mioC transcription, initiation of replication, and the eclipse in Escherichia coli.
The potential role of mioC transcription as a negative regulator of initiation of chromosome replication in Escherichia coli was evaluated. When initiation was aligned by a shift of dnaC2(Ts) mutants to nonpermissive temperature (40 degrees C), mioC transcript levels measured at the 5' end or reading through oriC disappeared within one mass doubling. Upon return to permissive temperature (30 degrees C), the transcripts reappeared coordinately about 15 min after the first synchronized initiation and then declined sharply again 10 min later, just before the second initiation. Although these observations were consistent with the idea that mioC transcription might have to be terminated prior to initiation, it was found that the interval between initiations at permissive temperature, i.e., the eclipse period, was not influenced by the time required to shut down mioC transcription, since the eclipse was the same for chromosomes and minichromosomes which lacked mioC transcription. This finding did not, in itself, rule out the possibility that mioC transcription must be terminated prior to initiation of replication, since it might normally be shut off before initiation, and never be limiting, even during the eclipse. Therefore, experiments were performed to determine whether the continued presence of mioC transcription during the process of initiation altered the timing of initiation. It was found that minichromosomes possessing a deletion in the DnaA box upstream of the promoter transcribed mioC continuously and replicated with the same timing as those that either shut down expression prior to initiation or lacked expression entirely. It was further shown that mioC transcription was present throughout the induction of initiation by addition of chloramphenicol to a dnaA5(Ts) mutant growing at a semipermissive temperature. Thus, transcription through oriC emanating from the mioC gene promoter is normally inhibited prior to initiation of replication by the binding of DnaA protein, but replication can initiate with the proper timing even when transcription is not shut down; i.e., mioC does not serve as a negative regulator of initiation. It is proposed, however, that the reappearance and subsequent disappearance of mioC transcription during a 10-min interval at the end of the eclipse serves as an index of the minimum time required for the establishment of active protein-DNA complexes at the DnaA boxes in the fully methylated origin region of the chromosome. On this basis, the eclipse constitutes the time for methylation of the newly formed DNA strands (15 to 20 min at 30 degrees C) followed by the time for DnaA protein to bind and activate oriC for replication (10 min).


Method to improve the noise figure and saturation power in multi-contact semiconductor optical amplifiers: simulation and experiment.
The consequences of tailoring the longitudinal carrier density along the active layer of a multi-contact bulk semiconductor optical amplifier (SOA) are investigated using a rate equation model. It is shown that both the noise figure and output power saturation can be optimized for a fixed total injected bias current. The simulation results are validated by comparison with experiment using a multi-contact SOA. The inter-contact resistance is increased using a focused ion beam in order to optimize the carrier density control. A chip noise figure of 3.8 dB and a saturation output power of 9 dBm are measured experimentally for a total bias current of 150 mA.


Polarization versus photon spin.
We examine whether the Stokes parameters of a two-mode electromagnetic field results from the superposition of the spins of the photons it contains. To this end we express any n-photon state as the result of the action on the vacuum of n creation operators generating photons which can have may different polarization states in general. We find that the macroscopic polarization holds as sum of the single-photon Stokes parameters only for the SU(2) orbits of photon-number states. The states that lack this property are entangled in every basis of independent field modes, so this is a class of entanglement beyond the reach of SU(2) transformations.


Medicalized Female Genital Mutilation/Cutting: Contentious Practices and Persistent Debates.
Female genital cutting/mutilation (FGM/C) performed by health care professionals (medicalization) and reduced severity of cutting have been advanced as strategies for minimizing health risks, sparking acrimonious ongoing debates. This study summarizes key debates and critically assesses supporting evidence. While medicalization is concentrated in Africa, health professionals worldwide have faced requests to perform FGM/C. Whether medicalization is hindering the decline of FGM/C is unclear. Factors motivating medicalization include, but are not limited to, safety concerns. Involvement of health professionals in advocacy to end FGM/C can address both the supply and demand side of medicalization, but raises ethical concerns regarding dual loyalty. Ongoing debates need to address competing rights claims. Polarizing debates have brought little resolution. We call for a focus on common goals of protecting the health and welfare of girls living in communities where FGM/C is upheld and encourage more informed and open dialog.


Slip-mediated dewetting of polymer microdroplets.
Classical hydrodynamic models predict that infinite work is required to move a three-phase contact line, defined here as the line where a liquid/vapor interface intersects a solid surface. Assuming a slip boundary condition, in which the liquid slides against the solid, such an unphysical prediction is avoided. In this article, we present the results of experiments in which a contact line moves and where slip is a dominating and controllable factor. Spherical cap-shaped polystyrene microdroplets, with nonequilibrium contact angle, are placed on solid self-assembled monolayer coatings from which they dewet. The relaxation is monitored using in situ atomic force microscopy. We find that slip has a strong influence on the droplet evolutions, both on the transient nonspherical shapes and contact line dynamics. The observations are in agreement with scaling analysis and boundary element numerical integration of the governing Stokes equations, including a Navier slip boundary condition.


Neutral metallated and meso-substituted porphyrins as antimicrobial agents against gram-positive pathogens.
Staphylococcus aureus is a bacterial pathogen that causes severe infections among humans. The increasing emergence of antibiotic resistance necessitates the development of new strategies to combat the spread of disease. One approach is photodynamic inactivation using porphyrin photosensitizers, which generate superoxide and other radicals in the presence of light, causing cell death via the oxidation of proteins and lipids. In this study, we analyzed a novel library of meso-substituted and metallated porphyrins for activity against multidrug-resistant S. aureus. From a library of 251 compounds, 51 showed antimicrobial activity, in three discrete classes of activity: those that functioned only in light, those that had toxicity only in darkness, and those that displayed activity regardless of illumination. We further demonstrated the broad-spectrum activity of these compounds against a variety of pathogens, including Bacillus anthracis, Enterococcus faecalis, and Escherichia coli. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) analyses of lead compounds (XPZ-263 and XPZ-271) revealed strong activity and killing towards methicillin-resistant S. aureus (MRSA) strains. An analysis of mutation frequencies revealed low incidences of resistance to lead compounds by E. coli and MRSA. Finally, an exploration of the underlying mechanism of action suggests that these compounds do not depend solely upon light-induced radical generation for toxicity, highlighting their potential for clinical applications.


The influence of water temperature and accelerometer-determined fight intensity on physiological stress and reflex impairment of angled largemouth bass.
Release of fish captured by recreational anglers is a common practice due to angler conservation ethics or compliance with fisheries regulations. As such, there is a need to understand the factors that influence mortality and sub-lethal impairments to ensure that catch-and-release angling is a sustainable practice. Longer angling times generally contribute to increased stress and mortality in fish such that reducing these times putatively reduces stress and improves survival. However, the relative importance of fight intensity (rather than simply duration) on fish condition is poorly understood. The objective of this research was to examine the effects of fight intensity on physiological stress and reflex impairment of largemouth bass (Micropterus salmoides). The largemouth bass were angled using conventional recreational fishing gear in May (water temperature ∼12°C) and June (∼22°C) of 2014 in Lake Opinicon, Ontario, Canada. Fight intensity was quantified using tri-axial accelerometer loggers mounted on the tips of fishing rods. Upon capture, reflex impairment measures were assessed, and fish were held for 1 h prior to blood sampling for measurement of physiological stress (blood glucose and lactate concentrations and pH). Physiological stress values showed a negative trend with fight duration and total fight intensity, but a positive trend with average fight intensity. Water temperature emerged as the most important predictor of the stress response in largemouth bass, while fight duration and intensity were not strong predictors. Reflex impairment was minimal, but higher reflex impairment scores were associated with elevated blood glucose. Overall, the findings of this study suggest that angling for largemouth bass at colder temperatures (<15°C) causes greater physiological stress than at warmer temperatures (>20°C). Based on our findings, we conclude that fight intensity is likely not to be a major driver of physiological stress in this species using typical largemouth bass angling gear, owing to the relatively short fight times (i.e. <2 min).


Modic changes-Their associations with low back pain and activity limitation: A systematic literature review and meta-analysis.
Previous systematic reviews have reported positive associations between Modic changes (MCs) and low back pain (LBP), but due to their narrow scope and new primary studies, there is a need for a comprehensive systematic review. Our objectives were to investigate if MCs are associated with non-specific LBP and/or activity limitation and if such associations are modified by other factors. A protocol for this review was registered at PROSPERO prior to commencing the work (PROSPERO record: CRD42015017350). The MEDLINE, CINAHL and EMBASE databases were searched for relevant studies from first record to June 15th 2016. Prospective or retrospective cross-sectional cohort studies and case-control studies including people of all ages from general, working and clinical study populations were eligible for inclusion. Risk of bias assessment and data extraction for associations and potential modifiers were completed independently by pairs of reviewers. Meta-analysis was performed for homogeneous studies and presented as odds ratios (OR) with 95% CI. In all, 5210 citations were identified and 31 studies were included. One study had low risk of bias. Fifteen studies (48%) reported statistically significant positive associations between MCs and LBP and one study found a statistically significant negative association. Meta-analysis performed for studies using concordant pain with provocative discography as the clinical outcome resulted in an OR of 4.01 (1.52-10.61). One of seven studies reported a statistically significant positive association between MCs and activity limitation. Lumbar disc level and disc degeneration were found to modify the association between MCs and LBP. The results from this comprehensive systematic review indicate that the associations between MCs and LBP-related outcomes are inconsistent. The high risk of bias and the heterogeneity in terms of study samples, clinical outcomes and prevalence estimates of MCs and LBP may explain these findings. It is likely that new studies with low risk of bias will affect the direction and strength of these associations.


