancer was selected. Cells were transfected at a density of 2×10(6) cells/mL by direct addition of DNA and PEI. Under optimized conditions, a 90% transfection efficiency (percentage of EGFP-positive cells) was obtained. In addition, we observed volumetric TNFR-Fc yields over 150μg/mL within 4 days of transfection. The method was found to be reproducible and scalable to 300mL. This plasmid-based transient transfection process is a simple and efficient alternative to the BEVS for recombinant protein production in H5 cells.


Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with albuminuria in hypertensive African Americans: the HyperGEN study.
MYH9 is a podocyte-expressed gene encoding nonmuscle myosin IIA that is associated with idiopathic and human immunodeficiency virus-associated focal segmental glomerulosclerosis (FSGS) and hypertensive end-stage renal disease in African Americans. Four single nucleotide polymorphisms comprising the major MYH9 E1 risk haplotype were tested for association with estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in 2,903 HyperGEN participants (1,458 African Americans (AA) in 895 families and 1,445 European Americans (EA) in 859 families) to determine the role of MYH9 in subclinical nephropathy. Association analyses employed general linear models in unrelated probands and generalized estimating equations in families. Adjustment was performed for age, sex, diabetes, BMI, medications, and mean arterial pressure separately in each race. Mean (SD) eGFR and ACR were 74.3 (16.0) ml/min/1.73 m(2) and 20.3 (119.9) mg/g in EA, and 88.6 (20.9) ml/min/1.73 m(2) and 76.8 (394.5) mg/g in AA (both p < 0.0001 across ethnicities). Urine ACR was associated with rs3752462 (p = 0.01) and rs4821481 (p = 0.05) in unrelated AA and with rs4821481 (p = 0.03), rs2032487 (p = 0.04) and the E1 3224 haplotype (p = 0.013) in AA families. Single nucleotide polymorphisms and the haplotype were not associated with ACR in EA or with eGFR in either ethnic group. MYH9 variants are associated with albuminuria in hypertensive AA. The strength of the association was weaker than that in FSGS and hypertensive end-stage renal disease. MYH9 risk variants appear to be associated with primary FSGS with secondary hypertension, although nephrosclerosis may develop in response to hypertension in subjects homozygous for the MYH9 E1 risk haplotype.


The Chest Pain Choice trial: a pilot randomized trial of a decision aid for patients with chest pain in the emergency department.
Chest pain is a common presenting complaint in the emergency department (ED). Despite the frequency with which clinicians evaluate patients with chest pain, accurately determining the risk of acute coronary syndrome (ACS) and sharing risk information with patients is challenging. The aims of this study are (1) to develop a decision aid (CHEST PAIN CHOICE) that communicates the short-term risk of ACS and (2) to evaluate the impact of the decision aid on patient participation in decision-making and resource use. This is a protocol for a parallel, 2-arm randomized trial to compare an intervention group receiving CHEST PAIN CHOICE to a control group receiving usual ED care. Adults presenting to the Saint Mary's Hospital ED in Rochester, MN USA with a primary complaint of chest pain who are being considered for admission for prolonged ED observation in a specialized unit and urgent cardiac stress testing will be eligible for enrollment. We will measure the effect of CHEST PAIN CHOICE on six outcomes: (1) patient knowledge regarding their short-term risk for ACS and the risks of radiation exposure; (2) quality of the decision making process; (3) patient and clinician acceptability and satisfaction with the decision aid; (4) the proportion of patients who decided to undergo observation unit admission and urgent cardiac stress testing; (5) economic costs and healthcare utilization; and (6) the rate of delayed or missed ACS. To capture these outcomes, we will administer patient and clinician surveys after each visit, obtain video recordings of the clinical encounters, and conduct 30-day phone follow-up. This pilot randomized trial will develop and evaluate a decision aid for use in ED chest pain patients at low risk for ACS and provide a preliminary estimate of its effect on patient participation in decision-making and resource use. Clinical Trials.gov Identifier: NCT01077037.


A STAT3-decoy oligonucleotide induces cell death in a human colorectal carcinoma cell line by blocking nuclear transfer of STAT3 and STAT3-bound NF-κB.
The transcription factor STAT3 (signal transducer and activator of transcription 3) is frequently activated in tumor cells. Activated STAT3 forms homodimers, or heterodimers with other TFs such as NF-κB, which becomes activated. Cytoplasmic STAT3 dimers are activated by tyrosine phosphorylation; they interact with importins via a nuclear localization signal (NLS) one of which is located within the DNA-binding domain formed by the dimer. In the nucleus, STAT3 regulates target gene expression by binding a consensus sequence within the promoter. STAT3-specific decoy oligonucleotides (STAT3-decoy ODN) that contain this consensus sequence inhibit the transcriptional activity of STAT3, leading to cell death; however, their mechanism of action is unclear. The mechanism of action of a STAT3-decoy ODN was analyzed in the colon carcinoma cell line SW 480. These cells' dependence on activated STAT3 was verified by showing that cell death is induced by STAT3-specific siRNAs or Stattic. STAT3-decoy ODN was shown to bind activated STAT3 within the cytoplasm, and to prevent its translocation to the nucleus, as well as that of STAT3-associated NF-κB, but it did not prevent the nuclear transfer of STAT3 with mutations in its DNA-binding domain. The complex formed by STAT3 and the STAT3-decoy ODN did not associate with importin, while STAT3 alone was found to co-immunoprecipitate with importin. Leptomycin B and vanadate both trap STAT3 in the nucleus. They were found here to oppose the cytoplasmic trapping of STAT3 by the STAT3-decoy ODN. Control decoys consisting of either a mutated STAT3-decoy ODN or a NF-κB-specific decoy ODN had no effect on STAT3 nuclear translocation. Finally, blockage of STAT3 nuclear transfer correlated with the induction of SW 480 cell death. The inhibition of STAT3 by a STAT3-decoy ODN, leading to cell death, involves the entrapment of activated STAT3 dimers in the cytoplasm. A mechanism is suggested whereby this entrapment is due to STAT3-decoy ODN's inhibition of active STAT3/importin interaction. These observations point to the high potential of STAT3-decoy ODN as a reagent and to STAT3 nucleo-cytoplasmic shuttling in tumor cells as a potential target for effective anti-cancer compounds.


