Small bowel imaging in Crohn's disease patients.
Crohn's disease (CD) is a lifelong, chronic inflammatory bowel disorder. The small bowel (SB) is involved to varying extents, and the clinical course may vary from an inflammatory type to a more complicated one with stricture, fistula, and abscess formation. Esophagogastroduodenoscopy and ileocolonoscopy with biopsies are the conventional endoscopic techniques that usually establish the diagnosis. On the other hand, CD may affect SB segments that cannot be reached through these procedures. Video capsule endoscopy and enteroscopy are additional endoscopic techniques that may allow further SB evaluation in such circumstances. Computed tomographic enterography, magnetic resonance enterography, and ultrasonography are radiologic techniques that serve as a crucial adjunct to endoscopic assessment. They enable the assessment of parts of the bowel that may be difficult to reach with conventional endoscopy; this allows for the detection of active inflammation, penetrating or stricturing disease, and the appreciation of extraintestinal complications. Both endoscopic and radiologic modalities play a role in establishing the diagnosis of CD, as well as determining the disease extent, activity and response to therapy. This review is intended to evaluate these modalities in terms of specificity, sensitivity, potential side-effects, and limiting factors. This should serve as a guide to the clinician for establishing the most appropriate and reliable test within a particular clinical context.


Environmental applications of graphene-based nanomaterials.
Graphene-based materials are gaining heightened attention as novel materials for environmental applications. The unique physicochemical properties of graphene, notably its exceptionally high surface area, electron mobility, thermal conductivity, and mechanical strength, can lead to novel or improved technologies to address the pressing global environmental challenges. This critical review assesses the recent developments in the use of graphene-based materials as sorbent or photocatalytic materials for environmental decontamination, as building blocks for next generation water treatment and desalination membranes, and as electrode materials for contaminant monitoring or removal. The most promising areas of research are highlighted, with a discussion of the main challenges that we need to overcome in order to fully realize the exceptional properties of graphene in environmental applications.


Does probability guided hysteroscopy reduce costs in women investigated for postmenopausal bleeding?
To evaluate whether a model to predict a failed endometrial biopsy in women with postmenopausal bleeding (PMB) and a thickened endometrium can reduce costs without compromising diagnostic accuracy. Model based cost-minimization analysis. A decision analytic model was designed to compare two diagnostic strategies for women with PMB: (I) attempting office endometrial biopsy and performing outpatient hysteroscopy after failed biopsy and (II) predicted probability of a failed endometrial biopsy based on patient characteristics to guide the decision for endometrial biopsy or immediate hysteroscopy. Robustness of assumptions regarding costs was evaluated in sensitivity analyses. Costs for the different strategies. At different cut-offs for the predicted probability of failure of an endometrial biopsy, strategy I was generally less expensive than strategy II. The costs for strategy I were always € 460; the costs for strategy II varied between € 457 and € 475. At a 65% cut-off, a possible saving of € 3 per woman could be achieved. Individualizing the decision to perform an endometrial biopsy or immediate hysteroscopy in women presenting with postmenopausal bleeding based on patient characteristics does not increase the efficiency of the diagnostic work-up.


Social and Non-social Mechanisms of Inequity Aversion in Non-human Animals.
Research over the last decades has shown that humans and other animals reveal behavioral and emotional responses to unequal reward distributions between themselves and other conspecifics. However, cross-species findings about the mechanisms underlying such inequity aversion are heterogeneous, and there is an ongoing discussion if inequity aversion represents a truly social phenomenon or if it is driven by non-social aspects of the task. There is not even general consensus whether inequity aversion exists in non-human animals at all. In this review article, we discuss variables that were found to affect inequity averse behavior in animals and examine mechanistic and evolutionary theories of inequity aversion. We review a range of moderator variables and focus especially on the comparison of social vs. non-social explanations of inequity aversion. Particular emphasis is placed on the importance of considering the experimental design when interpreting behavior in inequity aversion tasks: the tasks used to probe inequity aversion are often based on impunity-game-like designs in which animals are faced with unfair reward distributions, and they can choose to accept the unfair offer, or reject it, leaving them with no reward. We compare inequity-averse behavior in such impunity-game-like designs with behavior in less common choice-based designs in which animals actively choose between fair and unfair rewards distributions. This review concludes with a discussion of the different mechanistic explanations of inequity aversion, especially in light of the particular features of the different task designs, and we give suggestions on experimental requirements to understand the "true nature" of inequity aversion.


Risk factors for sexually transmitted infections among young adolescents.
Significant numbers of adolescents are initiating sexual activity at age 17 and younger. Little is known about this younger population of adolescents. This includes risk or protective factors for sexual activity and sexually transmitted infection (STI) acquisition. To safeguard all adolescents from the consequences of risky sexual behaviors, and to insure age appropriate and effective interventions, further study is critical to address risky behaviors specific to early adolescents. This study was a retrospective chart review of 155 sexually active adolescent girls. Students were divided into those who never had a documented STI and those who had 1 or more STIs. Data were collected from a sexual history questionnaire. These data were grouped into risk or protective domains. Domains were made up of 5 items of protective factors, 3 items of peer risks, 2 items of family risks, and 7 items of individual risks. STI outcomes were compared to these characteristics. One hundred fifty-five sexually active adolescents were studied. A univariate and multivariate analysis of risk and protective factors for testing positive for an STI demonstrated that high levels of protective factors reduced the risk of STIs. This suggests that STI prevention programs should focus on increasing protective factors among young adolescents in addition to reducing risk factors.


The safety of digital mobile cellular telephones with minute ventilation rate adaptive pacemakers.
In vitro tests suggest that rate adaptive pacemakers using changes in transthoracic impedance to vary pacing rate may be affected by digital mobile telephones. Electromagnetic fields generated by digital mobile telephones (Global System for Mobile [GSM]) represent a potential source of electromagnetic interference (EMI) for the Telectronics META rate adaptive pacemakers, which use transthoracic impedance as a sensor to determine changes in minute ventilation. Sixteen implanted Telectronics META pulse generators were exposed to 25-W simulated GSM transmissions (900-MHz carrier pulsed at 2, 8, and 217 Hz with a pulse width of 0.6 ms) and the antenna of a 2-W digital mobile telephone (900-MHz, 217-Hz pulse, 0.6-ms pulse width). The 12 dual and four single chamber devices were programmed to maximum sensitivity and assessed in unipolar and bipolar settings and rate adaptive and nonrate adaptive modes. In all cases of EMI, testing was repeated at lower, more routinely set bipolar sensitivity levels. At maximum sensitivity, 11 of 16 devices displayed no evidence of EMI. Brief ventricular triggering occurred in 2, a brief pause in 1, a combination of both in 1, and a brief episode of pacemaker-mediated tachycardia in 1. With pulse generators programmed to more routine sensitivities, only one device displayed rare single beat ventricular triggering. No changes in minute ventilation rate adaptive pacing were observed. At maximum unipolar sensitivities, the META series of rate adaptive pacemakers are resistant to clinically important EMI from digital mobile telephones. Set at routine sensitivities, these devices perform reliably in the presence of digital mobile telephones.


Nutritional Genomics and the Mediterranean Diet's Effects on Human Cardiovascular Health.
The synergies and cumulative effects among different foods and nutrients are what produce the benefits of a healthy dietary pattern. Diets and dietary patterns are a major environmental factor that we are exposed to several times a day. People can learn how to control this behavior in order to promote healthy living and aging, and to prevent diet-related diseases. To date, the traditional Mediterranean diet has been the only well-studied pattern. Stroke incidence, a number of classical risk factors including lipid profile and glycaemia, emergent risk factors such as the length of telomeres, and emotional eating behavior can be affected by genetic predisposition. Adherence to the Mediterranean diet could exert beneficial effects on these risk factors. Our individual genetic make-up should be taken into account to better prevent these traits and their subsequent consequences in cardiovascular disease development. In the present work, we review the results of nutritional genomics explaining the role of the Mediterranean diet in human cardiovascular disease. A multidisciplinary approach is necessary to extract knowledge from large-scale data.


Comparison of the pharmacokinetic and pharmacodynamic properties of two recombinant granulocyte colony-stimulating factor formulations after single subcutaneous administration to healthy volunteers.
The aim of this randomized, single dose, two-period crossover study with two weeks wash-out period was the demonstration of bioequivalence of two recombinant human granulocyte colony-stimulating factor (rG-CSF) formulations after subcutaneous administration of 300μg comparing their pharmacokinetic (primary endpoints AUC0-24, AUC0-∞ and Cmax) and pharmacodynamic (primary endpoints ANC AUC0-72, ANC AUC0-∞ and ANCmax) profiles in healthy male subjects. A total of 36 (23.0±6.0 years, 76.6±7.2kg) healthy subjects were recruited. Using a 1:1 randomization ratio, subjects were randomly assigned to one of two possible treatment-sequence groups to receive the single dose of test formulation (Gp-02) and reference product (Neupogen™) concentrations were measured by enzyme-linked immunosorbent assay (ELISA) up to 24h and the Absolute Neutrophil Count (ANC) was determined using hematology analyzer Coulter STKS™ (Beckman Coulter) up to 72h after injection. The geometric mean of primary pharmacokinetic and pharmacodynamic variables were considered bioequivalent if the 90% confidence intervals (CI) would fall in the bioequivalence range of 80%-125%. AUC0-24 (ratio of means 103.4, 90% CI: 95.6-111.9), AUC0-∞ (103.4, 90% CI: 95.7-111.7), Cmax (99.6, 90% CI: 89.0-111.4), ANC AUC0-72 (100.0, 90% CI: 96.6-103.5), ANC AUC0-∞ (100.8, 90% CI: 96.5-105.3), and ANCmax (100.2, 90% CI: 95.4-105.1) were determined. Single doses of test and reference formulations were well tolerated. The incidence of AEs was equally distributed across treatment groups with the most frequent AEs being headache, fever, and back pain. The study results demonstrated the bioequivalence of Gp-02, a new formulation of filgrastim, and the reference product Neupogen™.


