The Schistosoma mansoni tegumental allergen protein, SmTAL1: Binding to an IQ-motif from a voltage-gated ion channel and effects of praziquantel.
SmTAL1 is a calcium binding protein from the parasitic worm, Schistosoma mansoni. Structurally it is comprised of two domains - an N-terminal EF-hand domain and a C-terminal dynein light chain (DLC)-like domain. The protein has previously been shown to interact with the anti-schistosomal drug, praziquantel (PZQ). Here, we demonstrated that both EF-hands in the N-terminal domain are functional calcium ion binding sites. The second EF-hand appears to be more important in dictating affinity and mediating the conformational changes which occur on calcium ion binding. There is positive cooperativity between the four calcium ion binding sites in the dimeric form of SmTAL1. Both the EF-hand domain and the DLC-domain dimerise independently suggesting that both play a role in forming the SmTAL1 dimer. SmTAL1 binds non-cooperatively to PZQ and cooperatively to an IQ-motif from SmCav1B, a voltage-gated calcium channel. PZQ tends to strengthen this interaction, although the relationship is complex. These data suggest the hypothesis that SmTAL1 regulates at least one voltage-gated calcium channel and PZQ interferes with this process. This may be important in the molecular mechanism of this drug. It also suggests that compounds which bind SmTAL1, such as six from the Medicines for Malaria Box identified in this work, may represent possible leads for the discovery of novel antagonists.


Vulnerable Workers and COVID-19: Insights from a Survey of Members of the International Commission for Occupational Health.
The COVID-19 pandemic has negatively impacted on the health and wellbeing of populations directly through infection, as well as through serious societal and economic consequences such as unemployment and underemployment. The consequences could be even more severe for those more vulnerable to the disease, such as the elderly and those with underlying health conditions. Indeed, there is evidence that such vulnerable populations are disproportionately affected in terms of both, their health and the socioeconomic impact. The aim of our study was to determine whether occupational health (OH) professionals thought that the COVID-19 pandemic might further disadvantage any particular group(s) of vulnerable workers globally, and if so, which group(s). A cross-sectional study was carried out with a sample of OH professionals by means of an online questionnaire which was shared via email within the ICOH (International Commission for Occupational Health) community. Data was collected over a period of two weeks in May 2020 and 165 responses from 52 countries were received. In this paper, the responses relating to questions about vulnerable workers are reported and discussed. Globally, our responders felt that those in less secure jobs (precarious employment (79%) and informal work (69%)), or unemployed (63%), were the most at risk of further disadvantage from this pandemic. The majority felt that their governments could act to mitigate these effects. There were suggestions of short-term alleviation such as financial and social support, as well as calls for fundamental reviews of the underlying inequalities that leave populations so vulnerable to a crisis such as COVID-19.


Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice.
The output of prolactin (PRL) is highly dynamic with dramatic changes in its secretion from the anterior pituitary gland depending on prevailing physiological status. In adult female mice, there are three distinct phases of output and each of these is related to the functions of PRL at specific stages of reproduction. Recent studies of the changes in the regulation of PRL during its period of maximum output, lactation, have shown alterations at both the level of the anterior pituitary and hypothalamus. The PRL-secreting cells of the anterior pituitary are organised into a homotypic network in virgin animals, facilitating coordinated bouts of activity between interconnected PRL cells. During lactation, coordinated activity increases due to the changes in structural connectivity, and this drives large elevations in PRL secretion. Surprisingly, these changes in connectivity are maintained after weaning, despite reversion of PRL output to that of virgin animals, and result in an augmented output of hormone during a second lactation. At the level of the hypothalamus, tuberoinfundibular dopamine (TIDA) neurons, the major inhibitors of PRL secretion, have unexpectedly been shown to remain responsive to PRL during lactation. However, there is an uncoupling between TIDA neuron firing and dopamine secretion, with a potential switch to enkephalin release. Such a process may reinforce hormone secretion through dual disinhibition and stimulation of PRL cell activity. Thus, integration of signalling along the hypothalamo-pituitary axis is responsible for increased secretory output of PRL cells during lactation, as well as allowing the system to anticipate future demands.


BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma.
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway. Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.


Acute kidney injury in Pediatric Intensive Care Unit: Incidence, risk factors, and outcome.
To determine incidence, risk factors, and outcome of acute kidney injury (AKI) in Pediatric Intensive Care Unit (PICU). This is a prospective, observational study conducted in PICU of Department of Paediatrics, S.P. Medical College, Bikaner, from October 2013 to May 2014. In this study, 536 patients of aged 29 days to 16 years were screened for AKI according to the Pediatric Risk, Injury, Failure, Loss, End-stage Renal Disease (pRIFLE) criteria. Their clinical and biochemical data were recorded and followed up to their discharge/death. During the study period, 230 (42.9%) out of 536 patients developed AKI. Younger age (<5 years) and females (P ≤ 0.013) were more prone to develop AKI. Most common etiologies were septicemia, multiple organ dysfunction syndrome (MODS), gastroenteritis, and severe malaria (P ≤ 0.05). The maximal stage of AKI was stage "R" (49.1%), followed by "I" (29.5%) and "F" (21.3%). Major PICU-related risk factors were use of vasoactive drug (VD) and nephrotoxic drug (ND) and need of mechanical ventilation (MV) (P ≤ 0.05). Length of stay was significantly longer than non-AKI patients (P ≤ 0.05). Mortality in AKI (47.5%) was higher (P ≤ 0.05%) in comparison to non-AKI (25.56%). AKI is common in critically sick children, especially in younger age and in females with septicemia and MODS. Use of VD and ND and need of MV are common risk factors. AKI is associated with longer hospital stay and higher mortality. pRIFLE is better diagnostic criteria in early detection of AKI and reduction of their morbidity and mortality.


How the surface structure determines the properties of CuH.
CuH is a material that appears in a wide diversity of circumstances ranging from catalysis to electrochemistry to organic synthesis. There are both aqueous and nonaqueous synthetic routes to CuH, each of which apparently leads to a different product. We developed synthetic methodologies that enable multigram quantities of CuH to be produced by both routes and characterized each product by a combination of spectroscopic, diffraction and computational methods. The results show that, while all methods for the synthesis of CuH result in the same bulk product, the synthetic path taken engenders differing surface properties. The different behaviors of CuH obtained by aqueous and nonaqueous routes can be ascribed to a combination of very different particle size and dissimilar surface termination, namely, bonded hydroxyls for the aqueous routes and a coordinated donor for the nonaqueous routes. This work provides a particularly clear example of how the nature of an adsorbed layer on a nanoparticle surface determines the properties.