The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression.
Biochanin A is an isoflavone isolated from red clover (Trifolium pratense), and is a commercially available nutraceutical for women suffering from postmenopausal symptoms. Isoflavones resemble the structure of oestrogen, and display agonistic and antagonistic interactions with the oestrogen receptor. Overexposure of oestrogen is a major contributing factor in the development of breast cancer, and cytochrome P450 (CYP) 19 enzyme, or aromatase, catalyses the reaction converting androgen to oestrogen. In the present study the effect of biochanin A on the gene regulation and enzyme activity of aromatase was investigated. By assaying MCF-7 cells stably transfected with CYP19, biochanin A inhibited aromatase activity and hampered cell growth attributing to the enzyme activity. In addition, 25 microm-biochanin A significantly reduced CYP19 mRNA abundance in the oestrogen receptor-negative breast cancer cells SK-BR-3. The transcriptional control of the CYP19 gene is exon-specific, and promoter regions I.3 and II have been shown to be responsible for CYP19 expression in SK-BR-3 cells. Luciferase reporter gene assays also revealed that biochanin A could repress the transcriptional control dictated by the promoter regulation. Interestingly, genistein did not inhibit aromatase but it might down regulate promoter I.3 and II transactivation. Since genistein is a major metabolite of biochanin A, it might contribute to biochanin A's suppressive effect on CYP19 expression. The present study illustrated that biochanin A inhibited CYP19 activity and gene expression.


Challenges to quality testing for bovine tuberculosis in Ireland; perspectives from major stakeholders.
Within the national bovine tuberculosis (bTB) eradication programme in Ireland, concern has been expressed about the quality of testing by veterinarians. However, there is little published evidence supporting this concern, or the challenges that undermine quality testing. Qualitative research methods were used to gather the perspectives of major stakeholders in the bTB eradication (BTE) scheme on the challenges to quality testing for bovine tuberculosis in Ireland. These stakeholders included private veterinarians, government veterinarians, senior managers and herd owners, on the quality of bTB testing and the barriers to improvement. Results are grouped into challenges that exist in the testing environment (ie, at a farm level), and challenges associated with the skills environment (ie, professional skills involved with conducting the test). Challenges in the testing environment include inadequate on-farm testing conditions; lack of clarity on responsibility to ensure adequate testing environment; and the influence of the veterinarian-client relationship. Challenges in the skills environment include deficiencies in the development and supervision of testing skills among trainees and newly qualified veterinarians; and deficiencies in testing standards at a practice level. Regular supervision of testing is necessary to ensure standards. The importance of a continued understanding of the disease (and its eradication) supported by a partnership, cooperative approach between all stakeholders, is emphasised.


Electron transfer in peptides.
In this review, we discuss the factors that influence electron transfer in peptides. We summarize experimental results from solution and surface studies and highlight the ongoing debate on the mechanistic aspects of this fundamental reaction. Here, we provide a balanced approach that remains unbiased and does not favor one mechanistic view over another. Support for a putative hopping mechanism in which an electron transfers in a stepwise manner is contrasted with experimental results that support electron tunneling or even some form of ballistic transfer or a pathway transfer for an electron between donor and acceptor sites. In some cases, experimental evidence suggests that a change in the electron transfer mechanism occurs as a result of donor-acceptor separation. However, this common understanding of the switch between tunneling and hopping as a function of chain length is not sufficient for explaining electron transfer in peptides. Apart from chain length, several other factors such as the extent of the secondary structure, backbone conformation, dipole orientation, the presence of special amino acids, hydrogen bonding, and the dynamic properties of a peptide also influence the rate and mode of electron transfer in peptides. Electron transfer plays a key role in physical, chemical and biological systems, so its control is a fundamental task in bioelectrochemical systems, the design of peptide based sensors and molecular junctions. Therefore, this topic is at the heart of a number of biological and technological processes and thus remains of vital interest.