Synergistic interactions between Drosophila orthologues of genes spanned by de novo human CNVs support multiple-hit models of autism.
Autism spectrum disorders (ASDs) are highly heritable and characterised by deficits in social interaction and communication, as well as restricted and repetitive behaviours. Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). These CNVs were found in the genomes of individuals with autism, including a patient carrying a 22q11.2 deletion. We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD-associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. For three of four CNVs with complete orthologous relationships, we observed significant synergistic effects following the simultaneous dosage change of gene pairs drawn from a single CNV. The phenotypic variation observed at the Drosophila synapse that results from these interacting genetic variants supports a concordant phenotypic outcome across all interacting gene pairs following the direction of human gene copy number change. We observe both specificity and transitivity between interactors, both within and between CNV candidate gene sets, supporting shared and distinct genetic aetiologies. We then show that different interactions affect divergent synaptic processes, demonstrating distinct molecular aetiologies. Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease.


[New insights into the pathogenesis of pre-eclampsia: the role of angiogenesis-inhibiting factors].
The pathogenesis of pre-eclampsia is biphasic. The first phase is characterised by insufficient placentation and the second phase by an increased placental release of 2 anti-angiogenic factors, namely, soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng). Within maternal circulation, sFlt-1 and sEng inhibit the effects of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGFβ). This results in endothelial cell activation and inflammation, and eventually leads to the clinical syndrome of pre-eclampsia. The rise in plasma concentrations of sFlt-1 and sEng precedes the development of pre-eclampsia with 6-8 weeks. Whether elevations in the plasma concentrations of sFlt and sEng, combined with a decrease in placental growth factor concentrations, can be utilised as a predictor for pre-eclampsia is currently under investigation.


UHC2030's Contributions to Global Health Governance that Advance the Right to Health Care: A Preliminary Assessment.
The September 2019 United Nations High Level Meeting on Universal Health Coverage (UHC) aims to mobilize top-level political support for action on UHC to advance the health Sustainable Development Goal (SDG). A driving force behind this meeting is the "UHC Movement," led by UHC2030, which focuses on coordinating and amplifying efforts by WHO, the World Bank, civil society, and the private sector to strengthen health systems and achieve UHC. In line with Horton and Das, this paper contends that while the argument about UHC is won, it is crucially important to focus on "how" UHC will be delivered, and specifically, whether ongoing efforts to advance UHC align with efforts to realize the right to health. This paper offers a preliminary assessment of how UHC2030's contributions to global health governance advance, or not, the right to health care. It builds on a 2014 Go4Health study which identified key normative overlap and gaps in UHC and right to health care principles. Given the importance of civil society participation in advancing health rights, this analysis is complemented by an examination of how UHC2030 might amplify ongoing efforts to advance the right to health care in two UHC2030 partner countries, Kenya and Uganda.


Rational HIV immunogen design to target specific germline B cell receptors.
Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.


Incidence and admission rates for severe malaria and their impact on mortality in Africa.
Appropriate treatment of life-threatening Plasmodium falciparum malaria requires in-patient care. Although the proportion of severe cases accessing in-patient care in endemic settings strongly affects overall case fatality rates and thus disease burden, this proportion is generally unknown. At present, estimates of malaria mortality are driven by prevalence or overall clinical incidence data, ignoring differences in case fatality resulting from variations in access. Consequently, the overall impact of preventive interventions on disease burden have not been validly compared with those of improvements in access to case management or its quality. Using a simulation-based approach, severe malaria admission rates and the subsequent severe malaria disease and mortality rates for 41 malaria endemic countries of sub-Saharan Africa were estimated. Country differences in transmission and health care settings were captured by use of high spatial resolution data on demographics and falciparum malaria prevalence, as well as national level estimates of effective coverage of treatment for uncomplicated malaria. Reported and modelled estimates of cases, admissions and malaria deaths from the World Malaria Report, along with predicted burden from simulations, were combined to provide revised estimates of access to in-patient care and case fatality rates. There is substantial variation between countries' in-patient admission rates and estimated levels of case fatality rates. It was found that for many African countries, most patients admitted for in-patient treatment would not meet strict criteria for severe disease and that for some countries only a small proportion of the total severe cases are admitted. Estimates are highly sensitive to the assumed community case fatality rates. Re-estimation of national level malaria mortality rates suggests that there is substantial burden attributable to inefficient in-patient access and treatment of severe disease. The model-based methods proposed here offer a standardized approach to estimate the numbers of severe malaria cases and deaths based on national level reporting, allowing for coverage of both curative and preventive interventions. This makes possible direct comparisons of the potential benefits of scaling-up either category of interventions. The profound uncertainties around these estimates highlight the need for better data.


Lead and zinc concentrations in household dust and toenails of the residents (Estarreja, Portugal): a source-pathway-fate model.
This paper describes a methodology developed to assess and apportion probable indoor and outdoor sources of potentially toxic elements while identifying chemical signatures in the household dust collected from private homes in an industrial city (Estarreja, central Portugal). Oral bioaccessibility estimates and the chemical composition of toenail clippings were used to assess indoor dust ingestion as a potential exposure pathway and further investigate exposure-biomarker relationships. Indoor and paired outdoor dust samples were collected from each household. A total of 30 individuals, who provided toenail clippings and a self-reported questionnaire, were recruited for the study. Total concentrations of 34 elements, including lead and zinc, were determined in washed toenail samples and household dust via Inductively Coupled Plasma-Mass Spectrometry. The oral bioaccessibility was estimated using the Unified BARGE Method. The enrichment factor shows that lead was enriched (10 < EF < 100) while zinc (EF > 100) was anomalously enriched in the household dust, thus indicating potential exposure in the home environment. The results from principal component analysis coupled to cluster analysis and linear discriminant analysis suggested that mixed contamination derived from multiple sources with a predominance of biomass burning. Stepwise multiple linear regression analysis was performed to model toenail data using the indoor dust elemental composition. Whereas the model obtained for lead was not reliable, indoor dust zinc and antimony contents arose as good predictors of toenail zinc. The exposure-biomarker relationships seem to be influenced by the oral bioaccessibility of the elements.


Increased Cellular Levels of MicroRNA-9 and MicroRNA-221 Correlate with Cancer Stemness and Predict Poor Outcome in Human Breast Cancer.
Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.


Harnessing spectral property of dual wavelength white LED to improve vertical scanning interferometry.
Unlike a conventional white light source that emits a continuous and broad spectrum of light, the dual wavelength white light emitting diode (LED) generates white light by mixing blue and yellow lights, so there are two distinct peaks in its intensity spectrum. Prior works had shown that the spectral property of the dual wavelength white LED can affect the vertical scanning interferometry negatively if the spectral effects are not compensated. In this paper, we shall examine this issue by modeling the spectral property and variation of the dual wavelength white LED, followed by investigating its effects on the interference signal of vertical scanning interferometry. Instead of compensating the spectral effects of the dual wavelength white LED, we harness its spectral property to improve the performance of a phase-based height reconstruction algorithm in vertical scanning interferometry.


Newborn hearing screening in the private health care sector - a national survey.
To determine: (i) the national status of newborn hearing screening services in the private health care sector of South Africa; (ii) screening approaches implemented; and (iii) challenges to screening implementation. A descriptive national survey in the private sector of South Africa was conducted within a quantitative paradigm. All private health sector institutions with obstetric units (N=166) were surveyed telephonically and self-administered questionnaires were subsequently sent to all audiologists in private practice (N=87) who provide newborn hearing screening services at the units with hearing screening. Nationally 53% of private sector obstetric units offer some form of newborn hearing screening. Universal hearing screening was only offered by 14% of units, while the most common approaches were universal screening on some days of the week (18%) and screening on request (18%). The most prominent challenge to successful screening implementation was the apparent omission of newborn hearing screening from maternity birthing packages at the health care institutions. The vast majority of newborns nationally are not screened for hearing loss, and existing programmes are not sufficiently systematic and integrated to ensure adequate coverage. Hospital management and paediatric health services must prioritise hearing screening as part of standard of care birthing services.