Separating the agony from ecstasy: R(-)-3,4-methylenedioxymethamphetamine has prosocial and therapeutic-like effects without signs of neurotoxicity in mice.
S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.


Reversible heat stress-related loss of phosphorylated Alzheimer-type epitopes in Tau proteins of human neuroblastoma cells.
Human neuroblastoma cells, LAN, were used to study the phosphorylation and dephosphorylation of tau proteins. These cells contained mainly a form of tau comparable to fetal brain tau in molecular weight (55 kDa). Neuroblastoma tau reacted with antibodies that recognize epitopes spanning the whole tau molecule (E-1, Alz50, Tau-1, and Tau46), and antibodies (PHF-1, NP8, and T3P) that recognize hyperphosphorylated tau (PHF-tau) in Alzheimer's disease (AD) brains. Exposure of the cells to 45 degrees C heat stress resulted in dephosphorylation of the epitopes recognized by PHF-1, NP8, and T3P. Transfer of the heat-stressed cells to 37 degrees C led to rephosphorylation of the dephosphorylated epitopes. Cells that had been treated with okadaic acid (OA), regardless of whether they were subsequently subjected to heat stress or heat stress and recovery, all contained tau with a molecular weight similar to that of control cells. These tau proteins, similar to tau in control cells, also reacted with antibodies to phosphorylated epitopes. However, unlike the tau from control or heat-stressed cells, the OA-treated and heat-stressed tau had decreased reactivity with Tau-1. Alteration of Tau-1 immunoreactivity has been reported to be an early event in AD neurodegeneration. The reduction of Tau-1 immunoreactivity observed in OA-treated samples could be restored by incubation of electroblots of isolated tau with alkaline phosphatase, indicating an induction of the Tau-1 epitope phosphorylation by OA.(ABSTRACT TRUNCATED AT 250 WORDS)


Thermotolerant desert lizards characteristically differ in terms of heat-shock system regulation.
We compare the properties and activation of heat-shock transcription factor (HSF1) and the synthesis of a major family of heat-shock proteins (HSP70) in lizard species inhabiting ecological niches with strikingly different thermal parameters. Under normal non-heat-shock conditions, all desert-dwelling lizard species studied so far differ from a northern, non-desert species (Lacerta vivipara) in the electrophoretic mobility and content of proteins constitutively bound to the regulatory heat-shock elements in the heat-shock gene promoter. Under these conditions, levels of activated HSF1 and of both HSP70 mRNA and protein are higher in the desert species than in the non-desert species. Upon heat shock, HSF1 aggregates in all species studied, although in desert species HSF1 subsequently disaggregates more rapidly. Cells of the northern species have a lower thermal threshold for HSP expression than those of the desert species, which correlates with the relatively low constitutive level of HSPs and high basal content of HSF1 in their cells.


Decision-making by adults with mental retardation in simulated situations of abuse.
The ability of women and men with mental retardation to suggest prevention-focused decisions in response to simulated social interpersonal situations of abuse was investigated. Decision-making performance across three types of abusive situations (physical, sexual, psychological/verbal) was examined. Participants were able to suggest direct prevention-focused decisions aimed at resisting or stopping abuse 45% of the time and other-dependent prevention-focused decisions in the form of reporting 20% of the time. Prevention-focused decision-making was higher in situations of physical abuse (59%) than in situations of sexual (51%) or psychological/verbal abuse (26%). Women and men did not differ significantly in their decision-making responses.


Site-directed mutagenesis of the proposed catalytic amino acids of the Sindbis virus capsid protein autoprotease.
The structural proteins of Sindbis virus are translated as a polyprotein precursor that is cleaved upon translation. The capsid protein is postulated to be a serine protease that releases itself from the N terminus of the nascent polyprotein by autoproteolysis. We have tested the importance in autoproteolysis of His-141, Asp-147, and Ser-215, previously postulated to form the catalytic triad of the protease, and of Asp-163. Several site-specific mutations were constructed at each of these positions, and the release of the capsid protein during translation in a cell-free system was examined. Because proteolysis occurs in cis during translation, the kinetics of release cannot be determined in this system, but the extent of proteolysis can be ascertained. Ser-215 appears to be the catalytic serine of the proteinase. Cys or Thr could substitute inefficiently for Ser-215, but substitution with Ala or Ile led to complete loss of activity. His-141 was also important for proteolysis. Substitution with Ala or Pro led to total loss of activity. Surprisingly, substitution with Arg resulted in complete proteolysis in vitro. Changes at the two Asp residues resulted in complete proteolysis of the substrate in vitro. All mutations that resulted in at least partial cleavage in vitro were incorporated into a full-length clone of Sindbis virus and an attempt was made to recover mutant virus. All changes tested were lethal for the virus except Asp-163 to Asn. Thus, production of infectious virus is either a more sensitive measure of the catalytic rate than the extent of in vitro cleavage, or these residues have necessary functions in addition to their possible role in proteolysis.


Temporal changes in FFRCT-Guided Management of Coronary Artery Disease - Lessons from the ADVANCE Registry.
The ADVANCE registry is a large prospective study of outcomes and resource utilization in patients undergoing coronary computed tomography angiography (CCTA) and CT-based fractional flow reserve (FFRCT). As experience with new technologies and practices develops over time, we investigated temporal changes in the use of FFRCT within the ADVANCE registry. 5083 patients with coronary artery disease (CAD) on CCTA were prospectively enrolled in the ADVANCE registry and were divided into 3 equally sized cohorts based on the temporal order of enrollment per site. Demographics, CCTA and FFRCT findings, and clinical outcomes through 1-year follow-up, were recorded and compared between tertiles. The number of patients with a ≥70% stenosis on CCTA was similar over time (33.6%, 30.9%, and 33.8% for cohort 1-3). The rate of positive FFRCT ≤0.80 was higher for cohorts 2 (67.3%) and 3 (74.6%) than for cohort 1 (57.1%, p < 0.001). Invasive FFR rates decreased from 25.8% to 22.4% between cohort 1 and 3 (p = 0.023). Moreover, patients with a FFRCT ≤0.80 were less frequently referred for invasive coronary angiography (ICA) (from 62.9% to 52.9%, p < 0.001), and underwent fewer revascularizations between cohort 1 and 3 (from 41.9% to 32.0%, p < 0.001). The prevalence of major events was low (1.2%) and similar between cohorts. Growing experience with FFRCT improved the likelihood of identifying hemodynamically significant CAD and safely reduced the need for ICA and revascularization in patients with anatomically significant disease even in the instance of an abnormal FFRCT.


National character does not reflect mean personality trait levels in 49 cultures.
Most people hold beliefs about personality characteristics typical of members of their own and others' cultures. These perceptions of national character may be generalizations from personal experience, stereotypes with a "kernel of truth," or inaccurate stereotypes. We obtained national character ratings of 3989 people from 49 cultures and compared them with the average personality scores of culture members assessed by observer ratings and self-reports. National character ratings were reliable but did not converge with assessed traits. Perceptions of national character thus appear to be unfounded stereotypes that may serve the function of maintaining a national identity.


First report of an outbreak of cerebral coenurosis in Dhofari goats in Oman.
This study documented the first outbreak of cerebral coenurosis in goats in Salalah, southern Oman. Deaths of 130 (16.6%) adult native goats in a herd (n=780) were reported from January to June 2017. Affected goats showed various nervous signs ended by death. Investigations for thiamine deficiency, polioencephalomalacia, caprine arthritis encephalitis, and listeriosis were negative. Upon necropsy, multiple (1-4) thin-walled cysts 2-3.5 cm in diameter containing clear fluid with numerous clusters of protoscolices in the cerebrum and cerebellum had replaced the brain parenchyma, causing space-occupying lesions. Parasitologically, the recovered cysts were Coenurus cerebralis, based on the arrangement of protoscolices, and the number and size of their hooks. Morphologically, each protoscolex had four suckers and a rostellum with double-crown hooks. The large and small hooks were 157.7±0.5 µm and 115±0.6 µm in length, respectively. Histopathologically, the parasite destroyed the affected tissues associated with multifocal to diffuse lymphocytic, non-suppurative meningoencephalitis; ischemic neuronal necrosis; and malacia. This is the first report of cerebral coenurosis in livestock in Oman, which should alert the local public health authorities for the application of prevention and control measures.


Fine-needle aspiration cytology can play a role in neoadjuvant chemotherapy in operable breast cancer.
Despite the fact that CNB has been progressively replaced by FNAC in the investigation of nonpalpable lesions or microcalcifications without a clinical or radiological mass lesion, FNAC has yet a role in palpable lesions provided it is associated with the triple diagnosis and experienced cytologist. In these conditions, FNAC is a safe, effective, economical, and accurate technique for breast cancer evaluation. Numerous literature reviews and meta-analyses illustrated the advantages and disadvantages of both methods CNB and FNAC. The difference does not seem significant when noninformative and unsatisfactory FNAC was excluded. Recently, cytological methods using liquid-based cytology (LBC) technology improve immunocytological and molecular tests with the same efficiency as classical immunohistochemistry. The indications of FNAC were, for palpable lesions, relative contraindication of CNB (elderly or frailty), staging of multiple nodules in conjunction or not with CNB, staging of lymph node status, newly appearing lesion in patient under neoadjuvant treatment, decreasing of anxiety with a rapid diagnosis, evaluation of biomarkers and new biomarkers, and chronological evaluation of biomarker following the neoadjuvant therapy response.