Sudden cardiac arrest in sports - need for uniform registration: A Position Paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation.
There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.


Escape of tumor cells from the NK cell cytotoxic activity.
In recent years, NK cells, initially identified as potent cytotoxic effector cells, have revealed an unexpected complexity, both at phenotypic and functional levels. The discovery of different NK cell subsets, characterized by distinct gene expression and phenotypes, was combined with the characterization of the diverse functions NK cells can exert, not only as circulating cells, but also as cells localized or recruited in lymphoid organs and in multiple tissues. Besides the elimination of tumor and virus-infected cells, these functions include the production of cytokines and chemokines, the regulation of innate and adaptive immune cells, the influence on tissue homeostasis. In addition, NK cells display a remarkable functional plasticity, being able to adapt to the environment and to develop a kind of memory. Nevertheless, the powerful cytotoxic activity of NK cells remains one of their most relevant properties, particularly in the antitumor response. In this review, the process of tumor cell recognition and killing mediated by NK cells, starting from the generation of cytolytic granules and recognition of target cell, to the establishment of the NK cell immunological synapse, the release of cytotoxic molecules, and consequent tumor cell death is described. Next, the review focuses on the heterogeneous mechanisms, either intrinsic to tumors or induced by the tumor microenvironment, by which cancer cells can escape the NK cell-mediated attack.


Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis.
Considerable controversy has transpired regarding the core features of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Current case definitions differ in the number and types of symptoms required. This ambiguity impedes the search for biological markers and effective treatments. This study sought to empirically operationalize symptom criteria and identify which symptoms best characterize the illness. Patients (n=236) and controls (n=86) completed the DePaul Symptom Questionnaire, rating the frequency and severity of 54 symptoms. Responses were compared to determine the threshold of frequency/severity ratings that best distinguished patients from controls. A Classification and Regression Tree (CART) algorithm was used to identify the combination of symptoms that most accurately classified patients and controls. A third of controls met the symptom criteria of a common CFS case definition when just symptom presence was required; however, when frequency/severity requirements were raised, only 5% met criteria. Employing these higher frequency/severity requirements, the CART algorithm identified three symptoms that accurately classified 95.4% of participants as patient or control: fatigue/extreme tiredness, inability to focus on multiple things simultaneously, and experiencing a dead/heavy feeling after starting to exercise. Minimum frequency/severity thresholds should be specified in symptom criteria to reduce the likelihood of misclassification. Future research should continue to seek empirical support of the core symptoms of ME and CFS to further progress the search for biological markers and treatments.


Osteoarthritis Pathophysiology: Therapeutic Target Discovery may Require a Multifaceted Approach.
Molecular understanding of osteoarthritis (OA) has greatly increased through careful analysis of tissue samples, preclinical models, and large-scale agnostic "-omic" studies. There is broad acceptance that systemic and biomechanical signals affect multiple tissues of the joint, each of which could potentially be targeted to improve patient outcomes. In this review six experts in different aspects of OA pathogenesis provide their independent view on what they believe to be good tractable approaches to OA target discovery. We conclude that molecular discovery has been high but future transformative studies require a multidisciplinary holistic approach to develop therapeutic strategies with high clinical efficacy.


Endothelial monolayer integrity. Perturbation of F-actin filaments and the dense peripheral band-vinculin network.
The role of the actin microfilaments in maintaining the integrity of the monolayer and activating endothelial repair processes is not well understood. This study was designed to characterize the prominent changes in F-actin distribution in endothelial cells that are associated with shape changes in the cells after perturbation of a confluent monolayer. F-actin was localized by using rhodamine phalloidin and fluorescence microscopy. The dense peripheral band (DPB) and vinculin cell-cell junctions were co-localized by using double fluorescence and immunofluorescence microscopy. Thrombin and 12-o-tetradecanoyl-myristyl-13-acetate (TPA) caused loss of the DPB and an increase in the central microfilament bundles, while agents that caused rounding of the cells (including plasmin, trypsin, and chymotrypsin) did not cause loss of the DPB although large gaps were formed between cells. The thrombin and TPA effects were rapid and reversible and were associated with an accompanying loss of vinculin cell-cell plaques. The mechanisms of the effects were not studied. It was postulated that thrombin and TPA were activating endothelial repair processes.


Factors of the physical environment associated with walking and bicycling.
The purpose of this study was to identify factors of the physical environment that may influence time spent on walking and bicycling. Demographic factors and time spent on walking and bicycling (during leisure time and for commuting purposes) were assessed with a self-administered questionnaire. GIS databases were used to objectively measure the total square area of green space and recreational space (woods, parks, sport grounds, allotments for vegetable gardens, and grounds for day trips) in a circle around the postal code of a respondent with a radius of 300 and 500 m. Multilevel regression analysis was used to study the association between walking and bicycling on the one hand, and green and recreational space on the other hand. Analyses were adjusted for gender, age, and educational level. In a neighborhood defined as a circle with a 300-m radius, the square area of sport grounds was associated with bicycling in general and the square area of parks was associated with bicycling for commuting purposes. It is, however, very likely that these results reflect the association of living in the outskirts of town and time spent on bicycling. The present study showed green and recreational space, specifically sport grounds and parks, to be associated with time spent on bicycling.


Efficacy of transarterial embolisation in the management of post-partum haemorrhage and its impact on subsequent pregnancies.
Transarterial embolisation (TAE) has been attracting attention as a treatment option for post-partum haemorrhage (PPH). We investigated cases in which TAE was performed for PPH to determine the efficacy of TAE for the treatment of PPH and its impact on subsequent pregnancies and childbirth in a multi-institutional case-series study. A total of 211 women who underwent emergency (n=161) or prophylactic (n=50) TAE for the management of PPH from 2002 to 2011 in the Chugoku and Shikoku regions of Japan were evaluated. Data on maternal background, treatment efficacy, adverse events in 113 cases followed up after TAE and subsequent pregnancies in 76 women were obtained. The overall success rate of emergency and prophylactic TAE was 91.9 and 96.0%, respectively. The rate of complications such as infection, uterine necrosis and amenorrhoea was 13.3% among women followed up after TAE. Forty women became pregnant after TAE, and the pregnancy rate among those who desired fertility was 52.6%. Twenty-eight gave birth, including four preterm deliveries. Five (16.7%) were associated with a hysterectomy due to placenta accreta. To reduce haemorrhage and avoid hysterectomy, TAE may be considered as a treatment option for PPH, however short and long terms complications are not uncommon.