Velocity during Strength and Power Training of the Ankle Plantar and Dorsiflexor Muscles in Older Patients Attending Day Hospital Rehabilitation.
Power training has been proposed as a more effective type of resistance training for older adults for functional performance. It is not yet known whether older adults respond appropriately to instructions for power versus strength training. The purpose of this study was to determine the velocity during strength and power training, with elastic resistance bands, in older adults attending a geriatric rehabilitation day program. It was hypothesized that power training would be faster than strength training, but that there would be large interindividual differences. Nine older patients (70 to 86 years) performed power and strength training of the ankle dorsiflexor and plantar flexor muscles using elastic resistance bands. Training sessions were filmed to assess the velocity of training. Power training occurred at faster velocities as compared to strength training (P < 0.01) for both muscle groups. However, a wide variation was observed between participants in the training velocities. Older adults attending geriatric rehabilitation do have the potential to develop faster contractions during power training as compared to strength training. Nevertheless, the actual velocities achieved differed between individuals. This could explain some of the mixed findings of studies on power training. Hence, researchers should monitor velocity when comparing different types of resistance training.


Predictors of Recurrent AKI.
Recurrent AKI is common among patients after hospitalized AKI and is associated with progressive CKD. In this study, we identified clinical risk factors for recurrent AKI present during index AKI hospitalizations that occurred between 2003 and 2010 using a regional Veterans Administration database in the United States. AKI was defined as a 0.3 mg/dl or 50% increase from a baseline creatinine measure. The primary outcome was hospitalization with recurrent AKI within 12 months of discharge from the index hospitalization. Time to recurrent AKI was examined using Cox regression analysis, and sensitivity analyses were performed using a competing risk approach. Among 11,683 qualifying AKI hospitalizations, 2954 patients (25%) were hospitalized with recurrent AKI within 12 months of discharge. Median time to recurrent AKI within 12 months was 64 (interquartile range 19-167) days. In addition to known demographic and comorbid risk factors for AKI, patients with longer AKI duration and those whose discharge diagnosis at index AKI hospitalization included congestive heart failure (primary diagnosis), decompensated advanced liver disease, cancer with or without chemotherapy, acute coronary syndrome, or volume depletion, were at highest risk for being hospitalized with recurrent AKI. Risk factors identified were similar when a competing risk model for death was applied. In conclusion, several inpatient conditions associated with AKI may increase the risk for recurrent AKI. These findings should facilitate risk stratification, guide appropriate patient referral after AKI, and help generate potential risk reduction strategies. Efforts to identify modifiable factors to prevent recurrent AKI in these patients are warranted.


Pentacyclic triterpenoids from Embelia schimperi.
Five oleanane-type pentacyclic triterpenoids were isolated by chromatographic separation of a chloroform extract of the stem bark of Embelia schimperi. Three of these compounds have a methyleneoxy bridge. Two compounds, embelinone and schimperinone, are reported here for the first time from a natural source (they have been synthesized previously during chemical transformations). Their structures were determined by spectroscopic techniques, among which 2-D NMR was useful for complete characterization. Three of the triterpenoids exhibited mild antibacterial properties against the gram-positive bacterial strain Rhodococcus sp.


Dissecting the self-assembly kinetics of multimeric pore-forming toxins.
Pore-forming toxins are ubiquitous cytotoxins that are exploited by both bacteria and the immune response of eukaryotes. These toxins kill cells by assembling large multimeric pores on the cell membrane. However, a quantitative understanding of the mechanism and kinetics of this self-assembly process is lacking. We propose an analytically solvable kinetic model for stepwise, reversible oligomerization. In biologically relevant limits, we obtain simple algebraic expressions for the rate of pore formation, as well as for the concentration of pores as a function of time. Quantitative agreement is obtained between our model and time-resolved kinetic experiments of Bacillus thuringiensis Cry1Ac (tetrameric pore), aerolysin, Staphylococcus aureus α-haemolysin (heptameric pores) and Escherichia coli cytolysin A (dodecameric pore). Furthermore, our model explains how rapid self-assembly can take place with low concentrations of oligomeric intermediates, as observed in recent single-molecule fluorescence experiments of α-haemolysin self-assembly. We propose that suppressing the concentration of oligomeric intermediates may be the key to reliable, error-free, self-assembly of pores.


Optical coherence tomography of fovea before and after laser treatment in retinopathy of prematurity.
To study the fovea in preterm babies with Type I retinopathy of prematurity (ROP) before and after laser treatment using optical coherence tomography (OCT). This was a prospective observational case-control study including preterm neonates undergoing screening for ROP from May 2009 to July 2011. Group 1 included 30 eyes of 15 neonates with Type I ROP. A 532-nm laser was used for treatment in all cases for Group 1. Group 2 included 14 eyes of 7 preterm neonates without ROP that served as controls. OCT was performed under sedation in the lateral position before and after laser treatment. P <0.05 was considered statistically significant. The mean initial central macular thickness (CMT) was comparable in both groups (P = 0.832) and statistically significantly correlated with gestational age (P = 0.015). No adverse effects on the anterior segment or posterior segment were observed. There was no significant difference in CMT before and after laser treatment in Group 1 (P = 0.007). There was one case of cystoid macular edema after laser treatment. The macula in preterm babies with Type 1 ROP was comparable to those without ROP. Gestational age was the only predictor of CMT.


On the (un)predictability of a large intragenic fitness landscape.
The study of fitness landscapes, which aims at mapping genotypes to fitness, is receiving ever-increasing attention. Novel experimental approaches combined with next-generation sequencing (NGS) methods enable accurate and extensive studies of the fitness effects of mutations, allowing us to test theoretical predictions and improve our understanding of the shape of the true underlying fitness landscape and its implications for the predictability and repeatability of evolution. Here, we present a uniquely large multiallelic fitness landscape comprising 640 engineered mutants that represent all possible combinations of 13 amino acid-changing mutations at 6 sites in the heat-shock protein Hsp90 in Saccharomyces cerevisiae under elevated salinity. Despite a prevalent pattern of negative epistasis in the landscape, we find that the global fitness peak is reached via four positively epistatic mutations. Combining traditional and extending recently proposed theoretical and statistical approaches, we quantify features of the global multiallelic fitness landscape. Using subsets of the data, we demonstrate that extrapolation beyond a known part of the landscape is difficult owing to both local ruggedness and amino acid-specific epistatic hotspots and that inference is additionally confounded by the nonrandom choice of mutations for experimental fitness landscapes.


Developmental neuroethology: changes in escape and defensive behavior during growth of the lobster.
The changes in relative efficacy of two incompatible behaviors was investigated during growth of the lobster, Homarus americanus. In larval and early juvenile stages, physiological and morphological factors favor use of the escape response over defensive behavior. In large animals, defensive behavior is preferred almost exclusively to escape behavior unless the claws are lost. The interaction of escape and defensive behavior is modified by neural and morphological factors, which are dependent on the stage in the life cycle of the organism.


Three-dimensional computed tomography imaging in an animal model of emphysema.
Emphysema is a major health problem and novel drugs are needed. Animal disease models are pivotal in their development, but the validity and sensitivity of current tools for the evaluation of drug efficacy is limited. The usefulness of micro computed tomography (CT) as an innovative tool to assess emphysema in a mouse model was investigated. Serial CT scans were performed in bi-weekly intervals in Smad3 knockout (KO) mice, which spontaneously develop airspace enlargement. Lung density was quantified in two- and three-dimensional images and correlated to mean linear intercept and lung compliance. CT scans of Smad3 KO lungs revealed a significant decrease in lung density at age 8 weeks and a further progression at age 14 weeks with respect to age-matched wild-type (WT) animals. Emphysema could be reliably assessed with both the two- and three-dimensional approach, but the three-dimensional approach was superior, due to normalisation to lung volumes and less variability. Lung compliance by week 14 was 0.053+/-0.005 and 0.034+/-0.002% of maximum volume.cmH(2)O(-1) for KO and WT mice, respectively, reflecting significant physiologically relevant emphysema. Small animal computed tomography imaging and density quantification in a reconstructed three-dimensional image is a useful tool for quantifying emphysematous changes in an animal disease model. It adds significant information to conventional assessment.


Overcoming challenges in designing and implementing a phase II randomized controlled trial using a presurgical model to test a dietary intervention in prostate cancer.
The time between the diagnosis of cancer and a planned definitive surgical procedure offers a strong and direct approach for assessing the impact of interventions (including lifestyle interventions) on the biology of the target tissue and the tumor. Despite the many strengths of presurgical models, there are practical issues and challenges that arise when using this approach. We recently completed an NIH-funded phase II trial that utilized a presurgical model in testing the comparative effects of flaxseed supplementation and/or dietary fat restriction on the biology and biomarkers associated with prostatic carcinoma. Herein, we report the rationale for our original design, discuss modifications in strategy, and relay experiences in implementing this trial related to the following topics: (1) subject accrual; (2) subject retention; (3) intervention delivery; and (4) retrieval and completion rates regarding the collection of paraffin-embedded and fresh frozen prostate tissue, blood, urine, ejaculate, anthropometric measures and survey data. This trial achieved its accrual target, i.e., a racially-representative (70% white, 30% minority) sample of 161 participants, low rates of attrition (7%); and collection rates that exceeded 90% for almost all biospecimens and survey data. While the experience gained from pilot studies was invaluable in designing this trial, the complexity introduced by the collection of several biospecimens, inclusion of a team of pathologists (to provide validated readings), and shifts in practice patterns related to prostatectomy, made it necessary to revise our protocol; lessons from our experiences are offered within this article. While our experience specifically relates to the implementation of a presurgical model-based trial in prostate cancer aimed at testing flaxseed-supplemented and fat-restricted diets, many of the lessons learned have broad application to trials that utilize a presurgical model or dietary modification within various cancer populations.