The Current Status of Research on the Integration of Sexual and Reproductive Health and HIV Services.
Integration of services for sexual and reproductive health (SRH) and HIV has been widely promoted globally in the belief that both clients and health providers benefit through improvements in quality, efficient use of resources, and lower costs, helping to maximize limited health resources and provide comprehensive client-centered care. This article builds on the growing body of research on integrated sexual SRH and HIV services. It brings together critical reviews on issues within the wider SRH and rights agenda and synthesizes recent research on integrated services, drawing on the Integra Initiative and other major research. Unintended pregnancy and HIV are intrinsically interrelated SRH issues, however broadening the constellation of services, scaling up, and mainstreaming integration continue to be challenging. Overcoming stigma, reducing gender-based violence, and meeting key populations' SRH needs are critical. Health systems research using SRH as the entry point for integrated services and interaction with communities and clients is needed to realize universal health coverage.


Automated detection of white matter changes in elderly people using fuzzy, geostatistical, and information combining models.
Detection of white matter changes of the brain using magnetic resonance imaging (MRI) has increasingly been an active and challenging research area in computational neuroscience. There have rarely been any single image analysis methods that can effectively address the issue of automated quantification of neuroimages, which are subject to different interests of various medical hypotheses. This paper presents new image segmentation models for automated detection of white matter changes of the brain in an elderly population. The methods are based on the computational models of fuzzy clustering, possibilistic clustering, geostatistics, and knowledge combination. Experimental results on MRI data have shown that the proposed image analysis methodology can be applied as a very useful computerized tool for the validation of our particular medical question, where white matter changes of the brain are thought to be the most important social medical evidence.


Profile of functional limitations and task performance among people with early- and middle-stage Parkinson disease.
Overall functional ability declines over time in people with Parkinson disease (PD). Established benchmarks are needed to allow clinicians and researchers to facilitate meaningful interpretation of data. The purposes of this study were: (1) to report typical values for standard measures of functional ability commonly used in intervention studies and clinical practice with individuals in the early and middle stages of PD and (2) to describe the profile of functional limitations using the Hoehn and Yahr (H&Y) stages of disease and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. Cross-sectional data were obtained from 5 different studies. Three hundred thirty-nine patients were evaluated for disease severity (UPDRS motor score); functional capacity (Continuous Scale Physical Functional Performance Test [CS-PFP]); balance and gait (Functional Reach Test [FRT], Timed "Up & Go" Test [TUG], 360-degree turn, Six-Minute Walk Test [6MWT], and Two-Minute Walk Test); and basic functional activities (supine-to-stand task, stand-to-supine task, and functional axial rotation [FAR]). The mean UPDRS motor score for the sample was 39.2 (SD=12.93). At each stage of PD (from least to most involved), scores on functional measures indicated a significant and progressively reduced functional status. Limitations began early in the disease for the CS-PFP and FAR. Losses in performance were consistent across all stages of disease for the CS-PFP, FRT, 6MWT, and FAR. Several measures demonstrated meaningful losses of function only in later stages of disease. Findings extend current appreciation of functional limitations that begin early in PD and can guide the choice of functional outcome measures at different stages of disease severity. Data were obtained only from participants in H&Y stages 1 through 3 and only for some of the performance measures typically used. The findings demonstrate that functional loss occurs at different points in the disease process, depending on the task under consideration. The resulting profile of functional limitations provides benchmarks that clinicians and researchers can use to interpret and monitor status of patients.


Molecular rheology of branched polymers: decoding and exploring the role of architectural dispersity through a synergy of anionic synthesis, interaction chromatography, rheometry and modeling.
An emerging challenge in polymer physics is the quantitative understanding of the influence of a macromolecular architecture (i.e., branching) on the rheological response of entangled complex polymers. Recent investigations of the rheology of well-defined architecturally complex polymers have determined the composition in the molecular structure and identified the role of side-products in the measured samples. The combination of different characterization techniques, experimental and/or theoretical, represents the current state-of-the-art. Here we review this interdisciplinary approach to molecular rheology of complex polymers, and show the importance of confronting these different tools for ensuring an accurate characterization of a given polymeric sample. We use statistical tools in order to relate the information available from the synthesis protocols of a sample and its experimental molar mass distribution (typically obtained from size exclusion chromatography), and hence obtain precise information about its structural composition, i.e. enhance the existing sensitivity limit. We critically discuss the use of linear rheology as a reliable quantitative characterization tool, along with the recently developed temperature gradient interaction chromatography. The latter, which has emerged as an indispensable characterization tool for branched architectures, offers unprecedented sensitivity in detecting the presence of different molecular structures in a sample. Combining these techniques is imperative in order to quantify the molecular composition of a polymer and its consequences on the macroscopic properties. We validate this approach by means of a new model asymmetric comb polymer which was synthesized anionically. It was thoroughly characterized and its rheology was carefully analyzed. The main result is that the rheological signal reveals fine molecular details, which must be taken into account to fully elucidate the viscoelastic response of entangled branched polymers. It is important to appreciate that, even optimal model systems, i.e., those synthesized with high-vacuum anionic methods, need thorough characterization via a combination of techniques. Besides helping to improve synthetic techniques, this methodology will be significant in fine-tuning mesoscopic tube-based models and addressing outstanding issues such as the quantitative description of the constraint release mechanism.


A continuous-time state-space model for rapid quality control of argos locations from animal-borne tags.
State-space models are important tools for quality control and analysis of error-prone animal movement data. The near real-time (within 24 h) capability of the Argos satellite system can aid dynamic ocean management of human activities by informing when animals enter wind farms, shipping lanes, and other intensive use zones. This capability also facilitates the use of ocean observations from animal-borne sensors in operational ocean forecasting models. Such near real-time data provision requires rapid, reliable quality control to deal with error-prone Argos locations. We formulate a continuous-time state-space model to filter the three types of Argos location data (Least-Squares, Kalman filter, and Kalman smoother), accounting for irregular timing of observations. Our model is deliberately simple to ensure speed and reliability for automated, near real-time quality control of Argos location data. We validate the model by fitting to Argos locations collected from 61 individuals across 7 marine vertebrates and compare model-estimated locations to contemporaneous GPS locations. We then test assumptions that Argos Kalman filter/smoother error ellipses are unbiased, and that Argos Kalman smoother location accuracy cannot be improved by subsequent state-space modelling. Estimation accuracy varied among species with Root Mean Squared Errors usually <5 km and these decreased with increasing data sampling rate and precision of Argos locations. Including a model parameter to inflate Argos error ellipse sizes in the north - south direction resulted in more accurate location estimates. Finally, in some cases the model appreciably improved the accuracy of the Argos Kalman smoother locations, which should not be possible if the smoother is using all available information. Our model provides quality-controlled locations from Argos Least-Squares or Kalman filter data with accuracy similar to or marginally better than Argos Kalman smoother data that are only available via fee-based reprocessing. Simplicity and ease of use make the model suitable both for automated quality control of near real-time Argos data and for manual use by researchers working with historical Argos data.


Harnessing FOXP3+ regulatory T cells for transplantation tolerance.
Early demonstrations that mice could be tolerized to transplanted tissues with short courses of immunosuppressive therapy and that with regard to tolerance to self, CD4+FOXP3+ regulatory T cells (Tregs) appeared to play a critical role, have catalyzed strategies to harness FOXP3-dependent processes to control rejection in human transplantation. This review seeks to examine the scientific underpinning for this new approach to finesse immunosuppression.


Antibody responses to the merozoite surface protein-1 complex in cerebral malaria patients in India.
Plasmodium falciparum infection causes cerebral malaria (CM) in a subset of patients with anti-malarial treatment protecting only about 70% to 80% of patients. Why a subset of malaria patients develops CM complications, including neurological sequelae or death, is still not well understood. It is believed that host immune factors may modulate CM outcomes and there is substantial evidence that cellular immune factors, such as cytokines, play an important role in this process. In this study, the potential relationship between the antibody responses to the merozoite surface protein (MSP)-1 complex (which consists of four fragments namely: MSP-1(83), MSP-1(30), MSP-1(38) and MSP-1(42)), MSP-6(36) and MSP-7(22) and CM was investigated. Peripheral blood antibody responses to recombinant antigens of the two major allelic forms of MSP-1 complex, MSP-6(36) and MSP-7(22) were compared between healthy subjects, mild malaria patients (MM) and CM patients residing in a malaria endemic region of central India. Total IgG and IgG subclass antibody responses were determined using ELISA method. The prevalence and levels of IgG and its subclasses in the plasma varied for each antigen. In general, the prevalence of total IgG, IgG1 and IgG3 was higher in the MM patients and lower in CM patients compared to healthy controls. Significantly lower levels of total IgG antibodies to the MSP-1(f38), IgG1 levels to MSP-1(d83), MSP-1(19) and MSP-6(36) and IgG3 levels to MSP-1(f42) and MSP-7(22) were observed in CM patients as compared to MM patients. These results suggest that there may be some dysregulation in the generation of antibody responses to some MSP antigens in CM patients and it is worth investigating further whether perturbations of antibody responses in CM patients contribute to pathogenesis.