Fractures, physical activity, and growth velocity in adolescent Belgian boys.
The relationship of fractures to physical activity and growth velocity in stature and metacarpal II bone dimensions was investigated in adolescent Belgian boys. Peak fracture incidence occurred between 12 and 14 yr of age and preceded the age at peak height velocity. The peak fracture rate occurred during mid adolescence (+/- 2 SD of the age at peak height velocity) and was twice as high as the rates before and after this period. The majority of fractures occurred during active participation in sports and general physical activities. The age at peak growth velocity for metacarpal cortical thickness, an indirect measure of bone mineral content, was about 6 months later than the ages at peak height velocity and peak growth velocity for metacarpal length. Peak fracture incidence occurred during a period when the amount of time spent in sports physical activity was low compared with later years. A lag in cortical bone thickness and mineralization, relative to linear skeletal growth, and unknown factors associated with active participation in sports, rather than an increase in the amount of physical activity, appear to be the predominant factors associated with the increased fracture incidence in Belgian boys during the growth spurt.


Clinical testing of the apnea prevention device: proof of concept data.
Narcotic-induced respiratory depression is a major cause of perioperative morbidity and mortality. Current monitoring modalities are inadequate to detect and treat respiratory depression in postoperative patients. Intermittent nursing assessments, even if conducted frequently, may not capture the rapid onset of airway obstruction, apnea, and hypoxia that can occur in many of these patients. Continuous nursing observation, as in an intensive care unit setting, is cost-prohibitive and impractical, given the large number of patients at risk. In an effort to address this problem, the author has created and tested the Apnea Prevention Device (APD), which is designed to detect the onset of hypoxia and instantly intervene to restore respiration and oxygen saturation in narcotized patients. The prototype APD used in this study consisted of a laptop computer running custom software, a pulse oximeter, and a nerve stimulator. Oxygen saturation data were acquired by the computer from the pulse oximeter, and stimuli to the patient were delivered either by headphones (verbal prompts) or a nerve stimulator (cutaneous). The APD program was written to analyze oximetry data and when indicated, deliver a series of stimuli of increasing intensity to arouse patients from narcosis. The device was tested on surgical patients in the postanesthesia care unit. An intervention delivered by the APD was scored as a success if the patient took a large tidal volume breath (as evidenced by chest rise) and there was a subsequent increase in oxygen saturation. The APD maintained a data log of oxygen saturations and interventions. In a subset of patients, it was possible to compare the functioning of the APD with routine nursing care. A total of 125 interventions were delivered by the APD to 10 patients with a 97% success rate. The depth of desaturations was less when the APD was in use than when patients received routine 1:1 nursing care. When the APD was functioning, the frequency with which nurses prompted the subjects to breathe was dramatically reduced. This study demonstrates that the prototype APD can successfully treat narcotic-induced respiratory depression in postoperative patients and does so in a manner that is superior to that provided by routine 1:1 nursing care. Such a device has the potential to decrease the morbidity associated with narcotic-induced respiratory depression in postoperative patients.


Molecular network analysis of endometriosis reveals a role for c-Jun-regulated macrophage activation.
Clinical management of endometriosis is limited by the complex relationship between symptom severity, heterogeneous surgical presentation, and variability in clinical outcomes. As a complement to visual classification schemes, molecular profiles of disease activity may improve risk stratification to better inform treatment decisions and identify new approaches to targeted treatment. We use a network analysis of information flow within and between inflammatory cells to discern consensus behaviors characterizing patient subpopulations. Unsupervised multivariate analysis of cytokine profiles quantified by multiplex immunoassays identified a subset of patients with a shared "consensus signature" of 13 elevated cytokines that was associated with common clinical features of endometriosis, but was not observed among patient subpopulations defined by morphologic presentation alone. Enrichment analysis of consensus markers reinforced the primacy of peritoneal macrophage infiltration and activation, which was demonstrably elevated in ex vivo cultures. Although familiar targets of the nuclear factor κB family emerged among overrepresented transcriptional binding sites for consensus markers, our analysis provides evidence for an unexpected contribution from c-Jun, c-Fos, and AP-1 effectors of mitogen-associated kinase signaling. Their crucial involvement in propagation of macrophage-driven inflammatory networks was confirmed via targeted inhibition of upstream kinases. Collectively, these analyses suggest a clinically relevant inflammatory network that may serve as an objective measure for guiding treatment decisions for endometriosis management, and in the future may provide a mechanistic endpoint for assessing efficacy of new agents aimed at curtailing inflammatory mechanisms that drive disease progression.


The Site of Action of DDT in the Cockroach.
(1) Although DDT undoubtedly affects motor nerves and muscle fibers in concentrations greater than 1,000 ppm, this action cannot be directly responsible for the clonic tremors in the DDT-poisoned cockroach which can be produced by internal concentrations of the order of 5 ppm. (2) DDT has no significant action on the cockroach central nervous system. (3) DDT emulsion perfused through the leg of the cockroach in concentrations as low as 0.01 ppm causes the appearance of a series of high frequency trains of axon spikes in the afferent fibers. (4) It is concluded that the tremors characteristic of DDT poisoning are due to an intense afferent bombardment of the motor neurons.