Aromatase inhibitors in premenopausal women with breast cancer: the state of the art and future prospects.
Approximately 11% of patients with breast cancer (bca) are diagnosed before menopause, and because in most of those patients the tumour expresses a hormone receptor, treatment with endocrine interventions can be applied in any setting of disease (early or advanced). In the past, hormonal treatment consisted only of the estrogen receptor modulator tamoxifen, associated with luteinizing hormone-releasing hormone (lhrh); more recently, aromatase inhibitors (ais) have come into widespread use. The ais interfere with the last enzymatic step of estrogen synthesis in which androgens are converted into estrogens. Initially, the ais were used alone in postmenopausal patients to prevent disease recurrence, but together with lhrh analogs, they can be used in premenopausal patients to produce better estrogen suppression than can be achieved with tamoxifen plus a lhrh analog. Using a systematic review of the scientific literature (prospective and retrospective studies), we set out to assess the efficacy of ais compared with other endocrine therapy in various disease settings (neoadjuvant, adjuvant, metastatic).


Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease.
The advent of PCR-based stool testing has identified a greatly increased number of infectious agents in IBD, but their clinical significance is unknown. To determine the infectious agent prevalence and the clinical significance of these infectious agents in IBD patients. This cross-sectional study compared the prevalence of GI infections among IBD patients with active and quiescent disease versus healthy controls. Among actively inflamed patients, we compared clinical characteristics, medication use, and disease course between those with positive and negative tests. Three hundred and thirty-three IBD patients and 52 healthy volunteers were included. The IBD group was divided into active Crohn's disease (CD, n = 113), inactive CD (n = 53), active ulcerative colitis (UC, n = 128), and inactive UC (n = 39). A significantly higher percentage of actively inflamed patients had positive stool tests (31.1%) compared to those with quiescent disease (7.6%, P = < 0.001) and healthy controls (13.5%, P = 0.01). In actively inflamed patients, shorter symptom duration and the use of multiple immunosuppressive agents were significantly associated with positive stool tests. Escalation of immunosuppressive therapy was less frequent in those with positive (61.3%) than with negative tests (77.7%, P = < 0.01). However, the need for surgery (13.3% vs. 18.7%, respectively, P = 0.31) and hospitalization (14.7% vs. 17.5%, respectively, P = 0.57) in 90 days was not significantly different. GI infections are common in IBD patients with active disease. Evaluating patients for infection may help avoid unnecessary escalation of immunosuppressants, especially during an acute flare or combination immunosuppression.


Neurologic recovery according to the spinal fracture patterns by Denis classification.
Although Denis classification is considered as one of most clinically useful schemes for the evaluation of spinal fracture, there is little documentation on the relationship between fracture pattern and the neurologic recovery. The purpose is to evaluate the correlation between the fracture patterns according to Denis classification and neurologic recovery. The 38 patients (26 men and 12 women) in this series had an average follow-up of 47.1 months, and they were all managed surgically. Denis classification had been used prospectively to determine the fracture morphology. Frankel Scale and American Spinal Injury Association Spinal Cord Injury Assessment Form [American Spinal Injury Association (ASIA) score] were obtained before surgery, after surgery and at the final follow-up. The common injuries making neurologic deterioration were burst fracture and fracture-dislocation. The degree of neurologic deficits seen first and at the final follow-up was more severe in fracture-dislocation than burst fracture. The neurologic recovery was not different between burst fracture and fracture-dislocation, assessed by Frankel grading and ASIA scoring system. The neurologic recovery evaluated by ASIA score was not different between the lumbar and thoracic spinal fracture. The neurologic recovery assessed by Frankel grade was greater in the lumbar spinal fractures in than the thoracic spinal fractures. The severity of initial and the final follow-up neurologic deficits were correlated with the fracture patterns according to Denis classification, but the neurologic recovery was not correlated.


Sinorhizobium fredii HH103 rkp-3 genes are required for K-antigen polysaccharide biosynthesis, affect lipopolysaccharide structure and are essential for infection of legumes forming determinate nodules.
The Sinorhizobium fredii HH103 rkp-3 region has been isolated and sequenced. Based on the similarities between the S. fredii HH103 rkpL, rkpM, rkpN, rkpO, rkpP, and rkpQ genes and their corresponding orthologues in Helicobacter pylori, we propose a possible pathway for the biosynthesis of the S. fredii HH103 K-antigen polysaccharide (KPS) repeating unit. Three rkp-3 genes (rkpM, rkpP, and rkpQ) involved in the biosynthesis of the HH103 KPS repeating unit (a derivative of the pseudaminic acid) have been mutated and analyzed. All the rkp-3 mutants failed to produce KPS and their lipopolysaccharide (LPS) profiles were altered. These mutants showed reduced motility and auto-agglutinated when early-stationary cultures were further incubated under static conditions. Glycine max, Vigna unguiculata (determinate nodule-forming legumes), and Cajanus cajan (indeterminate nodules) plants inoculated with mutants in rkpM, rkpQ, or rkpP only formed pseudonodules that did not fix nitrogen and were devoid of bacteria. In contrast, another indeterminate nodule-forming legume, Glycyrrhiza uralensis, was still able to form some nitrogen-fixing nodules with the three S. fredii HH103 rifampicin-resistant rkp-3 mutants tested. Our results suggest that the severe symbiotic impairment of the S. fredii rkp-3 mutants with soybean, V. unguiculata, and C. cajan is mainly due to the LPS alterations rather than to the incapacity to produce KPS.


Realization of "trapped rainbow" in 1D slab waveguide with surface dispersion engineering.
We present a design of a one dimensional dielectric waveguide that can trap a broadband light pulse with different frequency component stored at different positions, effectively forming a "trapped rainbow" [Nature 450, 397 (2007)]. The spectrum of the rainbow covers the whole visible range. To do this, we first show that the dispersion of a SiO(2) waveguide with a Si grating placed on top can be engineered by the design parameter of the grating. Specifically, guided modes with zero group velocity(frozen modes) can be realized. Negative Goos-Hänchen shift along the surface of the grating is responsible for such a dispersion control. The frequency of the frozen mode is tuned by changing the lateral feature parameters (period and duty cycle) of the grating. By tuning the grating feature point by point along the waveguide, a light pulse can be trapped with different frequency components frozen at different positions, so that a "rainbow" is formed. The device is expected to have extremely low ohmic loss because only dielectric materials are used. A planar geometry also promises much reduced fabrication difficulty.


A metabolic inhibitor arms macrophages to kill intracellular fungal pathogens by manipulating zinc homeostasis.
Macrophages deploy numerous strategies to combat invasion by microbes. One tactic is to restrict acquisition of diverse nutrients, including trace metals, a process termed nutritional immunity. Intracellular pathogens adapt to a resource-poor environment by marshaling mechanisms to harvest nutrients. Carbon acquisition is crucial for pathogen survival; compounds that reduce availability are a potential strategy to control intracellular replication. Treatment of macrophages with the glucose analog 2-deoxy-D-glucose (2-DG) armed phagocytes to eliminate the intracellular fungal pathogen Histoplasma capsulatum in vitro and in vivo. Killing did not rely on altering access to carbon-containing molecules or changes in ATP, ER stress, or autophagy. Unexpectedly, 2-DG undermined import of exogenous zinc into macrophages, decreasing the quantity of cytosolic and phagosomal zinc. The fungus perished as a result of zinc starvation. This change in metal ingress was not ascribed to a defect in a single importer; rather, there was a collective impairment in transporter activity. This effect promoted the antifungal machinery of macrophages and expanded the complexity of 2-DG activities far beyond manipulating glycolysis. Mechanistic metabolic studies employing 2-DG will have to consider its effect on zinc transport. Our preclinical data support consideration of this agent as a possible adjunctive therapy for histoplasmosis.


Prostanoid synthesis in response to high CO2 in newborn pig brain microvascular endothelial cells.
Hypercapnia-induced cerebral vasodilation involves prostanoids in newborn pigs. However, the source of prostanoids has not been determined. The current study was designed to address the hypothesis that piglet cerebral microvascular endothelial cells increase their synthesis of prostanoids in response to high CO2. Microvascular endothelial cells, smooth muscle cells, and glia were isolated and grown in primary culture. They were identified morphologically and by indirect immunofluorescence staining. Cerebral microvascular endothelial cell cultures from newborn pigs produced equal amounts of 6-ketoprostaglandin (PG) F1 alpha (stable hydrolysis product of PGI2), PGE2 and a small amount of PGF2 alpha under basal conditions. Administration of calcium ionophore A23187 to the endothelial cells increased release of all three prostanoids in a dose- and time-dependent manner. Exposure of piglet cerebral microvascular endothelial cells to higher than normal CO2 increased the production of 6-keto-PGF1 alpha and PGE2 but not of PGF2 alpha. The enhanced prostanoid biosynthesis was concentration dependent, peaking at 14% CO2, and was detected during the first 10 min exposure to 14% CO2. Hypercapnia-induced increased synthesis of prostanoids was blocked dose dependently by the simultaneous addition of PGH synthase inhibitor indomethacin. High CO2 did not increase prostanoid production by cerebral microvascular smooth muscle cells or glia, although A23187 enhanced prostanoid formation by both cell types. These data show that high CO2 stimulates prostanoid synthesis by newborn pig cerebral microvascular endothelial cells, which is consistent with an involvement of cerebral vascular endothelium in hypercapnia-induced vasodilation.