Differential transmission of the genospecies of Borrelia burgdorferi sensu lato by game birds and small rodents in England.
The genetic diversity of Borrelia burgdorferi sensu lato was assessed in a focus of Lyme borreliosis in southern Britain dominated by game birds. Ticks, rodents, and pheasants were analyzed for spirochete infections by PCR-targeting the 23S-5S rRNA genes, followed by genotyping by the reverse line blot method. In questing Ixodes ricinus ticks, three genospecies of B. burgdorferi sensu lato were detected, with the highest prevalences found for Borrelia garinii and Borrelia valaisiana. B. burgdorferi sensu stricto was rare (< 1%) in all tick stages. Borrelia afzelia was not detected in any of the samples. More than 50% of engorged nymphs collected from pheasants were infected with borreliae, mainly B. garinii and/or B. valaisiana. Although 19% of the rodents harbored B. burgdorferi sensu stricto and/or B. garinii in internal organs, only B. burgdorferi sensu stricto was transmitted to xenodiagnostic tick larvae (it was transmitted to 1% of the larvae). The data indicate that different genospecies of B. burgdorferi sensu lato can be maintained in nature by distinct transmission cycles involving the same vector tick species but different vertebrate host species. Wildlife management may have an influence on the relative risk of different clinical forms of Lyme borreliosis.


Clonal analysis of human colorectal tumors.
The clonal composition of human colorectal tumors was studied by means of restriction fragment length polymorphisms (RFLPs). First, X-linked RFLPs were used to examine the pattern of X chromosome inactivation in colorectal tumors of females. All 50 tumors examined showed monoclonal patterns of X chromosome inactivation; these tumors included 20 carcinomas as well as 30 adenomas of either familial or spontaneous type. Second, RFLPs of autosomes were used as clonal markers to detect the somatic loss or gain of specific chromosomal sequences in colorectal tumors. Among other changes, it was found that somatic loss of chromosome 17p sequences occurred in over 75 percent of the carcinomas examined, but such loss was rare in adenomas. These data support a monoclonal origin for colorectal neoplasms, and suggest that a gene on the short arm of chromosome 17 may be associated with progression from the benign to the malignant state.


Decrypting the structure of major histocompatibility complex class I-restricted cytotoxic T lymphocyte epitopes with complex peptide libraries.
Complex synthetic peptide libraries with defined amino acids in one or more positions of the H-2Kb-restricted cytotoxic T lymphocyte (CTL) epitopes SIINFEKL and RGYVYQGL and mixtures of 19 amino acids in the remaining positions were used to analyze the structural requirements of peptide binding to MHC class I molecules and antigen recognition by CTLs. This approach provides means to assess semiquantitatively the contribution of every amino acid to the binding of peptides to major histocompatibility complex (MHC) molecules without biases introduced by naturally processed peptides. Primary and secondary anchor residues were defined for their major contribution to the binding efficiency of the peptides. In contrast to primary anchors, secondary anchor amino acids vary greatly in their side chains and position in the sequences. All amino acids in the octapeptide sequences were found to exhibit positive or negative influences on binding to the MHC molecules and on recognition of the resulting complexes by CTLs. Strong interdependence of the effects of the individual residues in the epitope sequences was demonstrated. CTL responses to peptide libraries were suppressed when residues were introduced; however, they were augmented when the critical residues for T cell recognition were fixed, suggesting a potential use of the peptide libraries for defining epitope sequences in general.


Expression of O6-Methylguanine-DNA Methyltransferase Examined by Alkyl-Transfer Assays, Methylation-Specific PCR and Western Blots in Tumors and Matched Normal Tissue.
The tumor selectivity of alkylating agents that produce guanine O6-chloroethyl (laromustine and carmustine) and O6-methyl (temozolomide) lesions, depends upon O6-methylguanine-DNA methyltransferase (MGMT) activity being lower in tumor than in host tissue. Despite the established role of MGMT as a tumor resistance factor, consensus on how to assess MGMT expression in clinical samples is unsettled. The aim of this study is to examine the relationship between the values derived from distinctive MGMT measurements in 13, 12, 6 and 2 pairs of human tumors and matched normal adjacent tissue from the colon, kidney, lung and liver, respectively, and in human cell lines. The MGMT measurements included (a) alkyl-transfer assays using [benzene-3H]O6-benzylguanine as a substrate to assess functional MGMT activity, (b) methylation-specific PCR (MSP) to probe MGMT gene promoter CpG methylations as a measure of gene silencing, and (c) western immunoblots to analyze the MGMT protein. In human cell lines, a strict negative correlation existed between MGMT activity and the extent of promoter methylation. In tissue specimens, by contrast, the correlation between these two variables was low. Moreover, alkyl-transfer assays identified 3 pairs of tumors and normal tissue with tumor-selective reduction in MGMT activity in the absence of promoter methylation. Cell line MGMT migrated as a single band in western analyses, whereas tissue MGMT was heterogeneous around its molecular size and at much higher molecular masses, indicative of multi-layered post-translational modifications. Malignancy is occasionally associated with a mobility shift in MGMT. Contrary to the prevalent expectation that MGMT expression is governed at the level of gene silencing, these data suggest that other mechanisms that can lead to tumor-selective reduction in MGMT activity exist in human tissue.


Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity.
Angiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raised in severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelial NO bioavailability would be inversely correlated with ang-2 concentrations in sepsis. Plasma ang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83 patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterial tonometry, RH-PAT, a measure of endothelial NO bioavailability. Plasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001). It correlated inversely with RH-PAT (r = -0.38, P < 0.0001) and positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (sequential organ function assessment score) (r = 0.58, P < 0.0001). The correlation of ang-2 with RH-PAT persisted after controlling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time was associated with decline in ang-2. Ang-2 is elevated in proportion to sepsis severity, and inversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak. Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity may have therapeutic potential in sepsis.


Enhanced pathogenicity and neurotropism of mouse-adapted H10N7 influenza virus are mediated by novel PB2 and NA mutations.
The H10 subtype of avian influenza viruses (AIVs) circulates globally in wild birds and poultry, and this subtype has been shown to be increasingly prevalent in China. Among the various H10 viruses, H10N7 AIVs have caused repeated mammal and human infections. To investigate their genetic adaptation in mammals, we generated a mouse-adapted avian H10N7 variant (A/mallard/Beijing/27/2011-MA; BJ27-MA) which exhibited increased virulence in mice compared to wild-type virus and acquired neurotropism. Sequencing showed the absence of the widely recognized mammalian adaptation markers of E627K and D701N in PB2 in the mouse-adapted strain; instead, five amino acid mutations were identified: E158G and M631L in PB2; G218E in haemagglutinin (H3 numbering); and K110E and S453I in neuraminidase (NA). The neurovirulence of the BJ27-MA virus necessitated the combined presence of the PB2 and NA mutations. Mutations M631L and E158G of PB2 and K110E of NA were required to mediate increased virus replication and severity of infection in mice and mammalian cells. PB2-M631L was functionally the most dominant mutation in that it strongly upregulated viral polymerase activity and played a critical role in the enhancement of virus replication and disease severity in mice. K110E mutation in NA, on the other hand, significantly promoted NA enzymatic activity. These results indicate that the novel mutations in PB2 and NA genes are critical for the adaptation of H10N7 AIV in mice, and they could serve as molecular signatures of virus transmission to mammalian hosts, including humans.


The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells.
The role of the blood-brain barrier (BBB) is to control trafficking of biomolecules and protect the brain. This function can be compromised by pathological conditions. Parkinson's disease (PD) is characterized by the accumulation of α-synuclein aggregates (αSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how αSN-AGs affect the BBB in in vitro co-culturing models consisting of human brain endothelial hCMEC/D3 cells (to overcome inter-species differences) alone and co-cultured with astrocytes and neurons/glial cells. When cultivated on their own, hCMEC/D3 cells were compromised by αSN-AGs, which decreased cellular viability, mitochondrial membrane potential, wound healing activity, TEER value, and enhanced permeability, as well as increased the levels of ROS and NO. Co-culturing of these cells with activated microglia also increased BBB impairment according to TEER and systemic immune cell transmigration assays. In contrast, hCMEC/D3 cells co-cultured with astrocytes or dopaminergic neurons or simultaneously treated with their conditioned media showed increased resistance against αSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), αSN-AGs and BBB.


Nanostructuring discotic molecules on ITO support.
Patterning of organic compounds on a nanometer length scale is of great interest for solar applications: defined control over the donor-acceptor interface will allow design of an optimized nano-morphology promoting exciton separation and reducing charge recombination. Herein we present an imprinting technique using anodized alumina oxide (AAO) hard templates as stamps. We show an exact pattern transfer of the AAO structures into a solution processable hexa-peri-hexabenzocoronene (HBC), a discotic small molecule with acrylate moieties which is polymerized in situ. Film fabrication is realized for a variety of nanowire dimensions on square centimeter areas. The fabrication directly on conductive glass support and control over the formation of a dense barrier layer render this approach appealing for the fabrication of fully organic nanostructured photovoltaic devices.


Clinical and biological assessment in systemic necrotizing vasculitides.
The systemic vasculitides are multi-system disorders with significant mortality and morbidity and frequent relapses. Treatment is usually effective but fraught with potentially serious effects. Disease Assessment is important to ensure that patients receive the appropriate treatment. Disease Assessment should comprise measurement of disease activity, chronic irreversible damage and impairment of function. Serological markers can be helpful in assessing disease activity but lack sufficient sensitivity and specificity to be used on their own. Radiological techniques such as Magnetic Resonance Imaging, Ultrasound and Positron Emission Tomography show promise in the large vessel vasculitides but require validation in large studies. Clinical Assessment tools are the current gold standard for the assessment of disease activity, damage and function.