Colletotrichum trifolii mutants disrupted in the catalytic subunit of cAMP-dependent protein kinase are nonpathogenic.
Colletotrichum trifolii is the fungal pathogen of alfalfa that causes anthracnose disease. For successful plant infection, this fungus must undergo a series of morphological transitions following conidial attachment, including germination and subsequent differentiation, resulting in appressorium formation. Our previous studies with pharmacological effectors of signaling pathways have suggested the involvement of cyclic AMP (cAMP)-dependent protein kinase (PKA) during these processes. To more precisely evaluate the role of PKA in C. trifolii morphogenesis, the gene encoding the catalytic (C) subunit of PKA (Ct-PKAC) was isolated, sequenced, and inactivated by gene replacement. Southern blot analysis with C. trifolii genomic DNA suggested that Ct-PKAC is a single-copy gene. Northern (RNA) blot analysis with total RNA from different fungal growth stages indicated that the expression of this gene was developmentally regulated. When Ct-PKAC was insertionally inactivated by gene replacement, the transformants showed a small reduction in growth relative to the wild type and conidiation patterns were altered. Importantly, PKA-deficient strains were unable to infect intact alfalfa (host) plants, though only a slight delay was observed in the timing for conidial germination and appressorial formation in the Ct-PKAC disruption mutants. Moreover, these mutants were able to colonize host tissues following artificial wounding, resulting in typical anthracnose disease lesions. Coupled with microscopy, these data suggest that the defect in pathogenicity is likely due to a failure in penetration. Our results demonstrate that PKA has an important role in regulating the transition between vegetative growth and conidiation, and is essential for pathogenic development in C. trifolii.


Can neutrophil/lymphocyte ratio predict recurrence of non-valvular atrial fibrillation after cardioversion?
High neutrophil/lymphocyte ratio (NLR) has been associated with post-operative AF development in patients who underwent cardiac surgery. In this study, effectiveness of NLR for prediction of recurrence after electrical cardioversion (CV) in non-valvular AF was investigated. A total of 149 patients who underwent a successful CV were included in this prospective cohort study. Baseline complete blood cell count, routine biochemical tests, high sensitive C-reactive protein (hs-CRP), and echocardiographic measurements were examined. After CV, patients were monitored over six months for recurrence. Baseline characteristics of recurrence group were compared with sinus rhythm group by using Student`s t -test. Logistic regression analysis was used to determine predictors of recurrence. Recurrence occurred in a total of 46 patients (30.9%). Median AF duration [16 (IQR:14.25) vs. 12 (IQR:11) months, p=0.01], baseline hs-CRP [9.80 (IQR: 8.50) mg/dL vs. 4.28 (IQR: 5.65) mg/dL, p=0.002] and left atrium (LA) diameter (4.5±0.4 cm, 4.3±0.5 cm, p=0.023) were significantly higher in the recurrence group than sinus rhythm group. Median NLR was comparable in recurrence and sinus groups [2.38 (IQR: 2.09) vs. 2.23, (IQR: 1.23) p=0.96, respectively]. There was a weak correlation between NLR and hs-CRP (r=0.22, p=0.05) and age (r=0.24, p=0.02). In multiple logistic regression analysis, hs-CRP [OR: 1.34 (1.09-1.65 95% CI) p=0.006], LA diameter [OR: 11.92 (1.84-77.07 95% CI) p=0.01], spontaneous echo contrast positivity, [OR: 5.40 (1.04-12.02 95% CI) p=0.045] and systolic blood pressure [OR: 1.05 (1.01-1.10 95% CI) p=0.03] were independent predictors of AF recurrence. NLR failed to predict AF recurrence after a successful electrical CV, but hs-CRP remained an inflammatory marker of AF recurrence.


Validation of a novel technique for creating simulated radiographs using computed tomography datasets.
Understanding radiographic anatomy and the effects of varying patient and radiographic tube positioning on image quality can be a challenge for students. The purposes of this study were to develop and validate a novel technique for creating simulated radiographs using computed tomography (CT) datasets. A DICOM viewer (ORS Visual) plug-in was developed with the ability to move and deform cuboidal volumetric CT datasets, and to produce images simulating the effects of tube-patient-detector distance and angulation. Computed tomographic datasets were acquired from two dogs, one cat, and one horse. Simulated radiographs of different body parts (n = 9) were produced using different angles to mimic conventional projections, before actual digital radiographs were obtained using the same projections. These studies (n = 18) were then submitted to 10 board-certified radiologists who were asked to score visualization of anatomical landmarks, depiction of patient positioning, realism of distortion/magnification, and image quality. No significant differences between simulated and actual radiographs were found for anatomic structure visualization and patient positioning in the majority of body parts. For the assessment of radiographic realism, no significant differences were found between simulated and digital radiographs for canine pelvis, equine tarsus, and feline abdomen body parts. Overall, image quality and contrast resolution of simulated radiographs were considered satisfactory. Findings from the current study indicated that radiographs simulated using this new technique are comparable to actual digital radiographs. Further studies are needed to apply this technique in developing interactive tools for teaching radiographic anatomy and the effects of varying patient and tube positioning.