A Novel Multiparametric Approach to 3D Quantitative MRI of the Brain.
Magnetic Resonance properties of tissues can be quantified in several respects: relaxation processes, density of imaged nuclei, magnetism of environmental molecules, etc. In this paper, we propose a new comprehensive approach to obtain 3D high resolution quantitative maps of arbitrary body districts, mainly focusing on the brain. The theory presented makes it possible to map longitudinal (R1), pure transverse (R2) and free induction decay ([Formula: see text]) rates, along with proton density (PD) and magnetic susceptibility (χ), from a set of fast acquisition sequences in steady-state that are highly insensitive to flow phenomena. A novel denoising scheme is described and applied to the acquired datasets to enhance the signal to noise ratio of the derived maps and an information theory approach compensates for biases from radio frequency (RF) inhomogeneities, if no direct measure of the RF field is available. Finally, the results obtained on sample brain scans of healthy controls and multiple sclerosis patients are presented and discussed.


Taar1 gene variants have a causal role in methamphetamine intake and response and interact with Oprm1.
We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, Taar1, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, Oprm1, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of Taar1 in methamphetamine intake and a genetically-associated thermal response to methamphetamine. The methamphetamine-related traits were rescued, converting them to levels found in methamphetamine-avoiding animals. We used a family of recombinant inbred mouse strains for interval mapping and to examine independent and epistatic effects of Taar1 and Oprm1. Both methamphetamine intake and the thermal response mapped to Taar1 and the independent effect of Taar1 was dependent on genotype at Oprm1. Our findings encourage investigation of the contribution of Taar1 and Oprm1 variants to human methamphetamine addiction.


Elucidating the structural properties that influence the persistence of PCBs in humans using the National Health and Nutrition Examination Survey (NHANES) dataset.
In human exposure studies involving Polychlorinated Biphenyls (PCBs), it is useful to establish when an individual was potentially exposed. Age dating PCB exposure is complex but assessments can be made because different PCB congeners have different residence times in the human body. The less chlorinated congeners generally tend to have shorter residence times because they are biotransformed and eliminated faster than more chlorinated congeners. Therefore, the presence of high proportions of less chlorinated congeners is often indicative of recent exposure. The 2003-04 National Health and Nutrition Examination Survey (NHANES) dataset contains results for the concentration of 37 PCBs in a sub-sample of the US population. Multivariate statistical analysis of the NHANES data showed that less chlorinated congeners are not always biotransformed faster than higher chlorinated compounds. For example, PCB 28 (a tri-chlorobiphenyl) appears to be more resistant to biotransformation than PCB 101 and 110 (penta-chlorobiphenyls). Using statistical analysis of the NHANES data in conjunction with previously published studies on PCB persistence in humans, it was possible to identify the structural relationships that determine if a PCB is likely to be from a recent exposure (termed 'episodic') or from steady state exposure. Congeners with chlorine atoms in the 2,5- and 2,3,6-positions appear to be more susceptible to biotransformation whereas congeners with chlorine bonds in the 2,3,4- 2,4,5- 3,4,5- and 2,3,4,5-positions appear to be more persistent. This work shows that future investigations to date PCB exposure would benefit from the analysis of a wide range of congeners, including the selection of key congeners based not only on the degree of chlorination but also on the positions of the chlorine atoms on the biphenyl.


Responsiveness of 8 Patient-Reported Outcomes Measurement Information System (PROMIS) measures in a large, community-based cancer study cohort.
The Patient-Reported Outcomes Measurement Information System (PROMIS) was a National Institutes of Health-funded initiative to develop measures of symptoms and function. Responsiveness is the degree to which a measure can detect underlying changes over time. The objective of the current study was to document the responsiveness of 8 PROMIS measures in a large, population-based cancer cohort. The Measuring Your Health study recruited 2968 patients who were diagnosed with 1 of 7 cancers between 2010 and 2012 through 4 Surveillance, Epidemiology, and End Results registries. Participants completed a baseline survey (6-13 months after diagnosis) and a 6-month follow-up survey. Changes in 8 PROMIS scores were compared with global ratings of transition, changes in performance status, and clinical events. Measures were responsive to 6-month declines and improvements in performance status with small to large effect sizes (ES) (Cohen d = 0.34-0.71; P < .01). Mean changes and effect sizes were larger for participants who reported declines compared with those who reported improvements. Small-to-medium ES were observed in patients who reported being "a little" worse (d = 0.31-0.56), and medium-to-large ES were observed in those who reported being "a lot" worse (d = 0.53-0.72). Hospitalized participants reported significant score increases, resulting in worsening of pain (d = 0.51), fatigue (d = 0.35), and depression (d = 0.57; all P < .01). Cancer recurrence and progression were associated with smaller increases in pain, fatigue, and sleep disturbance (d = 0.22-0.27). The current results indicated that all 8 PROMIS measures were sensitive to patient-perceived worsening and improvement and to major clinical events. These findings will be able to inform the design and interpretation of future research studies and clinical initiatives administering PROMIS measures. Cancer 2017;123:327-335. © 2016 American Cancer Society.


A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia.
Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.


Environmental effects of ozone depletion, UV radiation and interactions with climate change: UNEP Environmental Effects Assessment Panel, update 2017.
The Environmental Effects Assessment Panel (EEAP) is one of three Panels of experts that inform the Parties to the Montreal Protocol. The EEAP focuses on the effects of UV radiation on human health, terrestrial and aquatic ecosystems, air quality, and materials, as well as on the interactive effects of UV radiation and global climate change. When considering the effects of climate change, it has become clear that processes resulting in changes in stratospheric ozone are more complex than previously held. Because of the Montreal Protocol, there are now indications of the beginnings of a recovery of stratospheric ozone, although the time required to reach levels like those before the 1960s is still uncertain, particularly as the effects of stratospheric ozone on climate change and vice versa, are not yet fully understood. Some regions will likely receive enhanced levels of UV radiation, while other areas will likely experience a reduction in UV radiation as ozone- and climate-driven changes affect the amounts of UV radiation reaching the Earth's surface. Like the other Panels, the EEAP produces detailed Quadrennial Reports every four years; the most recent was published as a series of seven papers in 2015 (Photochem. Photobiol. Sci., 2015, 14, 1-184). In the years in between, the EEAP produces less detailed and shorter Update Reports of recent and relevant scientific findings. The most recent of these was for 2016 (Photochem. Photobiol. Sci., 2017, 16, 107-145). The present 2017 Update Report assesses some of the highlights and new insights about the interactive nature of the direct and indirect effects of UV radiation, atmospheric processes, and climate change. A full 2018 Quadrennial Assessment, will be made available in 2018/2019.


Mycothiol biosynthesis is essential for ethionamide susceptibility in Mycobacterium tuberculosis.
Spontaneous mutants of Mycobacterium tuberculosis that were resistant to the anti-tuberculosis drugs ethionamide and isoniazid were isolated and found to map to mshA, a gene encoding the first enzyme involved in the biosynthesis of mycothiol, a major low-molecular-weight thiol in M. tuberculosis. Seven independent missense or frameshift mutations within mshA were identified and characterized. Precise null deletion mutations of the mshA gene were generated by specialized transduction in three different strains of M. tuberculosis. The mshA deletion mutants were defective in mycothiol biosynthesis, were only ethionamide-resistant and required catalase to grow. Biochemical studies suggested that the mechanism of ethionamide resistance in mshA mutants was likely due to a defect in ethionamide activation. In vivo, a mycothiol-deficient strain grew normally in immunodeficient mice, but was slightly defective for growth in immunocompetent mice. Mutations in mshA demonstrate the non-essentiality of mycothiol for growth in vitro and in vivo, and provide a novel mechanism of ethionamide resistance in M. tuberculosis.


EANM position paper on the role of radiobiology in nuclear medicine.
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.


Flaxseed and pure secoisolariciresinol diglucoside, but not flaxseed hull, reduce human breast tumor growth (MCF-7) in athymic mice.
Previous studies have shown that dietary flaxseed (FS) can reduce the growth of established human breast tumors in athymic mice with low circulating estrogen concentrations. In this study, we determined the effect of FS compared with pure lignan at the level it is present in FS [secoisolariciresinol diglucoside (SDG)] and to the lignan-rich fraction [FS hull (FH)] on human breast tumor growth and their potential mechanisms of action. Ovariectomized, athymic mice, each with an implanted 17 beta-estradiol (E2) pellet (0.36 mg), were injected with human estrogen receptor (ER) positive breast cancer cells (MCF-7). When tumors were established, the E2 pellet was removed. Mice were fed either the control basal diet (BD), FS (100 g/kg diet), SDG (1 g/kg diet), or FH (18 g/kg diet) for 8 wk. Compared with the BD, FS and SDG significantly decreased the palpable tumor size, but effects of FS, SDG, and FH did not differ from one another. All treatments significantly inhibited cell proliferation, but only FS and SDG induced significantly higher apoptosis. Both FS and SDG significantly decreased mRNA expressions of Bcl2, cyclin D1, pS2, ERalpha, and ERbeta, epidermal growth factor receptor, and insulin-like growth factor receptor. FS also reduced human epidermal growth factor receptor 2 mRNA and SDG decreased phospho-specific mitogen-activated protein kinase expression. FH did not significantly reduce these biomarkers. In conclusion, pure SDG has a similar effect as FS in reducing tumor growth and in mechanisms of action, including downregulating ER- and growth factor-mediated cell signaling. The lesser effects of FH indicate a need for a higher dose to be more effective.