Ulcerative keratitis in contact lens wearers. Incidence and risk factors.
A case-control study of ulcerative keratitis in soft contact lens (CL) users compared three groups of daily wear or extended wear patients: (a) 86 patients with ulcerative keratitis, (b) 61 hospital-based controls, and (c) 410 population-based controls. Overnight lens use, whether regularly with extended wear lenses or occasionally with daily wear lenses, emerged as the preeminent risk factor for ulcerative keratitis. It increased risk by 10 to 15 times in users of extended wear lenses and by 9 times in users of daily wear lenses when these groups were compared with subjects engaged in strict daily wear of daily wear lenses. Even when actual overnight wear was not taken into account, the relative risk was four times greater in users of extended wear lenses than in users of daily wear lenses. The study found a marginal association (p = 0.056) between lens care frequency in general and ulcerative keratitis in comparing ulcerative keratitis cases with population controls. Of the individual hygiene-related measures, evidence of a protective effect was strongest for cleaning the lens case. Smokers showed a threefold greater risk than nonsmokers, regardless of the type of lens worn. An incidence study found the rate of ulcerative keratitis to be approximately 1 in 2,500 daily wear lens users and 1 in 500 extended wear lens users per year. This finding was statistically consistent with the risk ratio noted in the case-control study. Extrapolations suggest that 4,000 of the 9 million U.S. users of daily wear soft lenses develop ulcerative keratitis annually. Among the 4 million U.S. extended wear soft lens users, 8,000 may do so per year.


Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function.
Myoferlin and dysferlin are members of the ferlin family of membrane proteins. Recent studies have shown that mutation or genetic disruption of myoferlin or dysferlin promotes muscular dystrophy-related phenotypes in mice, which are the result of impaired plasma membrane integrity. However, no biological functions have been ascribed to myoferlin in non-muscle tissues. Herein, using a proteomic analysis of endothelial cell (EC) caveolae/lipid raft microdomains we identified myoferlin in these domains and show that myoferlin is highly expressed in ECs and vascular tissues. The loss of myoferlin results in lack of proliferation, migration, and nitric oxide (NO) release in response to vascular endothelial growth factor (VEGF). Western blotting and surface biotinylation experiments show that loss of myoferlin reduces the expression level and autophosphorylation of VEGF receptor-2 (VEGFR-2) in native ECs. In a reconstituted cell system, transfection of myoferlin increases VEGFR-2 membrane expression and autophosphorylation in response to VEGF. In vivo, VEGFR-2 levels and VEGF-induced permeability are impaired in myoferlin-deficient mice. Mechanistically, myoferlin forms a complex with dynamin-2 and VEGFR-2, which prevents CBL-dependent VEGFR-2 polyubiquitination and proteasomal degradation. These data are the first to report novel biological activities for myoferlin and reveal the role of membrane integrity to VEGF signaling.


A picture's worth a thousand words: engaging youth in CBPR using the creative arts.
Engaging youth and incorporating their unique expertise into the research process is important when addressing issues related to their health. Visual Voices is an arts-based participatory data collection method designed to work together with young people and communities to collaboratively elicit, examine, and celebrate the perspectives of youth. To present a process for using the creative arts with young people as a participatory data collection method and to give examples of their perspectives on safety and violence. Using the creative arts, this study examined and illustrates the perspectives of how community factors influence safety and violence. Visual Voices was conducted with a total of 22 African-American youth in two urban neighborhoods. This method included creative arts-based writing, drawing, and painting activities designed to yield culturally relevant data generated and explored by youth. Qualitative data were captured through the creative content of writings, drawings, and paintings created by the youths as well as transcripts from audio recorded group discussion. Data was analyzed for thematic content and triangulated across traditional and nontraditional mediums. Findings were interpreted with participants and shared publicly for further reflection and utilization. The youth participants identified a range of issues related to community factors, community safety, and violence. Such topics included the role of schools and social networks within the community as safe places and corner stores and abandoned houses as unsafe places. Visual Voices is a creative research method that provides a unique opportunity for youth to generate a range of ideas through access to the multiple creative methods provided. It is an innovative process that generates rich and valuable data about topics of interest and the lived experiences of young community members.


The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder.
In an attempt to surmount the problem of retrospectively establishing the childhood diagnosis of attention deficit hyperactivity disorder, the authors constructed the 61-item Wender Utah Rating Scale (WURS) for adults to use to describe their own childhood behavior. In this paper they present their initial data collection and evaluation of the instrument's validity. The scale was administered to 81 adult outpatients with attention deficit hyperactivity disorder, 100 "normal" adults, and 70 psychiatric adult outpatients with unipolar depression. The authors analyzed data from the 25 items of the scale that showed the greatest difference between the patients with attention deficit hyperactivity disorder and the normal comparison subjects and the relationship between the WURS and the patients' parents' judgment of childhood activity as measured by the Parents' Rating Scale. The patients with attention deficit hyperactivity disorder had significantly higher mean scores on all 25 items than did the two comparison groups. The difference between the mean total scores of the patients with attention deficit hyperactivity disorder and the normal subjects was also highly significant. A cutoff score of 46 or higher correctly identified 86% of the patients with attention deficit hyperactivity disorder, 99% of the normal subjects, and 81% of the depressed subjects. Correlations obtained between WURS scores and Parents' Rating Scale scores were moderate but impressive. The ability of WURS scores to predict response to methylphenidate replicated the authors' finding regarding the ability of Parents' Rating Scale scores to predict response to pemoline. The WURS is sensitive in identifying childhood attention deficit hyperactivity disorder and may be useful in recognizing attention deficit hyperactivity disorder in patients with ambiguous adult psychopathology.


Decubitus ulcers: a review of the literature.
Decubitus ulcers are a worldwide health care concern affecting tens of thousands of patients and costing over a billion dollars a year. Susceptibility to pressure ulcers comes from a combination of external factors (pressure, friction, shear force, and moisture), and internal factors (e.g. fever, malnutrition, anaemia, and endothelial dysfunction). Often, enough damage is done to create the basis for a decubitus ulcer after as little as 2 h of immobility, a situation which may be difficult to avoid if the patient must undergo prolonged surgery or remain bedridden. Damage owing to pressure may also occur hours before the patient receives medical attention, especially if the patient falls or becomes immobilized owing to a vascular event. Several classification systems for decubitus ulcers have been described, based on where injury first occurs. The histologic progression of decubitus ulcers is a dynamic process involving several stages, each having characteristic histologic features. A team-focused approach integrating all aspects of care, including pressure relief, infection control, nutrition, and surgery, may improve healing rates. With accurate risk assessment and preventative care, we can hope to minimize complications and mortality owing to decubitus ulcers.


Epidermal Growth Factor Receptor Mutation and Anaplastic Lymphoma Kinase Gene Fusion: Detection in Malignant Pleural Effusion by RNA or PNA Analysis.
Analyzing EGFR mutations and detecting ALK gene fusion are indispensable when planning to treat pulmonary adenocarcinoma. Malignant pleural effusion (MPE) is a devastating complication of lung cancer and sometimes the only source for mutation analysis. The percentage of tumor cells in the pleural effusion may be low; therefore, mutant enrichment is required for a successful analysis. The EGFR mutation status in MPE was determined using three methods: (1) PCR sequencing of genomic DNA (direct sequencing), (2) mutant-enriched PCR sequencing of genomic DNA using peptide nucleic acid (PNA-sequencing), and (3) PCR sequencing of cDNA after reverse transcription for cellular RNA (RNA-sequencing). RT-PCR was also used to test cases for ALK gene fusion. PNA-sequencing and RNA-sequencing had similar analytical sensitivities (< 1%), which indicates similar enrichment capabilities. The clinical sensitivity in 133 cases when detecting the common EGFR exon 19 and exon 21 mutations was 56.4% (75/133) for direct sequencing, 63.2% (84/133) for PNA-sequencing, and 65.4% (87/133) for RNA-sequencing. RT-PCR and sequencing showed 5 cases (3.8%) with ALK gene fusion. All had wild-type EGFR. For EGFR analysis of MPE, RNA-sequencing is at least as sensitive as PNA-sequencing but not limited to specific mutations. Detecting ALK fusion can be incorporated in the same RNA workflow. Therefore, RNA is a better source for comprehensive molecular diagnoses in MPE.


Late adverse effects of radiation therapy for rectal cancer - a systematic overview.
The use of radiation therapy (RT) together with improvement in the surgical treatment of rectal cancer improves survival and reduces the risk for local recurrences. Despite these benefits, the adverse effects of radiation therapy limit its use. The aim of this review was to present a comprehensive overview of published studies on late adverse effects related to the RT for rectal cancer. Meta-analyses, reviews, randomised clinical trials, cohort studies and case-control studies on late adverse effects, due to pre- or postoperative radiation therapy and chemo-radiotherapy for rectal cancer, were systematically searched. Most information was obtained from the randomised trials, especially those comparing preoperative short-course 5 x 5 Gy radiation therapy with surgery alone. The late adverse effects due to RT were bowel obstructions; bowel dysfunction presented as faecal incontinence to gas, loose or solid stools, evacuation problems or urgency; and sexual dysfunction. However, fewer late adverse effects were reported in recent studies, which generally used smaller irradiated volumes and better irradiation techniques; although, one study revealed an increased risk for secondary cancers in irradiated patients. These results stress the importance of careful patient selection for RT for rectal cancer. Improvements in the radiation technique should further be developed and the long-term follow-up of the randomised trials is the most important source of information on late adverse effects and should therefore be continued.