Cross correlations between 13C-1H dipolar interactions and 15N chemical shift anisotropy in nucleic acids.
Two sets of cross-correlated relaxation rates involving chemical shift anisotropy and dipolar interactions have been measured in an RNA kissing complex. In one case, both the CSA and dipolar interaction tensors are located on the same nucleotide base and are rigidly fixed with respect to each other. In the other case, the CSA tensor is located on the nucleotide base whereas the dipolar interaction is located on the adjoining ribose unit. Analysis of the measured rates in terms of isotropic or anisotropic rotational diffusion has been carried out for both cases. A marked difference between the two models is observed for the cross-correlation rates involving rigidly fixed spin interactions. The influence of internal motions about the glycosidic linkage between the nucleotide base and the ribose unit on cross-correlated relaxation rates has been estimated by applying a model of restricted rotational diffusion. Local motions seem to have a more pronounced effect on cross-correlated relaxation rates when the two spin interactions are not rigidly fixed with respect to each other.


Improved sensitivity of DNA microarrays using photonic crystal enhanced fluorescence.
DNA microarrays are used to profile changes in gene expression between samples in a high-throughput manner, but measurements of genes with low expression levels can be problematic with standard microarray substrates. In this work, we expand the detection capabilities of a standard microarray experiment using a photonic crystal (PC) surface that enhances fluorescence observed from microarray spots. This PC is inexpensively and uniformly fabricated using a nanoreplica molding technique, with very little variation in its optical properties within- and between-devices. By using standard protocols to process glass microarray substrates in parallel with PCs, we evaluated the impact of this substrate on a one-color microarray experiment comparing gene expression in two developmental stages of Glycine max. The PCs enhanced the signal-to-noise ratio observed from microarray spots by 1 order of magnitude, significantly increasing the number of genes detected above substrate fluorescence noise. PC substrates more than double the number of genes classified as differentially expressed, detecting changes in expression even for low expression genes. This approach increases the dynamic range of a surface-bound fluorescence-based assay to reliably quantify small quantities of DNA that would be impossible with standard substrates.


Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.
High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.


Molecular actions of ovarian cancer G protein-coupled receptor 1 caused by extracellular acidification in bone.
Extracellular acidification occurs under physiologic and pathologic conditions, such as exercise, ischemia, and inflammation. It has been shown that acidosis has various adverse effects on bone. In recent years there has been increasing evidence which indicates that ovarian cancer G protein-coupled receptor 1 (OGR1) is a pH-sensing receptor and mediates a variety of extracellular acidification-induced actions on bone cells and other cell types. Recent studies have shown that OGR1 is involved in the regulation of osteoclast differentiation, survival, and function, as well as osteoblast differentiation and bone formation. Moreover, OGR1 also regulates acid-induced apoptosis of endplate chondrocytes in intervertebral discs. These observations demonstrate the importance of OGR1 in skeletal development and metabolism. Here, we provide an overview of OGR1 regulation ofosteoclasts, osteoblasts, and chondrocytes, and the molecular actions of OGR1 induced by extracellular acidification in the maintenance of bone health.


Antifungal activity of ZnO nanoparticles and their interactive effect with a biocontrol bacterium on growth antagonism of the plant pathogen Fusarium graminearum.
Fungal plant pathogens such as Fusarium graminearum cause severe global economic losses in cereals crops, and current control measures are limited. This work addresses the potential for ZnO nanoparticles (NPs) and biocontrol bacteria to be used in plant fungal control strategies. Growth of F. graminearum was significantly (p = 0.05) inhibited by inclusion of the NPs in a mung bean broth agar and in sand. Suspension in mung bean broth medium modified the surface charge, dissolution, and aggregation state of the ZnO NPs, in comparison to processes occurring in water suspension. The ZnO NPs were significantly more inhibitory to fungal growth than micro-sized particles of ZnO, although both types of particles released similar levels of soluble Zn, indicating size-dependent toxicity of the particles. Zn ions produced dose-dependent inhibition, noticeable at the level of soluble Zn released from NPs after seven-day suspension in medium; inhibitory levels caused acidification of the growth medium. Transfer of fungal inoculum after exposure to the ZnO NPs to fresh medium did not indicate adaptation to the stress because growth was still inhibited by the NPs. The ZnO NPs did not prevent metabolites from a biocontrol bacterium, Pseudomonas chlororaphis O6, from inhibiting Fusarium growth: no synergism was observed in the mung bean agar. Because other studies find that soil amendment with ZnO NPs required high doses for inhibition of plant growth, the findings of pathogen growth control reported in this paper open the possibility of using ZnO NP-based formulations to complement existing strategies for improving crop health in field settings.


Current management strategies for visceral artery aneurysms: an overview.
Visceral artery aneurysms (VAAs) are rare and affect the celiac artery, superior mesenteric artery, and inferior mesenteric artery, and their branches. The natural history of VAAs is not well understood as they are often asymptomatic and found incidentally; however, they carry a risk of rupture that can result in death from hemorrhage in the peritoneal cavity, retroperitoneal space, or gastrointestinal tract. Recent advances in imaging technology and its availability allow us to diagnose all types of VAA. VAAs can be treated by open surgery, laparoscopic surgery, endovascular therapy, or a hybrid approach. However, there are still no specific indications for the treatment of VAAs, and the best strategy depends on the anatomical location of the aneurysm as well as the clinical presentation of the patient. This article reviews the literature on the etiology, clinical features, diagnosis, and anatomic characteristics of each type of VAA and discusses the current options for their treatment and management.