The iron-age of superconductivity: structural correlations and commonalities among the various families having -Fe-Pn- slabs (Pn = P, As and Sb).
The fascination of mankind towards a sudden change of a property, like colour, shape, elasticity, viscosity, electrical conductivity and magnetism, is well known. If the change in property is such that it leads to disapperance of an existing property or development of a new property then the effect is magical. It is for this reason that superconductivity remains an enigma for scientists for over a century after Kammerlingh Onnes discovered that the electrical resistance of mercury falls to zero below a temperature of 4.2 K. Since then scientists have been enchanted by superconductivity. Over these hundred years attempts have been made to discover materials which show this effect at higher temperatures. After a very exciting period of Cu oxide superconductors (1986-1993) there has been a lull in the search for high T(c) materials. The discovery of superconductivity in 2008 at 26 K in LaOFeAs (F-doped) has renewed the excitement in the field of superconductivity. This breakthrough in an Fe-containing compound led to the discovery of several new families of Fe-based superconductors having either pnictogens (P, As) or chalcogen (Se, Te) of the type AFFeAs (A = alkaline-earth metal), AFe(2)As(2), AFeAs (A = alkali metals), A(3)M(2)O(5)Fe(2)As(2) (M = transition metals) and A(4)M(2)O(6)Fe(2)As(2). This review article discusses in detail the structural aspects of these new Fe-based superconductors which primarily consist of edge-shared distorted FeX(4) (X = pnictogen and chalcogen) tetrahedra and these tetrahedral layers are reponsible for enabling superconductivity. Extremely large upper critical field (>200 Tesla) of these superconductors make them promising for high field application. Structural commonalities and differences among different families of these superconductors have been outlined. We also discuss the common features and differences with the copper-oxide based superconductors. Here we have discussed all the Fe-based oxypnictide families (like LnOFePn, AFe(2)Pn(2), AFFePn and A(4)M(2)M'Fe(2)As(2)O(6)etc.) known today and have also included the phosphides and antimonides other than the arsenides. We have in addition discussed in detail the various factors like pressure, hole and electron doping, transition metal doping, which have not been reviewed earlier.


The Effects of Cannabidiol and Prognostic Role of TRPV2 in Human Endometrial Cancer.
Several studies support, both in vitro and in vivo, the anti-cancer effects of cannabidiol (CBD), a transient receptor potential vanilloid 2 (TRPV2) ligand. TRPV2, often dysregulated in tumors, is associated with altered cell proliferation and aggressiveness. Endometrial cancer (EC) is historically divided in type I endometrioid EC and type II non-endometrioid EC, associated with poor prognosis. Treatment options with chemotherapy and combinations with radiation showed only limited efficacy. Since no data are reported concerning TRPV2 expression as well as CBD potential effects in EC, the aim of this study was to evaluate the expression of TRPV2 in biopsies and cell lines as well as the effects of CBD in in vitro models. Overall survival (OS), progression-free survival (PFS), cell viability, migration, and chemo-resistance have been evaluated. Results show that TRPV2 expression increased with the malignancy of the cancer tissue and correlated with shorter PFS (p = 0.0224). Moreover, in vitro TRPV2 over-expression in Ishikawa cell line increased migratory ability and response to cisplatin. CBD reduced cell viability, activating predominantly apoptosis in type I cells and autophagy in mixed type EC cells. The CBD improved chemotherapeutic drugs cytotoxic effects, enhanced by TRPV2 over-expression. Hence, TRPV2 could be considered as a marker for optimizing the therapy and CBD might be a useful therapeutic option as adjuvant therapy.


Estimation of mid-and long-term benefits and hypothetical risk of Guillain-Barre syndrome after human papillomavirus vaccination among boys in France: A simulation study.
The burden of human papillomavirus (HPV) infection can be substantially reduced through vaccination of girls, and gender-neutral policies are being adopted in many countries to accelerate disease control among women and expand direct benefits to men. Clinical direct benefit of boys HPV vaccination has been established for ano-genital warts and anal cancer. HPV vaccines are considered safe, but an association with Guillain-Barre syndrome has been found in French reimbursement and hospital discharge data. We conducted a Monte-Carlo simulation assuming a stable French population of 11- to 14-year-old boys, adult men and men having sex with men. We modelled and quantified the mid-term benefits as the annually prevented ano-genital warts among the 8.72 M men aged 15-35 years and the long-term benefits as the annually prevented anal cancer cases among the 17.4 M men aged 25-65 years. We also estimated the number of Guillain-Barre syndrome cases hypothetically induced by vaccination. With a vaccine coverage of 30%, an annual number of 9310 (95% uncertainty interval [7050-11,200]) first ano-genital warts episodes among the 8.72 M men aged 15-35 years are prevented. According to more or less optimistic hypotheses on the proportion of HPV cancers covered by the vaccine, between 15.1 [11.7-17.7] and 19.2 [15.0-22.6] cases of anal cancer among the 17.4 M men aged 25-65 years would be annually avoided. Among men having sex with men, the corresponding figures were 1907 (1944-2291) for ano-genital warts and between 2.0 [0.23-4.5] and 2.6 [0.29-5.7] for anal cancer. Among 11- to 14-year-old boys, 0.82 (0.15-2.3) Guillain-Barre syndrome cases would be induced annually. A long-term program of HPV vaccination among boys in France would avoid substantially more cancer cases than hypothetically induce Guillain-Barre syndrome cases, in the general and specifically the homosexual population. Additional benefits may arise with the possible vaccine protection against oro-laryngeal and -pharyngeal cancer.


Supporting underserved patients with their medicines: a study protocol for a patient/professional coproduced education intervention for community pharmacy staff to improve the provision and delivery of Medicine Use Reviews (MURs).
Community pharmacy increasingly features in global strategies to modernise the delivery of primary healthcare. Medicine Use Reviews (MURs) form part of the English Government's medicines management strategy to improve adherence and reduce medicine waste. MURs provide space for patient-pharmacist dialogue to discuss the well-known problems patients experience with medicine taking. However, 'underserved' communities (eg, black and minority ethnic communities, people with mental illness), who may benefit the most, may not receive this support. This study aims to develop, implement and evaluate an e-learning education intervention which is coproduced between patients from underserved communities and pharmacy teams to improve MUR provision. This mixed-methods evaluative study will involve a 2-stage design. Stage 1 involves coproduction of an e-learning resource through mixed patient-professional development (n=2) and review (n=2) workshops, alongside informative semistructured interviews with patients (n=10) and pharmacy staff (n=10). Stage 2 involves the implementation and evaluation of the intervention with community pharmacy staff within all community pharmacies within the Nottinghamshire geographical area (n=237). Online questionnaires will be completed at baseline and postintervention (3 months) to assess changes in engagement with underserved communities and changes in self-reported attitudes and behaviour. To triangulate findings, 10 pharmacies will record at baseline and postintervention, details of actual numbers of MURs performed and the proportion that are from underserved communities. Descriptive and inferential statistics will be used to analyse the data. The evaluation will also include a thematic analysis of one-to-one interviews with pharmacy teams to explore the impact on clinical practice (n=20). Interviews with patients belonging to underserved communities, and who received an MUR, will also be conducted (n=20). The study has received ethical approval from the NHS Research Ethics Committee (East Midlands-Derby) and governance clearance through the NHS Health Research Authority. Following the evaluation, the educational intervention will be freely accessible online.


Clustering of Helicobacter pylori VacA in lipid rafts, mediated by its receptor, receptor-like protein tyrosine phosphatase beta, is required for intoxication in AZ-521 Cells.
Helicobacter pylori vacuolating cytotoxin, VacA, induces multiple effects on epithelial cells through different cellular events: one involves pore formation, leading to vacuolation, mitochondrial damage, and apoptosis, and the second involves cell signaling, resulting in stimulation of proinflammatory responses and cell detachment. Our recent data demonstrated that VacA uses receptor-like protein tyrosine phosphatase beta (RPTPbeta) as a receptor, of which five residues (QTTQP) at positions 747 to 751 are involved in binding. In AZ-521 cells, which mainly express RPTPbeta, VacA, after binding to RPTPbeta in non-lipid raft microdomains on the cell surface, is localized with RPTPbeta in lipid rafts in a temperature- and VacA concentration-dependent process. Methyl-beta-cyclodextrin (MCD) did not block binding to RPTPbeta but inhibited translocation of VacA with RPTPbeta to lipid rafts and all subsequent events. On the other hand, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), which disrupts anion channels, did not inhibit translocation of VacA to lipid rafts or VacA-induced activation of p38 mitogen-activated protein (MAP) kinase, but inhibited VacA internalization followed by vacuolation. Thus, p38 MAP kinase activation did not appear to be required for internalization. In contrast, phosphatidylinositol-specific phospholipase C (PI-PLC) inhibited translocation, as well as p38 MAP kinase/ATF-2 activation, internalization, and VacA-induced vacuolation. Neither NPPB nor PI-PLC affected VacA binding to cells and to its receptor, RPTPbeta. Thus, receptor-dependent translocation of VacA to lipid rafts is critical for signaling pathways leading to p38 MAP kinase/ATF-2 activation and vacuolation.