Aniline/alpha-cyano-4-hydroxycinnamic acid is a highly versatile ionic liquid for matrix-assisted laser desorption/ionization mass spectrometry.
The performance of a matrix-assisted laser desorption/ionization (MALDI) ionic liquid matrix (ILM) consisting of alpha-cyano-4-hydroxycinnamic acid (CHCA) and aniline (ANI) was evaluated to assess whether it could offer possible advantages over conventional matrices. Ultraviolet (UV), Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) and laser desorption/ionization mass spectrometry (LDI-MS) experiments were carried out with the aim of confirming the structure of the ANI-CHCA ILM. Different model analytes such as amino acids, peptides, proteins, lipids, phospholipids, synthetic polymers, and sugars were tested. Mass spectra with similar or improved signal-to-noise (S/N) ratio (compared to CHCA) were invariably obtained demonstrating the potential of this ILM as a general purpose matrix. Furthermore, protein identification by peptide mass fingerprinting (PMF) and database search was facilitated compared to CHCA since higher scores and increased sequence coverage were observed. Finally, a complex lipid mixture (i.e. a raw extract of a milk sample) analysed by MALDI-MS showed improved S/N ratio, a reduced chemical noise and a limited formation of matrix-clusters.


Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier.
We attempted to assess regional differences in cerebral P-glycoprotein (P-gp) function by performing paired positron emission tomography (PET) scans with the P-gp substrate (R)-[(11)C]verapamil in five healthy subjects before and after i.v. infusion of tariquidar (2 mg/kg). Comparison of tariquidar-induced changes in distribution volumes (DVs) in 42 brain regions of interest (ROIs) failed to detect significant differences among brain ROIs. Statistical parametric mapping analysis of parametric DV images visualized symmetrical bilateral clusters with moderately higher DV increases in response to tariquidar administration in cerebellum, parahippocampal gyrus, olfactory gyrus, and middle temporal lobe and cortex, which might reflect moderately decreased P-gp function and expression.


Menstrual Problems and Lifestyle among Spanish University Women.
Menstrual problems affect many young women worldwide, conditioning both their academic performance and quality of life. This study sought to analyse the prevalence of menstrual problems and their possible relationship with lifestyle among Spanish university women, as part of a research project (UniHcos Project) involving a cohort of 11 Spanish universities with 7208 university students. A descriptive analysis was performed using the bivariate chi-square test and the Student's t-test together with a binary logistic regression, in which the dependent variable was 'suffering from menstrual problems'. Menstrual problems were identified in 23.8% of the students, representing women who paid more visits to the doctor and to emergency rooms, and who consumed more painkillers and contraceptives. In relation to dietary preferences, menstrual problems were 1.39 (CI 95% 1.22-1.61; p = 0.000) times more likely among women classified as high-risk alcohol users according to the AUDIT questionnaire, and 1.187 (CI 95% 1.029-1.370; p = 0.019) times greater among those who consumed sweets daily, 1.592 (CI 95% 1.113-2.276; p = 0.011) times more frequent among those who eat fish daily, and 1.199 (CI 95% 1.004-1.432; p = 0.045) times greater among those who were dieting. Menstrual problems affect many college students and potentially modifiable lifestyle variables exist which may influence their prevalence. It would be interesting to develop programmes to promote women's health in the university context.


Pediatric meningitis in the Western Cape Province of South Africa.
During the 9 years 1985-1993 a prospective survey of all cases of meningitis in children < 13 years of age presenting to our hospital in the Western Cape Province of South Africa was carried out. Two-thousand-nine-hundred-and-twenty cases of meningitis were identified. The commonest form of bacterial meningitis was tuberculous meningitis (TBM) diagnosed in 282 children (mean age 2.94 years). N. meningitidis identified in 220 children (mean age 2.87 years), Haemophilus influenzae in 156 children (mean age 1.15 years) and S. pneumoniae in 106 children (mean age 2.14) were the next commonest causes of bacterial meningitis diagnosed. One-hundred-and-eighteen cases of bacterial meningitis were confirmed in infants < 1 month of age and the commonest bacteria identified were group B beta-haemolytic Streptococcus in 27, E. coli in 21, Klebsiella species in 11, and Candida species in 15 neonates. The emergence of TBM as the predominant cause of bacterial meningitis in childhood at our hospital is probably a reflection of the worsening tuberculosis situation in the Western Cape Province of South Africa.


Safety evaluation of the food enzyme with β-glucanase and β-xylanase activities from the Trichoderma reesei strain DP-Nya67.
The food enzyme with β-glucanase and β-xylanase (4-β-d-xylan xylanohydrolase, EC 220.127.116.11) activities is produced with the non-genetically modified Trichoderma reesei (strain DP-Nya67) by DuPont. The food enzyme is intended to be used in brewing processes, grain treatment for the production of starch and gluten fractions, and distilled alcohol production. Since residual amounts of the food enzyme are removed by distillation and during grain treatment, dietary exposure was only calculated for brewing processes. Based on the maximum recommended use levels for brewing processes, dietary exposure to the food enzyme-Total Organic Solids (TOS) was estimated to be up to 4.585 mg TOS/kg body weight (bw) per day. Since the compositional data provided was insufficient to characterise the food enzyme batches used for toxicological testing, their suitability for use in the toxicological tests could not be established. As result, the toxicological studies provided were not further considered by the Panel. Similarities of the amino acid sequences to those of known allergens were searched and no matches were found. The Panel considered that, under the intended conditions of use, the risk of allergic sensitisation and elicitation reactions by dietary exposure cannot be excluded, but the likelihood to occur is considered to be low. In the absence of compositional data sufficient to characterise the food enzyme batches used for toxicological testing, the Panel is unable to complete its assessment of the safety of the food enzyme.