Total and isoform-specific quantitative assessment of circulating fibulin-1 using selected reaction monitoring MS and time-resolved immunofluorometry.
Targeted proteomics using SRM-MS combined with stable-isotope dilution has emerged as a promising quantitative technique for the study of circulating protein biomarkers. The purpose of this study was to develop and characterize robust quantitative assays for the emerging cardiovascular biomarker fibulin-1 and its circulating isoforms in human plasma. We used bioinformatics analysis to predict total and isoform-specific tryptic peptides for absolute quantitation using SRM-MS. Fibulin-1 was quantitated in plasma by nanoflow-LC-SRM-MS in undepleted plasma and time-resolved immunofluorometric assay (TRIFMA). Both methods were validated and compared to a commercial ELISA (CircuLex). Molecular size determination was performed under native conditions by SEC analysis coupled to SRM-MS and TRIFMA. Absolute quantitation of total fibulin-1, isoforms -1C, and -1D was performed by SRM-MS. Fibulin-1C was the most abundant isoform in plasma. Circulating fibulin-1 isoforms were homo -or hetero multimeric complexes (range 318-364 kDa). Good correlation was obtained between SRM-MS and TRIFMA but not CircuLex. For biomarker studies using smaller cohorts, SRM-MS provides an alternative measure of total and specific fibulin-1 isoforms in undepleted plasma. For larger cohorts TRIFMA provides a faster platform for fibulin-1 quantitation in plasma. While the correlation between these methods was acceptable, low correlation was obtained between the commercial CircuLex assay and SRM-MS or TRIFMA.


Planning of movement parameters in a visuo-motor tracking task.
Monkeys trained to track a continuously moving visual target with a joystick do so by making a series of intermittent positional corrections rather than in a single smooth movement. The amplitude of each correction is highly correlated both with the error between the target and joystick positions, and with the velocity of the target, measured at movement onset. This velocity estimate is used to predict where the target will be by the end of each movement, and thus helps to set its amplitude correctly. To do this successfully, the monkey must know in advance how long his next movement will take. But, confusingly, the eventual duration of each movement is also highly correlated with its amplitude. So it appears that the monkeys need to simultaneously know the amplitude and duration of a movement, but cannot determine one without prior knowledge of the other. We have examined two possible solutions to this problem; only one agrees with our data. The monkeys seem to select the amplitude of their movements by scaling target velocity by a standard time constant which gives the additional distance the target will move. They then add this to the positional error estimated at or near to the start of each movement, to get the final movement amplitude. The velocity scaling value that gives the best fit to the observed amplitudes is very close to the average duration of all the monkeys movements. We therefore propose that the monkeys use a standard time constant for the purpose of calculating how far the target will move during each of their positional corrections.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition Underlies Fast Undulatory Locomotion in Caenorhabditis elegans.
Inhibition plays important roles in modulating the neural activities of sensory and motor systems at different levels from synapses to brain regions. To achieve coordinated movement, motor systems produce alternating contractions of antagonist muscles, whether along the body axis or within and among limbs, which often involves direct or indirect cross-inhibitory pathways. In the nematode Caenorhabditis elegans, a small network involving excitatory cholinergic and inhibitory GABAergic motoneurons generates the dorsoventral alternation of body-wall muscles that supports undulatory locomotion. Inhibition has been suggested to be necessary for backward undulation because mutants that are defective in GABA transmission exhibit a shrinking phenotype in response to a harsh touch to the head, whereas wild-type animals produce a backward escape response. Here, we demonstrate that the shrinking phenotype is exhibited by wild-type as well as mutant animals in response to harsh touch to the head or tail, but only GABA transmission mutants show slow locomotion after stimulation. Impairment of GABA transmission, either genetically or optogenetically, induces lower undulation frequency and lower translocation speed during crawling and swimming in both directions. The activity patterns of GABAergic motoneurons are different during low-frequency and high-frequency undulation. During low-frequency undulation, GABAergic VD and DD motoneurons show correlated activity patterns, while during high-frequency undulation, their activity alternates. The experimental results suggest at least three non-mutually exclusive roles for inhibition that could underlie fast undulatory locomotion in C. elegans, which we tested with computational models: cross-inhibition or disinhibition of body-wall muscles, or neuronal reset.


Advances, challenges, and opportunities in extracellular RNA biology: insights from the NIH exRNA Strategic Workshop.
Extracellular RNA (exRNA) has emerged as an important transducer of intercellular communication. Advancing exRNA research promises to revolutionize biology and transform clinical practice. Recent efforts have led to cutting-edge research and expanded knowledge of this new paradigm in cell-to-cell crosstalk; however, gaps in our understanding of EV heterogeneity and exRNA diversity pose significant challenges for continued development of exRNA diagnostics and therapeutics. To unravel this complexity, the NIH convened expert teams to discuss the current state of the science, define the significant bottlenecks, and brainstorm potential solutions across the entire exRNA research field. The NIH Strategic Workshop on Extracellular RNA Transport helped identify mechanistic and clinical research opportunities for exRNA biology and provided recommendations on high priority areas of research that will advance the exRNA field.


Event-based prospective memory in patients with Parkinson's disease: the effect of emotional valence.
The present study investigated the effect of Parkinson's disease (PD) on prospective memory (PM) tasks by varying the emotional content of the PM actions. Twenty-one older adults with PD and 25 healthy older adults took part in the present study. Participants performed three virtual days in the Virtual Week task. On each virtual day, participants performed actions with positive, negative or neutral content. Immediately following each virtual day, participants completed a recognition task to assess their retrospective memory for the various PM tasks. PD patients were less accurate than the control group at both PM accuracy and recognition task accuracy. The effect of emotional valence was also evident, indicating that all participants were more accurate on positive PM tasks than both negative and neutral. This study confirmed PM impairment in PD patients and extended previous research showing how positive emotional stimuli can influence PM performance.


Gene Editing, Identity and Benefit.
Some suggest that gene editing human embryos to prevent genetic disorders will be in one respect morally preferable to using genetic selection for the same purpose: gene editing will benefit particular future persons, while genetic selection would merely replace them. We first construct the most plausible defence of this suggestion-the benefit argument-and defend it against a possible objection. We then advance another objection: the benefit argument succeeds only when restricted to cases in which the gene-edited child would have been brought into existence even if gene editing had not been employed. Our argument relies on a standard account of comparative benefit which has recently been criticised on the grounds that it succumbs to the so-called 'pre-emption problem'. We end by considering how our argument would be affected were the standard account revised in an attempt to evade this problem. We consider three revised accounts and argue that, on all three, our critique of the benefit argument stands.