Hormone levels and cognitive function in postmenopausal midlife women.
Gonadal hormones may influence cognitive function. Postmenopausal midlife women in the population-based Melbourne Women's Midlife Health Project cohort were administered a comprehensive battery of neuropsychological tests on two occasions 2 years apart. Participants (n = 148, mean age 60 years) had undergone natural menopause and were not using hormone therapy. Estrone, total and free estradiol, and total and free testosterone levels were measured at time of the first testing. Principal-component analysis identified four cognitive factors. In multiple linear regression analyses, better semantic memory performance was associated with higher total (p = 0.02) and free (p = 0.03) estradiol levels and a lower ratio of testosterone to estradiol (p = 0.007). There were trends for associations between better verbal episodic memory and lower total testosterone (p = 0.08) and lower testosterone/estradiol ratio (p = 0.06). Lower free testosterone levels were associated with greater 2-year improvement on verbal episodic memory (p = 0.04); higher testosterone/estradiol predicted greater semantic memory improvement (p = 0.03). In postmenopausal midlife women, endogenous estradiol and testosterone levels and the testosterone/estradiol ratio are associated with semantic memory and verbal episodic memory abilities.


Identification of TFB5, a new component of general transcription and DNA repair factor IIH.
We previously described the use of quantitative proteomics to study macromolecular complexes. Applying the method to analyze a yeast RNA polymerase II preinitiation complex, we identified a new 8-kDa protein, encoded by the uncharacterized open reading frame YDR079c-a, as a potential new component of the preinitiation complex. Here we show that YDR079c-a is a bona fide component of polymerase II preinitiation complexes and investigate its role in transcription. YDR079c-a is recruited to promoters both in vivo and in vitro and is required for efficient transcription in vitro and for normal induction of GAL genes. In addition, YDR079c-a is a core component of general transcription and DNA repair factor IIH and is required for efficient recruitment of TFIIH to a promoter. Yeast lacking YDR079c-a grow slowly, and, like strains carrying mutations in core TFIIH subunits, are sensitive to ultraviolet radiation. YDR079c-a is conserved throughout evolution, and mutations in the human ortholog account for a DNA repair-deficient form of the tricothiodystrophy disorder called TTD-A(2). The identification of a new, evolutionarily conserved, core TFIIH subunit is essential for our understanding of TFIIH function in transcription, DNA repair and human disease.


The effectiveness of buprenorphine for treating cancer pain: an abridged Cochrane review.
To assess the effectiveness and tolerability of buprenorphine for cancer pain in adults and children. We searched CENTRAL, MEDLINE, EMBASE, ISI Web of Science, ISI BIOSIS, ClinicalTrials.gov, metaRegister of Controlled Trials, WHO International Clinical Trials Registry Platform and the Proceedings of the Congress of the European Federation of International Association for the Study of Pain to early 2015. We included 19 randomised controlled trials comparing buprenorphine with placebo, buprenorphine or another active drug for cancer pain. The trials included 1421 patients and examined 16 different intervention comparisons. Of the 11 studies that compared buprenorphine to another drug, 5, 3 and 3 studies, respectively, found that buprenorphine was superior, no different or inferior to the alternative treatment in side effects profile or patient preference/acceptability. Pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository, although intramuscular treatment was associated with more adverse events (1 study). One study found faster onset of pain relief after sublingual than subdermal buprenorphine, with similar analgesia duration and adverse event rates. 2 studies found transdermal buprenorphine superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine. No clear dose-response relationship was found for transdermal buprenorphine. The quality of this evidence base was limited by under-reporting, small sample sizes and attrition. Buprenorphine might be considered as a fourth-line option compared with the more standard therapies of morphine, oxycodone and fentanyl, and even then it would only be suitable for some patients.


Characteristics Associated with HIV Drug Resistance Among Women Screening for an HIV Prevention Trial in KwaZulu-Natal, South Africa.
While the expansion of antiretroviral therapy (ART) in sub-Saharan Africa has reduced morbidity and mortality from HIV/AIDS, it has increased concern about drug resistance. The Microbicide Trials Network 009 study assessed the prevalence of drug-resistance mutations among women at clinical sites in Durban, South Africa who tested seropositive for HIV-1 at screening for the VOICE trial. The objective of this paper was to identify characteristics and behaviors associated with drug resistance. Factors found to be significantly associated with increased resistance were high perceived risk of getting HIV and prior participation in a microbicide trial, a likely proxy for familiarity with the health care system. Two factors were found to be significantly associated with reduced resistance: having a primary sex partner and testing negative for HIV in the past year. Other variables hypothesized to be important in identifying women with resistant virus, including partner or friend on ART who shared with the participant and being given antiretrovirals during pregnancy or labor, or the proxy variable-number of times given birth in a health facility-were not significantly associated. The small number of participants with resistant virus and the probable underreporting of sensitive behaviors likely affected our ability to construct a comprehensive profile of the type of HIV-positive women at greatest risk of developing resistance mutations.


Bonding of dental porcelain to non-cast titanium with different surface treatments.
This study investigated the bonding of dental porcelain to non-cast Ti surface with different treatments. Mechanically ground non-cast Ti strips, simulating surface conditions produced by CAD/CAM, were Al(2)O(3)-sandblasted, then subjected to different surface treatments, including immersion in HNO(3)-containing acid, NaOH-containing alkaline, and NaOH-containing alkaline then HNO(3)-containing acid. Ti-porcelain specimens preparations and their bend strength measurements were based on ISO 9693. Ti surface treatment changed not only surface roughness but also surface chemistry, leading to influence on bond strength. Bond strengths of all Ti-porcelain groups were higher than ISO 9693 minimum requirement. The sandblasted/acid-treated Ti surface showed the highest bond strength (34.60 MPa) with porcelain; no significant difference in bond strength (27.92-29.63 MPa) was found among other Tiporcelain groups. All Ti-porcelain specimens showed adhesive bond failure. Bonding between non-cast Ti and dental porcelain was strengthened by a simple and practical sandblasting/acid-etching treatment of the Ti surface prior to porcelain sintering.


Caenorhabditis briggsae recombinant inbred line genotypes reveal inter-strain incompatibility and the evolution of recombination.
The nematode Caenorhabditis briggsae is an emerging model organism that allows evolutionary comparisons with C. elegans and exploration of its own unique biological attributes. To produce a high-resolution C. briggsae recombination map, recombinant inbred lines were generated from reciprocal crosses between two strains and genotyped at over 1,000 loci. A second set of recombinant inbred lines involving a third strain was also genotyped at lower resolution. The resulting recombination maps exhibit discrete domains of high and low recombination, as in C. elegans, indicating these are a general feature of Caenorhabditis species. The proportion of a chromosome's physical size occupied by the central, low-recombination domain is highly correlated between species. However, the C. briggsae intra-species comparison reveals striking variation in the distribution of recombination between domains. Hybrid lines made with the more divergent pair of strains also exhibit pervasive marker transmission ratio distortion, evidence of selection acting on hybrid genotypes. The strongest effect, on chromosome III, is explained by a developmental delay phenotype exhibited by some hybrid F2 animals. In addition, on chromosomes IV and V, cross direction-specific biases towards one parental genotype suggest the existence of cytonuclear epistatic interactions. These interactions are discussed in relation to surprising mitochondrial genome polymorphism in C. briggsae, evidence that the two strains diverged in allopatry, the potential for local adaptation, and the evolution of Dobzhansky-Muller incompatibilities. The genetic and genomic resources resulting from this work will support future efforts to understand inter-strain divergence as well as facilitate studies of gene function, natural variation, and the evolution of recombination in Caenorhabditis nematodes.


Pregnancy following oocyte donation and tubal embryo transfer in patients with premature ovarian failure: report of two cases.
Two pregnancies in patients with premature ovarian failure utilizing donated oocytes, in-vitro fertilization (IVF) and tubal embryo transfer (TET), are reported. The recipients received cyclic hormone replacement therapy for six months to prepare the endometrium for implantation. An evaluation cycle was tested to document that the hormone milieu established by the hormone replacement protocol was similar to that of a natural ovulatory cycle. During the oocyte donation cycle, the recipient received incremental estrogen replacement treatment of flexible length during the follicular phase of the donor's stimulated cycle to synchronize the recipient's endometrium to the donor's embryo. Concurrently, the donor underwent controlled ovarian hyperstimulation and transvaginal ultrasound-guided oocyte retrieval. After fertilization of the donated oocytes with sperm from the recipient's husband and cleavage of the fertilized oocytes into the 2- to 4-cell stage, laparoscopic embryo transfer into the recipient's fallopian tube was performed. Case 1 received 4 embryos by the TET procedure. Pregnancy was confirmed by visualization of a gestational sac in the uterine cavity 3 weeks after TET, but miscarriage occurred at the tenth gestational week. In Case 2, the pregnancy was established after TET of 2 embryos. Estrogen and progesterone supplements were maintained until day 100 after TET. The patient delivered a healthy male baby, weighing 2,520 g at 38 weeks of gestation.