The impact of child maltreatment and intimate partner violence surveillance initiatives.
Child maltreatment (CM) and intimate partner violence (IPV) take a tremendous toll on communities around the world. Despite the impact of CM and IPV, data on their incidence are drawn from disparate sources of varying quality. To improve data resources in these areas, the Centers for Disease Control and Prevention's (CDC) Division of Violence Prevention funded state-based IPV and CM surveillance activities in nine states between 1994 and 2005. This article describes reported outcomes of these surveillance programmes; assesses factors affecting their sustainability; and provides recommendations for similar programmes through document review and interviews with state representatives. Findings indicate that states achieved outcomes with these surveillance initiatives; however, states noted concerns with sustaining systems because of a lack of resources and ineffective collaborations. Highlighted in this article are several lessons that other countries can learn from the experiences of these states in testing CM and IPV surveillance systems.


Avoiding counterproductive results: an experimental pretest of a harm reduction intervention on attitude toward party drugs among users and nonusers.
In two experimental studies, the authors tested written health education materials on the personal acceptance of party drug use. Following a harm reduction strategy, the materials provided information on minimizing potential hazards associated with drug use. Among users and nonusers, potential aversive effects of these materials were examined on measures of attitude, intention, and outcome expectancy toward party drug use. Participants were recruited in the city center of Maastricht, The Netherlands, in nightlife settings that were popular among young people. In the first experiment, a leaflet on ecstasy use was evaluated among ecstasy users and nonusers. Results showed neither health promoting effects, nor counterproductive results on the outcome measures. In the second experiment, the effects of two different formats (leaflet vs. infocard) about two different kinds of party drugs (ecstasy vs. GHB) were compared within a nonusing population. Again, results showed no positive changes on the outcome measures toward ecstasy use as a result of exposure to the ecstasy materials. However, exposure to the GHB materials resulted into a more negative attitude toward GHB use (leaflet and infocard) and lower estimates of the likelihood of positive outcomes of use (infocard). The study's limitations and implications are discussed, including the need for experimental pretesting.


Statistical methods in recent HIV noninferiority trials: reanalysis of 11 trials.
In recent years the "noninferiority" trial has emerged as the new standard design for HIV drug development among antiretroviral patients often with a primary endpoint based on the difference in success rates between the two treatment groups. Different statistical methods have been introduced to provide confidence intervals for that difference. The main objective is to investigate whether the choice of the statistical method changes the conclusion of the trials. We presented 11 trials published in 2010 using a difference in proportions as the primary endpoint. In these trials, 5 different statistical methods have been used to estimate such confidence intervals. The five methods are described and applied to data from the 11 trials. The noninferiority of the new treatment is not demonstrated if the prespecified noninferiority margin it includes in the confidence interval of the treatment difference. Results indicated that confidence intervals can be quite different according to the method used. In many situations, however, conclusions of the trials are not altered because point estimates of the treatment difference were too far from the prespecified noninferiority margins. Nevertheless, in few trials the use of different statistical methods led to different conclusions. In particular the use of "exact" methods can be very confusing. Statistical methods used to estimate confidence intervals in noninferiority trials have a strong impact on the conclusion of such trials.


Ultrafast mid-infrared response of YBa(2)Cu(3)O(7-delta)
Optical spectra of high-transition-temperature superconductors in the mid-infrared display a gap of in-plane conductivity whose role for superconductivity remains unresolved. Femtosecond measurements of the mid-infrared reflectivity of YBa(2)Cu(3)O(7-delta) after nonequilibrium optical excitation are used to demonstrate the ultrafast fill-in of this gap and reveal two gap constituents: a picosecond recovery of the superconducting condensate in underdoped and optimally doped material and, in underdoped YBa(2)Cu(3)O(7-delta), an additional subpicosecond component related to pseudogap correlations. The temperature-dependent amplitudes of both contributions correlate with the antiferromagnetic 41-millielectronvolt peak in neutron scattering, supporting the coupling between charges and spin excitations.