Improving water quality communications at beaches: input from stakeholders.
Water quality communication practices vary widely and stakeholder input has not played a role in defining acceptable levels of risk. Although the 2012 Recreational Water Quality Criteria (RWQC) emphasize the importance of promptly notifying the public about hazardous conditions, little is known about the public's understanding of notifications, or about levels of risk deemed acceptable. We sought to address these gaps. A mixed methods approach was used. Focus groups (FGs) provided qualitative data regarding the understanding of surface water quality, awareness, and use, of currently available water quality information, and acceptability of risk. Intercept interviews (INTs) at recreation sites provided quantitative data. INTs of 374 people and 15 FG sessions were conducted. Participants had limited awareness about water quality information posted at beaches, even during swim bans and advisories. Participants indicated that communication content should be current, from a trusted source, and describe health consequences. Communicating via mobile electronics should be useful for segments of the population. Risk acceptability is lower with greater outcome severity, or if children are impacted. Current water quality communications approaches must be enhanced to make notification programs more effective. Further work should build on this initial effort to evaluate risk acceptability among US beachgoers.


Considerations for the measurement of core, skin and mean body temperatures.
Despite previous reviews and commentaries, significant misconceptions remain concerning deep-body (core) and skin temperature measurement in humans. Therefore, the authors have assembled the pertinent Laws of Thermodynamics and other first principles that govern physical and physiological heat exchanges. The resulting review is aimed at providing theoretical and empirical justifications for collecting and interpreting these data. The primary emphasis is upon deep-body temperatures, with discussions of intramuscular, subcutaneous, transcutaneous and skin temperatures included. These are all turnover indices resulting from variations in local metabolism, tissue conduction and blood flow. Consequently, inter-site differences and similarities may have no mechanistic relationship unless those sites have similar metabolic rates, are in close proximity and are perfused by the same blood vessels. Therefore, it is proposed that a gold standard deep-body temperature does not exist. Instead, the validity of each measurement must be evaluated relative to one's research objectives, whilst satisfying equilibration and positioning requirements. When using thermometric computations of heat storage, the establishment of steady-state conditions is essential, but for clinically relevant states, targeted temperature monitoring becomes paramount. However, when investigating temperature regulation, the response characteristics of each temperature measurement must match the forcing function applied during experimentation. Thus, during dynamic phases, deep-body temperatures must be measured from sites that track temperature changes in the central blood volume.


Transcriptomic analysis reveals protein homeostasis breakdown in the coral Acropora millepora during hypo-saline stress.
Coral reefs can experience salinity fluctuations due to rainfall and runoff; these events can have major impacts on the corals and lead to bleaching and mortality. On the Great Barrier Reef (GBR), low salinity events, which occur during summer seasons and can involve salinity dropping ~ 10 PSU correlate with declines in coral cover, and these events are predicted to increase in frequency and severity under future climate change scenarios. In other marine invertebrates, exposure to low salinity causes increased expression of genes involved in proteolysis, responses to oxidative stress, and membrane transport, but the effects that changes in salinity have on corals have so far received only limited attention. To better understand the coral response to hypo-osmotic stress, here we investigated the transcriptomic response of the coral Acropora millepora in both adult and juvenile life stages to acute (1 h) and more prolonged (24 h) exposure to low salinity. Differential gene expression analysis revealed the involvement of both common and specific response mechanisms in Acropora. The general response to environmental stressors included up-regulation of genes involved in the mitigation of macromolecular and oxidative damage, while up-regulation of genes involved in amino acid metabolism and transport represent specific responses to salinity stress. This study is the first comprehensive transcriptomic analysis of the coral response to low salinity stress and provides important insights into the likely consequences of heavy rainfall and runoff events on coral reefs.


Human migratory meniscus progenitor cells are controlled via the TGF-β pathway.
Degeneration of the knee joint during osteoarthritis often begins with meniscal lesions. Meniscectomy, previously performed extensively after meniscal injury, is now obsolete because of the inevitable osteoarthritis that occurs following this procedure. Clinically, meniscus self-renewal is well documented as long as the outer, vascularized meniscal ring remains intact. In contrast, regeneration of the inner, avascular meniscus does not occur. Here, we show that cartilage tissue harvested from the avascular inner human meniscus during the late stages of osteoarthritis harbors a unique progenitor cell population. These meniscus progenitor cells (MPCs) are clonogenic and multipotent and exhibit migratory activity. We also determined that MPCs are likely to be controlled by canonical transforming growth factor β (TGF-β) signaling that leads to an increase in SOX9 and a decrease in RUNX2, thereby enhancing the chondrogenic potential of MPC. Therefore, our work is relevant for the development of novel cell biological, regenerative therapies for meniscus repair.


A framework for the animal health risk analysis of biotechnology-derived animals: a Canadian perspective.
This paper describes the framework used by the Canadian Food Inspection Agency to assess the risks to animal health associated with biotechnology-derived animals and their products. In Canada the risks to animal health associated with biotechnology-derived animals are one consideration among several other regulatory concerns (e.g. human health, the environment). The risk analysis process begins with hazard identification, includes a risk assessment for each hazard, and concludes with risk management and risk communication.


Cervicothoracic Lordosis Can Influence Outcome After Posterior Cervical Spine Surgery.
Previous studies on the correlation between cervical sagittal balance with improvement in quality of life showed significant results only for parameters of the anterior translation of the cervical spine (such as C2-C7 SVA). We test whether a new parameter, cervicothoracic lordosis, can predict clinical success in this type of surgery. The focused group involved patients who underwent surgical treatment of cervical degenerative disk disease by the posterior approach, due to myelopathy, radiculopathy or a combination of both. Neurologic deficit was measured before and after surgery with the Nurick Scale, postoperative quality of life, physical and mental components of SF-36 and NDI. Cervicothoracic lordosis and various sagittal balance parameters were also measured. Cervicothoracic lordosis was defined as the angle between: a) the line between the centroid of C2 and the centroid of C7; b) the line between the centroid of C7 and the centroid of T6. Correlations between postoperative quality of life and sagittal parameters were calculated. Twenty-nine patients between 27 and 78 years old were evaluated. Surgery types were simple decompression (laminectomy or laminoforaminotomy) (3 patients), laminoplasty (4 patients) and laminectomy with fusion in 22 patients. Significant correlations were found for C2-C7 SVA and cervicothoracic lordosis. C2-C7 SVA correlated negatively with MCS (r=-0.445, p=0.026) and PCS (r=-0.405, p=0.045). Cervicothoracic lordosis correlated positively with MCS (r=0.554, p= 0.004) and PCS (r=0.462, p=0.020) and negatively with NDI (r=-0.416, p=0.031). The parameter cervicothoracic lordosis correlates with improvement of quality life after surgery for cervical degenerative disk disease by the posterior approach.