Directly interrogating single quantum dot labelled UvrA2 molecules on DNA tightropes using an optically trapped nanoprobe.
In this study we describe a new methodology to physically probe individual complexes formed between proteins and DNA. By combining nanoscale, high speed physical force measurement with sensitive fluorescence imaging we investigate the complex formed between the prokaryotic DNA repair protein UvrA2 and DNA. This approach uses a triangular, optically-trapped "nanoprobe" with a nanometer scale tip protruding from one vertex. By scanning this tip along a single DNA strand suspended between surface-bound micron-scale beads, quantum-dot tagged UvrA2 molecules bound to these '"DNA tightropes" can be mechanically interrogated. Encounters with UvrA2 led to deflections of the whole nanoprobe structure, which were converted to resistive force. A force histogram from all 144 detected interactions generated a bimodal distribution centered on 2.6 and 8.1 pN, possibly reflecting the asymmetry of UvrA2's binding to DNA. These observations successfully demonstrate the use of a highly controllable purpose-designed and built synthetic nanoprobe combined with fluorescence imaging to study protein-DNA interactions at the single molecule level.


Timely Hemodynamic Resuscitation and Outcomes in Severe Pediatric Traumatic Brain Injury: Preliminary Findings.
Early resuscitation may improve outcomes in pediatric traumatic brain injury (TBI). We examined the association between timely treatment of hypotension and hypoxia during early care (prehospital or emergency department locations) and discharge outcomes in children with severe TBI. Hypotension was defined as systolic blood pressure less than 70 + 2 (age in years), and hypoxia was defined as PaO2 less than 60 mm Hg or oxygen saturation less than 90% in accordance with the 2003 Brain Trauma Foundation guidelines. Timely treatment of hypotension and hypoxia during early care was defined as the treatment within 30 minutes of a documented respective episode. Two hundred thirty-six medical records of children younger than 18 years with severe TBI from 5 regional pediatric trauma centers were examined. Main outcomes were in-hospital mortality and discharge Glasgow Outcome Scale (GOS) score. Hypotension occurred in 26% (60/234) during early care and was associated with in-hospital mortality (23.3% vs 8.6%; P = 0.01). Timely treatment of hypotension during early care occurred in 92% (55/60) by use of intravenous fluids, blood products, or vasopressors and was associated with reduced in-hospital mortality [adjusted relative risk (aRR), 0.46; 95% confidence interval, 0.24-0.90] and less likelihood of poor discharge GOS (aRR, 0.54; 95% confidence interval, 0.39-0.76) when compared to children with hypotension who were not treated in a timely manner. Early hypoxia occurred in 17% (41/236) and all patients received timely oxygen treatment. Timely resuscitation during early care was common and associated with lower in-hospital mortality and favorable discharge GOS in severe pediatric TBI.


Risk of breast cancer following fertility treatment--a registry based cohort study of parous women in Norway.
Despite increasing numbers of women availing themselves of assisted reproductive technology (ART), effects on cancer risk remain unresolved. Given hormonal exposures, breast cancer risk is of particular concern. The aim of this study is to investigate breast cancer risk amongst women giving birth following ART as compared to that amongst women who gave birth without ART. Data on all women who gave birth in Norway with or without ART, between 1984 and 2010 were obtained from the Medical Birth Registry of Norway (MBRN). 808,834 women eligible for study were linked to the Cancer Registry of Norway. Cox proportional models computed hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer between the two groups, adjusting for age, parity, age at first birth, calendar period and region of residence. In total, 8,037 women were diagnosed with breast cancer during the study period, 138 ART women and 7,899 unexposed. Total follow-up time was 12,401,121 person-years (median 16.0); median age at entry was 32.5 years (range 18.6-49.9) for ART women and 26.3 (range 10.5-54.6) for unexposed. Women exposed to ART had an elevated risk of breast cancer (adjusted HR 1.20, 95% CI 1.01-1.42). Subgroup analyses gave an HR of 1.30 (95% CI 1.07-1.57) for women treated with IVF and 1.35 (95 % CI 1.07-1.71) for women with follow-up >10 years, compared with controls. Our findings of increased risk in the study population warrant continued monitoring of women treated with ART as this population advances into more typical cancer age ranges.


Validation of population-based cutoffs for low muscle mass and strength in a population of Turkish elderly adults.
Despite differences between the studies regarding methods for estimating low muscle mass, the European Working Group on Sarcopenia in Older People (EWGSOP) recommends use of two standard deviations (SDs) below the reference sex-specific means of healthy young adults. The aim of this study was to determine the cutoff points of skeletal muscle mass index (SMI) and handgrip strength (HS) in Turkish population and to compare the power of different cutoff points to predict comprehensive geriatric assessment (CGA) parameters. Two hundred and eight young healthy volunteers (104 women, 104 men) were included in the study to define SMI, HS cutoff values. 1150 older adults (784 women, 366 men) underwent CGA, including physical performance, activities of daily living (ADL), HS and frailty. Body composition was obtained from every participant by bioimpedance analysis (BIA). CGA parameters of sarcopenic patients according to EWGSOP and new Turkish cutoff points were compared. SMI cutoff points were defined 5.70 kg/m2 for women, 8.33 kg/m2 for men. HS thresholds were calculated as 14 kg for women, 28 kg for men using measurements of healthy young adult reference. Considering the new threshold values, the prevalence of sarcopenia was 10% (7% women, 17% men). When new sarcopenia criteria were applied and covariates were adjusted, sarcopenia was found to be more closely related to ADL impairment, balance, frailty in men, and balance, slow walking speed, ADL impairment, frailty in women (p < 0.05). Muscle mass and strength may vary between populations because of ethnicity and other related discrepancies. The evaluation of sarcopenia according to the present guidelines may cause overdiagnosis in some populations. Cutoff points specific to populations should be determined.


Use of proton pump inhibitors: an exploration of the attitudes, knowledge and perceptions of general practitioners.
Proton pump inhibitor (PPI) prescribing is costly. The volume of PPI prescription is also increasing, despite little evidence that would justify the increase. General practitioners (GPs) are largely responsible for PPI prescribing, yet knowledge of their views concerning PPIs which might explain the apparent anomaly of prescribing costly drugs without justification is lacking. The aim of this study is therefore to investigate how GPs make decisions about PPI prescribing. Qualitative study design using focus groups of 34 GPs and 15 training GPs analysed according to grounded theory principles and use of constant comparative analysis. The participants showed agreement about the clinical factors potentially relevant to PPI prescribing such as age of presentation and endoscopy, issues of Helicobacter pylori eradication and issues around malignancy. There was considerable controversy, however, as to how to apply those factors in real clinical consultations. GPs in training and academic GPs tended to be more conservative; service-based GPs more pragmatic. There was agreement about the need to review long-term PPI medication, but controversy about whether the conventional 'step-up step-down' approach was realistic in practice. Good agreement was apparent about the effectiveness, the cost implications, and some of the ethical issues surrounding PPIs, but considerable controversy as to how far such factors should influence prescribing of PPIs. The GPs showed good understanding and knowledge of the issues surrounding PPI prescribing. There was considerable controversy as to how such knowledge should be translated into practice.


Distribution and effects of 2,4,5-trichlorophenoxyacetic acid in cells of Bacillus megaterium.
Cell death in a resting population of an asporogenous Bacillus megaterium was accelerated by ambient concentrations of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) equal to or greater than 10 mug/ml or 5 mug/mg of cells (dry weight), but only after prolonged exposure. Conversely, populations of growing cells were not markedly influenced even at 100 mug/ml. Effects on cell respiration were not manifest until the ambient concentration reached 1,000 mug of 2,4,5-T/ml, or 500 mug/mg. Cells of B. megaterium did, however, accumulate 2,4,5-T passively to a level approximately twofold above the ambient concentration. Most of the accumulated compound was easily washed from the cells, but, of the firmly bound herbicide, about 0.5 mug/mg of cells (dry weight), nearly 60% by weight, was localized in the protoplast membrane. The foregoing results, obtained with a purified preparation of 2,4,5-T were also elicited by 2,4,5-T analytical standards. The extracted contaminants did not produce the results alone nor did they influence the results when present in combination with 2,4,5-T.


Total knee arthroplasty for patients 90 years of age and older.
This study was done to review the reliability, durability, and safety of primary and revision total knee arthroplasty for patients 90 years of age and older. Because little data exist about the safety or efficacy of total knee replacement in this elderly population some physicians may be hesitant to recommend elective surgery to patients of this age. Fifty-one total knee replacements were done for 41 patients age 90 to 102 years (mean, 92 years). Forty-four primary total knee replacements and seven revision total knee replacements were done. Each patient was followed up until death or for a minimum of 2 years (mean, 4.0 years). The Knee Society pain scores improved significantly for the primary and revision groups from preoperative mean scores of 30 and 29 points to latest followup scores of 86 and 87 points, respectively. One patient died in the early postoperative period of causes related to the operation. The remaining patients have lived an average of 4.4 +/- 2.2 years after the primary knee arthroplasties and 5.7 +/- 2.8 years after the revision knee arthroplasties. No knees have required revision subsequently. Total knee replacement was reliable, durable, and safe in this group of patients older than 90 years. Primary care physicians and surgeons should be aware that primary and revision total knee replacement can be done safely and effectively for patients 90 years and older and result in years of marked pain relief for those patients.