Dynamic alteration in splenic function during acute falciparum malaria.
Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.


Sensitivity towards fear of electric shock in passive threat situations.
Human judgment and decision-making (JDM) requires an assessment of different choice options. While traditional theories of choice argue that cognitive processes are the main driver to reach a decision, growing evidence highlights the importance of emotion in decision-making. Following these findings, it appears relevant to understand how individuals asses the attractiveness or riskiness of a situation in terms of emotional processes. The following study aims at a better understanding of the psychophysiological mechanisms underlying threat sensitivity by measuring skin conductance responses (SCRs) in passive threat situations. While previous studies demonstrate the role of magnitude on emotional body reactions preceding an outcome, this study focuses on probability. In order to analyze emotional body reactions preceding negative events with varying probability of occurrence, we have our participants play a two-stage card game. The first stage of the card game reveals the probability of receiving an unpleasant electric shock. The second stage applies the electric shock with the previously announced probability. For the analysis, we focus on the time interval between the first and second stage. We observe a linear relation between SCRs in anticipation of receiving an electric shock and shock probability. This finding indicates that SCRs are able to code the likelihood of negative events. We outline how this coding function of SCRs during the anticipation of negative events might add to an understanding of human JDM.


Nanosecond time scale motions in proteins revealed by high-resolution NMR relaxometry.
Understanding the molecular determinants underlying protein function requires the characterization of both structure and dynamics at atomic resolution. Nuclear relaxation rates allow a precise characterization of protein dynamics at the Larmor frequencies of spins. This usually limits the sampling of motions to a narrow range of frequencies corresponding to high magnetic fields. At lower fields one cannot achieve sufficient sensitivity and resolution in NMR. Here, we use a fast shuttle device where the polarization builds up and the signals are detected at high field, while longitudinal relaxation takes place at low fields 0.5 < B0 < 14.1 T. The sample is propelled over a distance up to 50 cm by a blowgun-like system in about 50 ms. The analysis of nitrogen-15 relaxation in the protein ubiquitin over such a wide range of magnetic fields offers unprecedented insights into molecular dynamics. Some key regions of the protein feature structural fluctuations on nanosecond time scales, which have so far been overlooked in high-field relaxation studies. Nanosecond motions in proteins may have been underestimated by traditional high-field approaches, and slower supra-τ(c) motions that have no effect on relaxation may have been overestimated. High-resolution relaxometry thus opens the way to a quantitative characterization of nanosecond motions in proteins.


Tralopyril bioconcentration and effects on the gill proteome of the Mediterranean mussel Mytilus galloprovincialis.
Antifouling (AF) systems are used worldwide as one of the most cost-effective ways of protecting submerged structures against heavy biofouling. The emergence of environmentally friendly AF biocides requires knowledge on their environmental fate and toxicity. In this study we measured the bioconcentration of the emerging AF biocide tralopyril (TP) in the Mediterranean mussel Mytilus galloprovincialis and investigated the effects of TP on the mussel gill proteome following acute (2days) and chronic (30days) exposure, as well as after a 10-day depuration period. The experiments were carried out with 1μg/L TP; blank and solvent (5×10(-5)% DMSO) controls were also included. Proteomics analysis was performed by mass spectrometry-based multidimensional protein identification technology (MudPIT). Differentially expressed proteins were identified using a label-free approach based on spectral counts and G-test. Our results show that TP is rapidly accumulated by mussels at concentrations up to 362ng/g dw (whole tissues), reaching steady-state condition within 13days. Ten days of depuration resulted in 80% elimination of accumulated TP from the organism, suggesting that a complete elimination could be reached with longer depuration times. In total, 46 proteins were found to be regulated in the different exposure scenarios. Interestingly, not only TP but also DMSO alone significantly modulated the protein expression in mussel gills following acute and chronic exposure. Both compounds regulated proteins involved in bioenergetics, immune system, active efflux and oxidative stress, often in the opposite way. Alterations of several proteins, notably several cytoskeletal ones, were still observed after the depuration period. These may reflect either the continuing chemical effect due to incomplete elimination or an onset of recovery processes in the mussel gills. Our study shows that exposure of adult mussels to sublethal TP concentration results in the bioconcentration of this biocide in the tissues and modulates the expression of several proteins that may intervene in important metabolic pathways.


Per- and polyfluoroalkyl substances in source and treated drinking waters of the United States.
Contaminants of emerging concern (CECs), including per- and polyfluoroalkyl substances (PFAS), are of interest to regulators, water treatment utilities, the general public and scientists. This study measured 17 PFAS in source and treated water from 25 drinking water treatment plants (DWTPs) as part of a broader study of CECs in drinking water across the United States. PFAS were quantitatively detected in all 50 samples, with summed concentrations of the 17 PFAS ranging from <1 ng/L to 1102 ng/L. The median total PFAS concentration was 21.4 ng/L in the source water and 19.5 ng/L in the treated drinking water. Comparing the total PFAS concentration in source and treated water at each location, only five locations demonstrated statistically significant differences (i.e. P < 0.05) between the source and treated water. When the perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) concentrations in the treated drinking water are compared to the existing US Environmental Protection Agency's PFOA and PFOS drinking water heath advisory of 70 ng/L for each chemical or their sum one DWTP exceeded the threshold. Six of the 25 DWTPs were along two large rivers. The DWTPs within each of the river systems had specific PFAS profiles, with the three DWTPs from one river being dominated by PFOA, while three DWTPs on the second river were dominated by perfluorobutyric acid (PFBA).


Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.


Setting the agenda for a healthy retail environment: content analysis of US newspaper coverage of tobacco control policies affecting the point of sale, 2007-2014.
Tobacco control policies affecting the point of sale (POS) are an emerging intervention, yet POS-related news media content has not been studied. We describe news coverage of POS tobacco control efforts and assess relationships between article characteristics, including policy domains, frames, sources, localisation and evidence present, and slant towards tobacco control efforts. High circulation state (n=268) and national (n=5) newspapers comprised the sampling frame. We retrieved 917 relevant POS-focused articles in newspapers from 1 January 2007 to 31 December 2014. 5 raters screened and coded articles, 10% of articles were double coded, and mean inter-rater reliability (IRR) was 0.74. POS coverage emphasised tobacco retailer licensing (49.1% of articles) and the most common frame present was regulation (71.3%). Government officials (52.3%), followed by tobacco retailers (39.6%), were the most frequent sources. Half of articles (51.3%) had a mixed, neutral or antitobacco control slant. Articles presenting a health frame, a greater number of protobacco control sources, and statistical evidence were significantly more likely to also have a protobacco control slant. Articles presenting a political/rights or regulation frame, a greater number of antitobacco control sources, or government, tobacco industry, tobacco retailers, or tobacco users as sources were significantly less likely to also have a protobacco control slant. Stories that feature procontrol sources, research evidence and a health frame also tend to support tobacco control objectives. Future research should investigate how to use data, stories and localisation to encourage a protobacco control slant, and should test relationships between content characteristics and policy progression.


OMNA Marine Tourniquet Self-Application.
The OMNA Marine Tourniquet is a 5.1cm-wide, simple redirect buckle, hoop-and-loop secured, ratcheting tourniquet designed for storage and use in marine environments. This study evaluated self-application effectiveness and pressures. Triplicate secured, occlusion, and completion pressures were measured during 60 subjects pulling down or up thigh applications and nondominant, single-handed arm applications. Arm pressure measurements required circumferences =30cm. Thirty-one subjects had arm circumferences ≥30cm. All 540 applications were effective; 376 of 453 applications had known secured pressures >150mmHg (89 of 93 arm). Thigh down versus up pulling directions were not different (secured, occlusion, and completion pressures and ladder tooth advances). Occlusion pressures were 348mmHg (275-521mmHg) for combined thighs and 285mmHg (211-372mmHg) for arms. Completion pressures were 414mmHg (320-588mmHg) for combined thighs and 344mmHg (261-404mmHg) for arms. Correlations between secured pressures and occlusion ladder tooth advances (clicks) were r2 = 0.44 for combined thighs and 0.68 for arms. Correlations between occlusion pressures and occlusion clicks were poor (r2 = 0.24, P < .0001 for combined thighs and r2 = 0.027, P = .38 for arms). The OMNA Marine Tourniquet can be self-applied effectively, including one-handed applications. Occlusion and completion pressures are similar to reported 3.8cm-wide Ratcheting Medical Tourniquet pressures.


Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110-FGFR1 fusion: report of a new case and review of the literature.
The 8p12 myeloproliferative syndrome is a rare, generally aggressive chronic myeloproliferative disorder (MPD). The hallmark of this MPD is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. In MPD cells FGFR1 is fused to several partners. The most frequent partner genes are BCR, CEP110, FOP, and ZNF198, localized on 22q11, 9q33, 6q27, and 13q12, respectively. We report here the tenth case of translocation (8;9)(p12;q33) in an acute myelomonocytic leukemia and provide a review of the literature that points to common syndrome features: the t(8;9)(p11;q33) MPD transforms rapidly, and always in myelomonocytic leukemia, with a possible B- or T-lymphoid involvement, which may include tonsil invasion. The FGFR1-MPD seems refractory to current chemotherapies and is not sensitive to imatinib. Currently, only the patients with bone marrow transplantation stand a chance of survival.