Pitch strength and pitch dominance of iterated rippled noises in hearing-impaired listeners.
Reports using a variety of psychophysical tasks indicate that pitch perception by hearing-impaired listeners may be abnormal, contributing to difficulties in understanding speech and enjoying music. Pitches of complex sounds may be weaker and more indistinct in the presence of cochlear damage, especially when frequency regions are affected that form the strongest basis for pitch perception in normal-hearing listeners. In this study, the strength of the complex pitch generated by iterated rippled noise was assessed in normal-hearing and hearing-impaired listeners. Pitch strength was measured for broadband noises with spectral ripples generated by iteratively delaying a copy of a given noise and adding it back into the original. Octave-band-pass versions of these noises also were evaluated to assess frequency dominance regions for rippled-noise pitch. Hearing-impaired listeners demonstrated consistently weaker pitches in response to the rippled noises relative to pitch strength in normal-hearing listeners. However, in most cases, the frequency regions of pitch dominance, i.e., strongest pitch, were similar to those observed in normal-hearing listeners. Except where there exists a substantial sensitivity loss, contributions from normal pitch dominance regions associated with the strongest pitches may not be directly related to impaired spectral processing. It is suggested that the reduced strength of rippled-noise pitch in listeners with hearing loss results from impaired frequency resolution and possibly an associated deficit in temporal processing.


Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma.
Abstract: Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as 'cold tumours' with very little lymphocyte infiltration, they can contain up to 30-40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients.


Coupling density functional theory to polarizable force fields for efficient and accurate Hamiltonian molecular dynamics simulations.
Hybrid molecular dynamics (MD) simulations, in which the forces acting on the atoms are calculated by grid-based density functional theory (DFT) for a solute molecule and by a polarizable molecular mechanics (PMM) force field for a large solvent environment composed of several 10(3)-10(5) molecules, pose a challenge. A corresponding computational approach should guarantee energy conservation, exclude artificial distortions of the electron density at the interface between the DFT and PMM fragments, and should treat the long-range electrostatic interactions within the hybrid simulation system in a linearly scaling fashion. Here we describe a corresponding Hamiltonian DFT/(P)MM implementation, which accounts for inducible atomic dipoles of a PMM environment in a joint DFT/PMM self-consistency iteration. The long-range parts of the electrostatics are treated by hierarchically nested fast multipole expansions up to a maximum distance dictated by the minimum image convention of toroidal boundary conditions and, beyond that distance, by a reaction field approach such that the computation scales linearly with the number of PMM atoms. Short-range over-polarization artifacts are excluded by using Gaussian inducible dipoles throughout the system and Gaussian partial charges in the PMM region close to the DFT fragment. The Hamiltonian character, the stability, and efficiency of the implementation are investigated by hybrid DFT/PMM-MD simulations treating one molecule of the water dimer and of bulk water by DFT and the respective remainder by PMM.


15N and 13C natural abundance of two mycoheterotrophic and a putative partially mycoheterotrophic species associated with arbuscular mycorrhizal fungi.
• In contrast to mycoheterotrophs that associate with ectomycorrhizal and saprotrophic fungi, we know little about the ecophysiology of arbuscular mycorrhizal mycoheterotrophs. Here, we identify the mycorrhizal fungi of two unrelated mycoheterotrophs and one putative partial mycoheterotroph that form arbuscular mycorrhizas, and analyse their carbon (C) and nitrogen (N) isotope signatures. • We used molecular methods to identify the mycorrhizal fungi of Dictyostega orobanchoides, Burmannia capitata (Burmanniaceae) and Voyria aphylla (Gentianaceae). Their C and N sources were investigated by analysing their stable isotope natural abundances (δ(13)C and δ(15)N). In addition, four putative partially mycoheterotrophic Burmannia species were grown ex situ. • We found that both mycoheterotrophs and a green Burmannia species are associated with nonoverlapping Glomeromycota fungi. The investigated mycoheterotrophs are significantly more enriched in (13)C than co-occurring autotrophic plants but lack significant (15)N enrichment. The green Burmannia species is not significantly enriched in (13)C and (15)N compared with surrounding plants and can grow fully autotrophically under controlled conditions. • Our results suggest that mycoheterotrophic Burmanniaceae and Gentianaceae are able to exploit arbuscular mycorrhizal fungi. Green relatives of mycoheterotrophic Burmanniaceae from high-light grassland sites also associate with arbuscular mycorrhizal fungi but we found no evidence that they receive detectable amounts of C from fungi.


Induction chemotherapy for head and neck cancer: will history repeat itself?
Locally advanced squamous cell head and neck cancer remains a therapeutic challenge for multidisciplinary teams. Despite high objective response rates, induction chemotherapy has not resulted in tangible benefit in multiple randomized trials. In recent years, as most evidence solidified the role of concurrent chemotherapy and radiation as either primary or postoperative therapy for locally advanced head and neck cancer, induction chemotherapy fell out of scope and practice. The failure of older randomized trials to show a survival benefit from induction chemotherapy can be attributed to several factors. It is possible that the predominance of locoregional failure did not allow any added benefit from better systemic control to translate into a survival advantage. Alternatively, seemingly active chemotherapy regimens may have been suboptimal. Nevertheless, recent developments have altered our perception of head and neck cancer and its treatment. Locoregional control has dramatically improved with concurrent chemoradiotherapy. Of note is that none of the previously conducted randomized trials of induction chemotherapy used concurrent chemoradiotherapy in the control arm. Moreover, we witnessed the development of better combination regimens that improved efficacy in the induction setting. The previously standard cisplatin/5-fluoruracil (5-FU) combination is being replaced by the triple combination of taxane/ cisplatin/5-FU. Randomized trials showed that increased activity with the triplet regimen resulted in improved long-term disease control and survival. Finally, cetuximab, an active epidermal growth factor receptor inhibitor, is entering clinical practice and is expected to change the standard of therapy. With the emergence of more efficacious systemic therapies, the role of induction therapy warrants reevaluation. A number of randomized trials are planned or currently ongoing to investigate concurrent chemoradiotherapy with or without induction. These trials are anticipated to redefine the role of induction chemotherapy for head and neck cancer.