Critical weight in the development of insect body size.
Body size is one of the most important life history characters of organisms, yet little is known of the physiological mechanisms that regulate either body size or variation in body size. Here, we examined one of these mechanisms, the critical weight, which is defined as the minimal mass at which further growth is not necessary for a normal time course to pupation. The critical weight occurred at 55% of peak larval mass in laboratory-reared larvae of the tobacco hornworm Manduca sexta. We examined the effects of genetic and environmental variation in the critical weight on body size. As in many other insects, Manduca larvae reared on poor diets were smaller and those reared at lower temperatures were larger than control animals. We demonstrated that the critical weight was lower on low quality diets but did not change with temperature. There was significant genetic variation for body size, for plasticity of body size, and for critical weight, but not for plasticity of critical weight. Variation in the critical weight accounted for 73% of between-family variance in peak larval size, whereas plasticity of critical weight was not significantly correlated with plasticity of body size. Our results suggest that although critical weight is an important factor in determining body size and enabling the evolution of body size, it may, at the same time, act as a constraint on the evolution of plasticity of body size. Thus, the determinants of body size and the determinants of plasticity of body size do not need to be identical.


Ergodicity breaking of iron displacement in heme proteins.
We present a model of the dynamical transition of atomic displacements in proteins. Increased mean-square displacement at higher temperatures is caused by the softening of the force constant for atomic/molecular displacements by electrostatic and van der Waals forces from the protein-water thermal bath. Displacement softening passes through a nonergodic dynamical transition when the relaxation time of the force-force correlation function enters, with increasing temperature, the instrumental observation window. Two crossover temperatures are identified. The lower crossover, presently connected to the glass transition, is related to the dynamical unfreezing of rotations of water molecules within nanodomains polarized by charged surface residues of the protein. The higher crossover temperature, usually assigned to the dynamical transition, marks the onset of water translations. All crossovers are ergodicity breaking transitions depending on the corresponding observation windows. Allowing stretched exponential relaxation of the protein-water thermal bath significantly improves the theory-experiment agreement when applied to solid protein samples studied by Mössbauer spectroscopy.


Phosphorylation of the oxidase-related 48K phosphoprotein family in the unusual autosomal cytochrome-negative and X-linked cytochrome-positive types of chronic granulomatous disease.
Activation of 32P-loaded neutrophils with phorbol myristate acetate causes the labeling of a family of three 48K proteins that focus near neutral pH. The relationship between these phosphoproteins and the activation of the respiratory burst has been supported by the previous finding that phosphorylation was defective in the two most common types of chronic granulomatous disease (CGD): X-linked cytochrome-negative (X/-) and autosomal cytochrome-positive (A/+). In this report, these studies have now been extended to the rare A/- and X/+ forms of the disease. In all three patients with A/- CGD examined, the two most acidic 48K proteins failed to undergo enhanced phosphorylation in response to phorbol stimulation, a finding similar to that seen in X/- patients. In contrast, neutrophils from two patients with X/+ CGD appeared to phosphorylate the neutral 48K proteins in a normal fashion. It thus appears that the different phosphorylation patterns seen in chronic granulomatous disease are a reflection of the genetic heterogeneity of this disorder. These findings lend further support to the conclusion that the 48K phosphoprotein family is related to the respiratory burst, although not necessarily in a straightforward manner.


Dindel: accurate indel calls from short-read data.
Small insertions and deletions (indels) are a common and functionally important type of sequence polymorphism. Most of the focus of studies of sequence variation is on single nucleotide variants (SNVs) and large structural variants. In principle, high-throughput sequencing studies should allow identification of indels just as SNVs. However, inference of indels from next-generation sequence data is challenging, and so far methods for identifying indels lag behind methods for calling SNVs in terms of sensitivity and specificity. We propose a Bayesian method to call indels from short-read sequence data in individuals and populations by realigning reads to candidate haplotypes that represent alternative sequence to the reference. The candidate haplotypes are formed by combining candidate indels and SNVs identified by the read mapper, while allowing for known sequence variants or candidates from other methods to be included. In our probabilistic realignment model we account for base-calling errors, mapping errors, and also, importantly, for increased sequencing error indel rates in long homopolymer runs. We show that our method is sensitive and achieves low false discovery rates on simulated and real data sets, although challenges remain. The algorithm is implemented in the program Dindel, which has been used in the 1000 Genomes Project call sets.


Role of protein conformational dynamics and DNA integrity in relevance to neuronal cell death in neurodegeneration.
Apoptosis has been implicated in the pathogenesis of various neurodegenerative disorders, although the extent to which it is responsible for the neurodegeneration along with other kind of cell death events is not known. Eventhough much information is available today on the apoptotic cascades in general, the precise mechanism and the exact sequence of events leading to neuronal degeneration in Alzheimer's disease (AD) and other neurodegenerative disorders is not understood till now. Amyloid beta (Abeta) proteins are the hallmark toxic proteins known to cause the activation of apoptotic cascades via caspase dependent and caspase-independent pathways. Abeta can cause neuronal apoptosis through multiple mechanisms involving mitochondria and endoplasmic reticulum as the key organelles. In this review, we have discussed the role of apoptosis in neurodegeneration and provided new thoughts on the role of protein conformational dynamics and DNA integrity associated with neurodegenerative disorders. An insight on whether the apoptosis observed in the neurodegenerative disorders is of any functional advantage has been discussed.


A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer.
Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.


Impact of Coronary Lesion Geometry on Fractional Flow Reserve: Data From Interventional Cardiology Research In-Cooperation Society-Fractional Flow Reserve and Intravascular Ultrasound Registry.
The impact of various coronary lesion geometries on fractional flow reserve (FFR) is poorly understood. A total of 1552 coronary lesions in 1236 patients from a prospective Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve and Intravascular Ultrasound registry were assessed using quantitative coronary angiography, intravascular ultrasound, and FFR. Computational fluid dynamics simulation was performed for theoretical validation. Patients with complex geometries, such as longitudinal eccentricity, cross-sectional eccentricity, and surface roughness, showed significantly lower FFR values. In multivariable analysis, distal longitudinal eccentricity (adjusted odds ratio, 1.55; 95% confidence interval, 1.04-2.87; P=0.031), cross-sectional eccentricity (adjusted odds ratio, 1.65; 95% confidence interval, 1.27-2.14; P<0.001), and surface roughness (adjusted odds ratio, 1.55; 95% confidence interval, 1.04-2.32; P=0.033), as well as male sex, left anterior descending artery territory, proximal location, high degree of diameter stenosis, long lesion, and high plaque burden, were identified as independent predictors for significantly low FFR values (≤0.80). Computational simulation supported the impact of lesion geometry on FFR. The complex coronary lesion geometries were independently associated with reduced FFR values. The visual-functional mismatch between coronary angiography and FFR could be partly attributable to local geometric factors. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01366404.


PARENTS 2 Study: a qualitative study of the views of healthcare professionals and stakeholders on parental engagement in the perinatal mortality review-from 'bottom of the pile' to joint learning.
Engaging bereaved parents in the review process that examines their care before and after a perinatal death might help parents deal with their grief more effectively and drive improvements in patient safety. The objective of this study is to explore whether healthcare professionals would accept or support parent engagement in the perinatal mortality review process. Qualitative focus group interviews. Transcripts were analysed with an inductive thematic approach. Two geographically distinct tertiary maternity hospitals in the UK. Five focus groups were conducted with clinical staff including midwives, obstetricians, neonatologists, nursing staff and chaplaincy services. Twenty-seven healthcare professionals unanimously agreed that parents' involvement in the perinatal mortality review process is useful and necessary. Six key themes emerged including: parental engagement; need for formal follow-up; critical structure of perinatal mortality review meeting; coordination and streamlining of care; advocacy for parents including role of the bereavement care lead; and requirement for training and support for staff to enable parental engagement. Healthcare professionals strongly advocated engaging bereaved parents in the perinatal mortality review: empowering parents to ask questions, providing feedback on care, helping generate lessons and providing them with the opportunity to discuss a summary of the review conclusions with their primary healthcare professional contact. The participants agreed it is time to move on from 'a group of doctors reviewing notes' to active learning and improvement together with parents, to enable better care and prevention of perinatal death.


High genetic diversity of common toad (Bufo bufo) populations under strong natural fragmentation on a Northern archipelago.
The last decades have shown a surge in studies focusing on the interplay between fragmented habitats, genetic variation, and conservation. In the present study, we consider the case of a temperate pond-breeding anuran (the common toad Bufo bufo) inhabiting a naturally strongly fragmented habitat at the Northern fringe of the species' range: islands offshore the Norwegian coast. A total of 475 individuals from 19 populations (three mainland populations and 16 populations on seven adjacent islands) were genetically characterized using nine microsatellite markers. As expected for a highly fragmented habitat, genetic distances between populations were high (pairwise F st values ranging between 0.06 and 0.33), with however little differences between populations separated by ocean and populations separated by terrestrial habitat (mainland and on islands). Despite a distinct cline in genetic variation from mainland populations to peripheral islands, the study populations were characterized by overall high genetic variation, in line with effective population sizes derived from single-sample estimators which were on average about 20 individuals. Taken together, our results reinforce the notion that spatial and temporal scales of fragmentation need to be considered when studying the interplay between landscape fragmentation and genetic erosion.


Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Council on Scientific Affairs, American Medical Association.
To deal with public and professional concern regarding possible overprescription of attention-deficit/hyperactivity disorder (ADHD) medications, particularly methylphenidate, by reviewing issues related to the diagnosis, optimal treatment, and actual care of ADHD patients and of evidence of patient misuse of ADHD medications. Literature review using a National Library of Medicine database search for 1975 through March 1997 on the terms attention deficit disorder with hyperactivity, methylphenidate, stimulants, and stimulant abuse and dependence. Relevant documents from the Drug Enforcement Administration were also reviewed. All English-language studies dealing with children of elementary school through high school age were included. All searched articles were selected and were made available to coauthors for review. Additional articles known to coauthors were added to the initial list, and a consensus was developed among the coauthors regarding the articles most pertinent to the issues requested in the resolution calling for this report. Relevant information from these articles was included in the report. Diagnostic criteria for ADHD are based on extensive empirical research and, if applied appropriately, lead to the diagnosis of a syndrome with high interrater reliability, good face validity, and high predictability of course and medication responsiveness. The criteria of what constitutes ADHD in children have broadened, and there is a growing appreciation of the persistence of ADHD into adolescence and adulthood. As a result, more children (especially girls), adolescents, and adults are being diagnosed and treated with stimulant medication, and children are being treated for longer periods of time. Epidemiologic studies using standardized diagnostic criteria suggest that 3% to 6% of the school-aged population (elementary through high school) may suffer from ADHD, although the percentage of US youth being treated for ADHD is at most at the lower end of this prevalence range. Pharmacotherapy, particularly use of stimulants, has been extensively studied and generally provides significant short-term symptomatic and academic improvement. There is little evidence that stimulant abuse or diversion is currently a major problem, particularly among those with ADHD, although recent trends suggest that this could increase with the expanding production and use of stimulants. Although some children are being diagnosed as having ADHD with insufficient evaluation and in some cases stimulant medication is prescribed when treatment alternatives exist, there is little evidence of widespread overdiagnosis or misdiagnosis of ADHD or of widespread overprescription of methylphenidate by physicians.


Impact of epitope specificity and precursor maturation in pro-B-type natriuretic peptide measurement.
Cardiac-derived natriuretic peptides are sensitive plasma markers of cardiac dysfunction. Recent reports have disclosed a more complex molecular heterogeneity of B-type natriuretic peptide precursor (proBNP)-derived peptides than previously suggested. In this study, we examined the impact of epitope specificity and precursor maturation on plasma measurement of proBNP-derived peptides. We compared 2 assays, N-terminal proBNP and proBNP 1-76, in a randomly collected set of human plasma specimens (n = 370). Additionally, we evaluated the clinical performance of 4 assays with different epitope specificities in a cohort of elderly patients presenting with symptoms associated with heart failure (n = 415). Comparison of N-terminal proBNP with proBNP 1-76 measurement in plasma revealed a high correlation on regression analysis (r(2) = 0.91, P < 0.0001). Nevertheless, the proBNP 1-76 assay measured lower concentrations in the high range than the N-terminal proBNP assay. Correlations between assay measurements in a clinical setting were comparable for all the assays (r(2) approximately 0.57-0.83), and ROC analyses revealed area-under-the-curve values ranging between 0.77 and 0.81 for identifying reduced left ventricular ejection fraction. In parallel, all assays displayed comparable abilities in predicting long-term mortality. Our results reveal marked assay differences in analytical assay comparison, contrasting the overall comparable clinical performance in cardiovascular diagnostics or prognosis in the elderly.


Illicit drug use in sexual settings ('chemsex') and HIV/STI transmission risk behaviour among gay men in South London: findings from a qualitative study.
'Chemsex' is a colloquial term used in the UK that describes sex under the influence of psychoactive substances (typically crystal methamphetamine, mephedrone and gamma-hydroxybutyric acid (GHB)/gamma-butyrolactone (GBL)). Recently, concern has been raised as to the impact of such behaviour on HIV/sexually transmitted infection (STI) transmission risk behaviour, which this qualitative study aimed to explore via semistructured interviews with gay men living in three South London boroughs. Interviews were conducted with 30 community-recruited gay men (age range 21-53) who lived in the boroughs of Lambeth, Southwark and Lewisham, and who had used crystal methamphetamine, mephedrone or GHB/GBL either immediately before or during sex with another man during the previous 12 months. Data were subjected to a thematic analysis. Chemsex typically featured more partners and a longer duration than other forms of sex, and the relationship between drug use and HIV/STI transmission risk behaviour was varied. While some men believed that engaging in chemsex had unwittingly led them to take risks, others maintained strict personal rules about having safer sex. Among many participants with diagnosed HIV, there was little evidence that the use of drugs had significantly influenced their engagement in condomless anal intercourse (primarily with other men believed to be HIV positive), but their use had facilitated sex with more men and for longer. Analysis revealed that, within this sample, chemsex is never less risky than sex without drugs, and is sometimes more so. Targeted clinic-based and community-based harm reduction and sexual health interventions are required to address the prevention needs of gay men combining psychoactive substances with sex.


Modifications in the International Study Group for Pancreatic Surgery (ISGPS) definition of postoperative pancreatic fistula.
Postoperative pancreatic fistula (POPF) remains the major postoperative cause of morbidity and mortality following pancreatic surgery. Since 2005, the International Study Group of Pancreatic Fistula (ISGPF) definition and classification has been adopted worldwide allowing the comparison among different surgical approaches and mitigation strategies. Over the last 11 years, several limitations have emerged from clinical practice and in 2016 the International Study Group for Pancreatic Surgery (ISGPS) updated the POPF definition and grading system. Objectives of this review article were to summarize modifications in the updated ISGPS definition and to illustrate their clinical impact.


Comparative analysis of carboxysome shell proteins.
Carboxysomes are metabolic modules for CO(2) fixation that are found in all cyanobacteria and some chemoautotrophic bacteria. They comprise a semi-permeable proteinaceous shell that encapsulates ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and carbonic anhydrase. Structural studies are revealing the integral role of the shell protein paralogs to carboxysome form and function. The shell proteins are composed of two domain classes: those with the bacterial microcompartment (BMC; Pfam00936) domain, which oligomerize to form (pseudo)hexamers, and those with the CcmL/EutN (Pfam03319) domain which form pentamers in carboxysomes. These two shell protein types are proposed to be the basis for the carboxysome's icosahedral geometry. The shell proteins are also thought to allow the flux of metabolites across the shell through the presence of the small pore formed by their hexameric/pentameric symmetry axes. In this review, we describe bioinformatic and structural analyses that highlight the important primary, tertiary, and quaternary structural features of these conserved shell subunits. In the future, further understanding of these molecular building blocks may provide the basis for enhancing CO(2) fixation in other organisms or creating novel biological nanostructures.


Light scattering measured with spatial frequency domain imaging can predict stromal versus epithelial proportions in surgically resected breast tissue.
This study aims to determine if light scatter parameters measured with spatial frequency domain imaging (SFDI) can accurately predict stromal, epithelial, and adipose fractions in freshly resected, unstained human breast specimens. An explicit model was developed to predict stromal, epithelial, and adipose fractions as a function of light scattering parameters, which was validated against a quantitative analysis of digitized histology slides for N = 31 specimens using leave-one-out cross-fold validation. Specimen mean stromal, epithelial, and adipose volume fractions predicted from light scattering parameters strongly correlated with those calculated from digitized histology slides (r = 0.90, 0.77, and 0.91, respectively, p-value <1 × 10 - 6). Additionally, the ratio of predicted epithelium to stroma classified malignant specimens with a sensitivity and specificity of 90% and 81%, respectively, and also classified all pixels in malignant lesions with 63% and 79%, at a threshold of 1. All specimens and pixels were classified as malignant, benign, or fat with 84% and 75% accuracy, respectively. These findings demonstrate how light scattering parameters acquired with SFDI can be used to accurately predict and spatially map stromal, epithelial, and adipose proportions in fresh unstained, human breast tissue, and suggest that these estimations could provide diagnostic value.


Fundamental Irreversibility: Planckian or Schrödinger-Newton?
The concept of universal gravity-related irreversibility began in quantum cosmology. The ultimate reason for universal irreversibility is thought to come from black holes close to the Planck scale. Quantum state reductions, unrelated to gravity or relativity but related to measurement devices, are completely different instances of irreversibilities. However, an intricate relationship between Newton gravity and quantized matter might result in fundamental and spontaneous quantum state reduction-in the non-relativistic Schrödinger-Newton context. The above two concepts of fundamental irreversibility emerged and evolved with few or even no interactions. The purpose here is to draw a parallel between the two approaches first, and to ask rather than answer the question: can both the Planckian and the Schrödinger-Newton indeterminacies/irreversibilities be two faces of the same universe. A related personal note of the author's 1986 meeting with Aharonov and Bohm is appended.


Drug instrumentalization and evolution: Going even further.
Müller & Schumann (M&S) deserve applause for their interdisciplinary examination of drug use, evolution, and learning. Further steps can deepen their evolutionary analysis: a focus on adaptive benefits, a distinction between approach and consummatory behaviors, an examination of how drugs can create adaptive lag through changing human niche construction, the importance of other neurobehavioral mechanisms in drug use besides instrumentalization, and the importance of sociocultural dynamics and neural plasticity in both human evolution and drug use.