The role of CSM3, MRC1, and TOF1 in minisatellite stability and large loop DNA repair during meiosis in yeast.
Double-stranded break (DSB) repair during meiotic recombination in yeast Saccharomyces cerevisiae leads to the formation of heteroduplex DNA, a hybrid DNA molecule composed of single strands from two homologous chromosomes. Differences in sequence between the strands within heteroduplex DNA generate mismatches or large unpaired loops that are substrates for repair. At least two pathways function to repair large loops that form within heteroduplex DNA: the RAD1-dependent large loop repair (LLR) pathway and another as yet uncharacterized RAD1-independent LLR pathway. Repair of large loops during meiotic recombination is especially important for the genomic stability of the repetitive DNA sequences known as minisatellites. Minisatellite DNA tracts are generally stable during mitotic cell divisions but frequently alter in length during meiosis. Using a yeast minisatellite system in which the human minisatellite associated with the HRAS1 proto-oncogene has been inserted into the recombination hotspot region upstream of HIS4 in S. cerevisiae, our lab previously showed that the RAD1-dependent LLR pathway controls minisatellite length expansions, but not contractions. Here we show that minisatellite length expansions are controlled by the products of the CSM3 and TOF1 genes, while contractions are controlled by MRC1. By examining meiotic segregation patterns in yeast strains heterozygous for the 26bp his4-lopd insert, we found that deleting CSM3 caused a loss of LLR activity similar to that seen in a RAD1 mutant. Double mutant analysis revealed that failure to repair loops is exacerbated upon deleting both RAD1 and CSM3 - specifically the type of repair that fills in loops, which would generate minisatellite length expansions. A model for minisatellite length alteration based on these results is presented.


Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial.
To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.


Recent studies on the reproductive biology of the schistosomes and their relevance to speciation in the Digenea.
The members of the family Schistosomatidae, dioecious Digenea, are discussed with regard to their distribution, intermediate and definitive host-parasite relationships. The biological species concept is considered together with the difficulties of its application to Schistosoma spp. and the Digenea. The correlation between pairing of adult schistosomes, physical and sexual development and the maintenance of reproductive potential is emphasised. Development of the female reproductive system does not depend upon species-specific pairing. In some combinations, e.g., Schistosoma haematobium/Schistosoma intercalatum and Schistosoma bovis/Schistosoma curassoni, a specific mate choice system apparently does not exist, whereas it does in other combinations, e.g., Schistosoma mansoni/Schistosoma intercalatum. In mixed infections change of mate may occur and when the opportunity arises heterospecific pairs of worms will change partners to conspecific pairs. Interspecific pairing in adult schistosomes will lead to either hybridisation or parthenogenesis. Yet the majority of schistosomes that inhabit the same definitive host maintain their genetic identity: specific mate recognition, site selection within the host and heterologous immunity have been suggested as isolating mechanisms. Experimental intraspecific crosses have enabled evaluation of the degree to which some populations separated and became reproductively isolated through pre-mating isolating mechanisms, indicative of incipient speciation, e.g., the Lower Guinea and Zaire strains of S. intercalatum. The occurrence and significance of parthenogenesis in schistosomes and other species of Digenea are discussed. The consequences of interspecific mating interactions in schistosomes with regard to parasite epidemiology, interspecific competition and genetic heterogeneity are debated. Geographical isolation and host specificity represent important pre-zygotic isolating mechanisms. It is suggested that site selection within the host and heterologous immunity may both reduce interspecific genetic interchange when digenean parasites utilise the same definitive host.


Mud compress therapy for the hands of patients with rheumatoid arthritis.
The aim of this study was to evaluate the efficacy of home treatment with mud compresses for the hands of patients with rheumatoid arthritis (RA). Forty-five patients suffering from RA were enrolled in a double-blind, randomized, controlled study. Twenty-two were treated with true mud compresses (treatment group) and 23 were treated with attenuated mud compresses (control group). The compresses were applied in the patients' homes five times a week during a 3-week period. Patients were assessed four times: at baseline, upon completion of the 3-week treatment period, 1 month after the treatment, and 3 months after conclusion of the treatment period. Positive response was defined as reductions of 30% or more in the number of tender and swollen joints, 20% or more in physician global assessment of disease activity, and 20% or more in patient global assessment of the severity of joint pain. In the treatment group, significant reductions in the number of swollen and tender joints and patients' global assessments of pain severity was observed at all post-treatment assessments. Significant improvement in the scores of physician global assessment was seen at the end of therapy and 1 month later. In the control group, no improvement in the number of swollen and tender joints or physician global assessment was found in any post-treatment evaluation. However, a significant reduction in patient global assessment of joint pain severity was reported at the end of therapy and 3 months after concluding treatment. Treatment with mud compresses relieves pain affecting the hands and reduces the number of swollen and tender joints in the hands of patients suffering from RA. This treatment can augment conventional medical therapy in these patients.


Human Platelet Lysate versus Fetal Calf Serum: These Supplements Do Not Select for Different Mesenchymal Stromal Cells.
Culture medium of mesenchymal stromal cells (MSCs) is usually supplemented with either human platelet lysate (HPL) or fetal calf serum (FCS). Many studies have demonstrated that proliferation and cellular morphology are affected by these supplements - it is therefore important to determine if they favor outgrowth of different subpopulations and thereby impact on the heterogeneous composition of MSCs. We have isolated and expanded human bone marrow-derived MSCs in parallel with HPL or FCS and demonstrated that HPL significantly increases proliferation and leads to dramatic differences in cellular morphology. Remarkably, global DNA-methylation profiles did not reveal any significant differences. Even at the transcriptomic level, there were only moderate changes in pairwise comparison. Furthermore, the effects on proliferation, cytoskeletal organization, and focal adhesions were reversible by interchanging to opposite culture conditions. These results indicate that cultivation of MSCs with HPL or FCS has no systematic bias for specific cell types.