Local area networks in an imaging environment.
There is great interest at present in incorporating image-management systems popularly referred to as picture archiving and communication systems (PACS) into imaging departments. This paper will describe various aspects of local area networks (LANs) for medical images and will give a definition of terms and classification of devices by describing a possible system which links various digital image sources through a high-speed data link and a common image format, allows for viewing and processing of all images produced within the complex, and eliminates the transport of films. The status of standards governing LAN and particularly PACS systems along with a proposed image exchange format will be given. Prototype systems, particularly a system for nuclear medicine images, will be presented, as well as the prospects for the immediate future in terms of installations started and commercial products available. A survey of the many questions that arise in the development of a PACS for medical images and also a survey of the presently suggested/adopted answers will be given.


Infectious delivery of 120-kilobase genomic DNA by an epstein-barr virus amplicon vector.
It has been shown in a wide variety of contexts that persistent gene expression can best be obtained by using the genomic locus of a transgene. However, the size of most genomic loci precludes their use in current viral gene therapy vectors. Large transgene capacity and extrachromosomal persistence make Epstein-Barr virus (EBV) a promising vector to deliver genomic transgenes for gene therapy. We constructed an EBV amplicon vector that contains the EBV lytic origin of replication, the terminal repeats for viral packaging, and the EBV latent origin of replication for episomal persistence. This vector was able to deliver inserts of 60-123 kb to B-cell lines in culture in three steps. First, clonal packaging cells lines were generated that produce infectious amplicons at a titer of approximately 3-4x10(6) transducing units/ml after concentration. Second, we show infectious vector delivery to the Loukes B-cell line and three different EBV-immortalized lymphoblastoid cell lines. This infectious delivery system was 2000 times more efficient than transfection in B cells. Third, clonal cell lines from infection of Loukes contained persistent episomes of recircularized infectious vector. This first demonstration of infectious delivery of 120 kb of genomic DNA shows the potential of this high-capacity vector system.


Gender-sensitive reporting in medical research.
Sex and gender differences influence the health and wellbeing of men and women. Although studies have drawn attention to observed differences between women and men across diseases, remarkably little research has been pursued to systematically investigate these underlying sex differences. Women continue to be underrepresented in clinical trials, and even in studies in which both men and women participate, systematic analysis of data to identify potential sex-based differences is lacking. Standards for reporting of clinical trials have been established to ensure provision of complete, transparent and critical information. An important step in addressing the gender imbalance would be inclusion of a gender perspective in the next Consolidated Standards of Reporting Trials (CONSORT) guideline revision. Uniform Requirements for Manuscripts Submitted to Biomedical Journals, as a set of well-recognized and widely used guidelines for authors and biomedical journals, should similarly emphasize the ethical obligation of authors to present data analyzed by gender as a matter of routine. Journal editors are also promoters of ethical research and adequate standards of reporting, and requirements for inclusion of gender analyses should be integrated into editorial policies as a matter of urgency.


Small vault RNA1-2 modulates expression of cell membrane proteins through nascent RNA silencing.
Gene expression can be regulated by transcriptional or post-transcriptional gene silencing. Recently, we described nuclear nascent RNA silencing that is mediated by Dicer-dependent tRNA-derived small RNA molecules. In addition to tRNA, RNA polymerase III also transcribes vault RNA, a component of the ribonucleoprotein complex vault. Here, we show that Dicer-dependent small vault RNA1-2 (svtRNA1-2) associates with Argonaute 2 (Ago2). Although endogenous vtRNA1-2 is present mostly in the cytoplasm, svtRNA1-2 localises predominantly in the nucleus. Furthermore, in Ago2 and Dicer knockdown cells, a subset of genes that are up-regulated at the nascent level were predicted to be targeted by svtRNA1-2 in the intronic region. Genomic deletion of vtRNA1-2 results in impaired cellular proliferation and the up-regulation of genes associated with cell membrane physiology and cell adhesion. Silencing activity of svtRNA1-2 molecules is dependent on seed-plus-complementary-paired hybridisation features and the presence of a 5-nucleotide loop protrusion on target RNAs. Our data reveal a role of Dicer-dependent svtRNA1-2, possessing unique molecular features, in modulation of the expression of membrane-associated proteins at the nascent RNA level.


Tribological interaction between polytetrafluoroethylene and silicon oxide surfaces.
We investigated the tribological interaction between polytetrafluoroethylene (PTFE) and silicon oxide surfaces. A simple rig was designed to bring about a friction between the surfaces via sliding a piece of PTFE on a thermally oxidized silicon wafer specimen. A very mild inclination (~0.5°) along the sliding motion was also employed in order to monitor the tribological interaction in a gradual manner as a function of increasing contact force. Additionally, some patterns were sketched on the silicon oxide surface using the PTFE tip to investigate changes produced in the hydrophobicity of the surface, where the approximate water contact angle was 45° before the transfer. The nature of the transferred materials was characterized by X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). XPS results revealed that PTFE was faithfully transferred onto the silicon oxide surface upon even at the slightest contact and SEM images demonstrated that stable morphological changes could be imparted onto the surface. The minimum apparent contact pressure to realize the PTFE transfer is estimated as 5 kPa, much lower than reported previously. Stability of the patterns imparted towards many chemical washing processes lead us to postulate that the interaction is most likely to be chemical. Contact angle measurements, which were carried out to characterize and monitor the hydrophobicity of the silicon oxide surface, showed that upon PTFE transfer the hydrophobicity of the SiO2 surface could be significantly enhanced, which might also depend upon the pattern sketched onto the surface. Contact angle values above 100° were obtained.