Identification and properties of 1,119 candidate lincRNA loci in the Drosophila melanogaster genome.
The functional repertoire of long intergenic noncoding RNA (lincRNA) molecules has begun to be elucidated in mammals. Determining the biological relevance and potential gene regulatory mechanisms of these enigmatic molecules would be expedited in a more tractable model organism, such as Drosophila melanogaster. To this end, we defined a set of 1,119 putative lincRNA genes in D. melanogaster using modENCODE whole transcriptome (RNA-seq) data. A large majority (1.1 of 1.3 Mb; 85%) of these bases were not previously reported by modENCODE as being transcribed. Significant selective constraint on the sequences of these loci predicts that virtually all have sustained functionality across the Drosophila clade. We observe biases in lincRNA genomic locations and expression profiles that are consistent with some of these lincRNAs being involved in the regulation of neighboring protein-coding genes with developmental functions. We identify lincRNAs that may be important in the developing nervous system and in male-specific organs, such as the testes. LincRNA loci were also identified whose positions, relative to nearby protein-coding loci, are equivalent between D. melanogaster and mouse. This study predicts that the genomes of not only vertebrates, such as mammals, but also an invertebrate (fruit fly) harbor large numbers of lincRNA loci. Our findings now permit exploitation of Drosophila genetics for the investigation of lincRNA mechanisms, including lincRNAs with potential functional analogues in mammals.


A comparison of the efficacy of doramectin, closantel and levamisole in the treatment of the 'oriental eye fluke', Philophthalmus gralli, in commercially reared ostriches (Struthio camelus).
Commercially reared ostriches at Msengi farm situated in the Chinhoyi area of Mashonaland West province in Zimbabwe were found to be infected with the 'oriental eye fluke', Philopthalmus gralli, in 2001. This was the ist record of the fluke in Zimbabwe. Trials were conducted to identify a suitable drug for the treatment of this fluke. A total of 12 ostriches confirmed to be infected with the fluke through clinical examination of the eyes and identification of the fluke were randomly divided into 3 equal groups, with each group receiving a different treatment protocol. The 3 drugs used were doramectin, levamisole and closantel. Each of the drugs was used in combination with chloramphenicol as an eye ointment. Levamisole was administered topically into the eye whereas doramectin and closantel were administered parenterally as an intramuscular injection. The results indicated a positive response in levamisole-treated birds but there were no noticeable responses to doramectin and closantel treatments.


Information Exchange Design Patterns for Robot Swarm Foraging and Their Application in Robot Control Algorithms.
In swarm robotics, a design pattern provides high-level guidelines for the implementation of a particular robot behaviour and describes its impact on swarm performance. In this paper, we explore information exchange design patterns for robot swarm foraging. First, a method for the specification of design patterns for robot swarms is proposed that builds on previous work in this field and emphasises modular behaviour design, as well as information-centric micro-macro link analysis. Next, design pattern application rules that can facilitate the pattern usage in robot control algorithms are given. A catalogue of six design patterns is then presented. The patterns are derived from an extensive list of experiments reported in the swarm robotics literature, demonstrating the capability of the proposed method to identify distinguishing features of robot behaviour and their impact on swarm performance in a wide range of swarm implementations and experimental scenarios. Each pattern features a detailed description of robot behaviour and its associated parameters, facilitated by the usage of a multi-agent modeling language, BDRML, and an account of feedback loops and forces that affect the pattern's applicability. Scenarios in which the pattern has been used are described. The consequences of each design pattern on overall swarm performance are characterised within the Information-Cost-Reward framework, that makes it possible to formally relate the way in which robots acquire, share and utilise information. Finally, the patterns are validated by demonstrating how they improved the performance of foraging e-puck swarms and how they could guide algorithm design in other scenarios.


A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer.
Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile. To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases. In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n=41), 50 kBq/kg (n=39), or 80 kBq/kg (n=42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥ 50% in baseline prostate-specific antigen (PSA) levels. Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups. The study met its primary end point with a statistically significant dose-response relationship in confirmed ≥ 50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p=0.0297). A ≥ 50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p<0.0001). The most common treatment-related AEs (≥ 10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline. Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses. ClinicalTrials.gov: NCT00337155.


Vinobot and Vinoculer: Two Robotic Platforms for High-Throughput Field Phenotyping.
In this paper, a new robotic architecture for plant phenotyping is being introduced. The architecture consists of two robotic platforms: an autonomous ground vehicle (Vinobot) and a mobile observation tower (Vinoculer). The ground vehicle collects data from individual plants, while the observation tower oversees an entire field, identifying specific plants for further inspection by the Vinobot. The advantage of this architecture is threefold: first, it allows the system to inspect large areas of a field at any time, during the day and night, while identifying specific regions affected by biotic and/or abiotic stresses; second, it provides high-throughput plant phenotyping in the field by either comprehensive or selective acquisition of accurate and detailed data from groups or individual plants; and third, it eliminates the need for expensive and cumbersome aerial vehicles or similarly expensive and confined field platforms. As the preliminary results from our algorithms for data collection and 3D image processing, as well as the data analysis and comparison with phenotype data collected by hand demonstrate, the proposed architecture is cost effective, reliable, versatile, and extendable.