OxLDL stimulates cell proliferation through a general induction of cell cycle proteins.
Oxidized low-density lipoprotein (oxLDL) may be involved in atherosclerosis by stimulating proliferation of cells in the vessel wall. The purpose of this study was to identify the mechanism by which oxLDL induces proliferation. Quiescent human fibroblasts and rabbit smooth muscle cells were treated with 0, 10, or 50 microg/ml oxLDL for 24-48 h. This resulted in significant increases in total cell counts at both concentrations of oxLDL, at both time points, for both types of cells. Western blot analysis revealed that oxLDL-stimulated cell proliferation was associated with significant increases in the expression of proteins that regulate entry into and progression through the cell cycle [cell division cycle 2, cyclin-dependent kinase (cdk) 2, cdk 4, cyclin B1, cyclin D1, and PCNA]. Surprisingly, the expression of cell cycle inhibitors (p21 and p27) was stimulated by oxLDL as well, but this was to a lesser extent than the effects on cell cycle-activating proteins. OxLDL also induced nuclear localization of all cell cycle proteins examined. The similar effects of oxLDL on the translocation and expression of both cell cycle-activating and -inhibiting proteins may explain the controlled proliferative phenomenon observed in atherosclerosis as opposed to the more rapid proliferative event characteristic of cancer.


County Coroners and Their Role in the Heart of the Opioid Epidemic.
As drug- and opiate/opioid-related deaths continue to rise in the Midwest, we must look at how the type of death investigation in these areas is affected and taxed by the increase. Many states with a large rural component rely on a local coroner system, where death investigation lacks uniformity and requirements for coroner investigative personnel are extremely variable. This has mixed implications for communities and potentially affects law enforcement and prosecution, data collection, and public policy. Both coroner and medical examiner systems benefit from strong leadership, properly trained personnel, and fiscal support. However, operational differences amongst jurisdictions should be addressed so that all stakeholders ultimately receive optimal data. This paper discusses the coroner system of death investigation in one Midwest state (Ohio) in the context of the region's burgeoning opiate/opioid epidemic and suggests opportunities for improvement.


The role of the right cerebral hemisphere in processing novel metaphoric expressions: a transcranial magnetic stimulation study.
Abstract Previous research suggests that the right hemisphere (RH) may contribute uniquely to the processing of metaphoric language. However, causal relationships between local brain activity in the RH and metaphors comprehension were never established. In addition, most studies have focused on familiar metaphoric expressions which might be processed similarly to any conventional word combination. The present study was designed to overcome these two problems by employing repetitive transcranial magnetic stimulation (rTMS) to examine the role of the RH in processing novel metaphoric expressions taken from poetry. Right-handed participants were presented with four types of word pairs, literal, conventional metaphoric and novel metaphoric expressions, and unrelated word pairs, and were asked to perform a semantic judgment task. rTMS of the right posterior superior temporal sulcus disrupted processing of novel but not conventional metaphors, whereas rTMS over the left inferior frontal gyrus selectively impaired processing of literal word pairs and conventional but not novel metaphors (Experiment 1). In a further experiment, we showed that these effects were due to right-left asymmetries rather than posterior-anterior differences (Experiment 2). This is the first demonstration of TMS-induced impairment in processing novel metaphoric expressions, and as such, confirms the specialization of the RH in the activation of a broader range of related meanings than the left hemisphere, including novel, nonsalient meanings. The findings thus suggest that the RH may be critically involved in at least one important component of novel metaphor comprehension, the integration of the individual meanings of two seemingly unrelated concepts into a meaningful metaphoric expression.


Mississippi Communities for Healthy Living.
Improving the diet of communities experiencing health inequities can be challenging given that multiple dietary components are low in quality. Mississippi Communities for Healthy Living was designed to test the comparative effectiveness of nutrition education using a single- versus multiple-message approach to improve the diet of adult residents in the Lower Mississippi Delta. The single-message approach targeted discretionary calories while the multiple-message approach also targeted vegetables, fruits, whole grains, and lean protein. Delta food frequency questionnaires were used to measure participants' diet, while the Healthy Eating Index-2005 (HEI-2005) was used to generate diet quality scores. Generalized linear mixed model regression was used to test for significant time, treatment, and time × treatment interaction effects in HEI-2005 component and total score changes. The majority of participants in the single- and multiple-message arms ( n = 114 and 127, respectively) were female (88% and 96%, respectively), African American (90% and 98%, respectively), overweight or obese (92% and 87%, respectively), and 41 to 60 years of age (57% and 43%, respectively). Significant time effects were present for HEI-2005 total and component scores, with three exceptions-whole fruit, total grains, and saturated fat. Significant treatment effects were present for two components-total and whole fruit; scores were higher in the multiple-message approach arm as compared to the single-message approach arm across time points. No interaction effects were significant for any of the HEI-2005 scores. Focusing nutrition education on the discretionary calories component of the diet may be as effective as focusing on multiple components for improving diet quality.


Modeling and mapping the burden of disease in Kenya.
Precision public health approaches are crucial for targeting health policies to regions most affected by disease. We present the first sub-national and spatially explicit burden of disease study in Africa. We used a cross-sectional study design and assessed data from the Kenya population and housing census of 2009 for calculating YLLs (years of life lost) due to premature mortality at the division level (N = 612). We conducted spatial autocorrelation analysis to identify spatial clusters of YLLs and applied boosted regression trees to find statistical associations between locational risk factors and YLLs. We found statistically significant spatial clusters of high numbers of YLLs at the division level in western, northwestern, and northeastern areas of Kenya. Ethnicity and household crowding were the most important and significant risk factors for YLL. Further positive and significantly associated variables were malaria endemicity, northern geographic location, and higher YLL in neighboring divisions. In contrast, higher rates of married people and more precipitation in a division were significantly associated with less YLL. We provide an evidence base and a transferable approach that can guide health policy and intervention in sub-national regions afflicted by disease burden in Kenya and other areas of comparable settings.


Transcriptome analysis of various flower and silique development stages indicates a set of class III peroxidase genes potentially involved in pod shattering in Arabidopsis thaliana.
Plant class III peroxidases exist as a large multigenic family involved in numerous functions suggesting a functional specialization of each gene. However, few genes have been linked with a specific function. Consequently total peroxidase activity is still used in numerous studies although its relevance is questionable. Transcriptome analysis seems to be a promising tool to overcome the difficulties associated with the study of this family. Nevertheless available microarrays are not completely reliable for this purpose. We therefore used a macroarray dedicated to the 73 class III peroxidase genes of A. thaliana to identify genes potentially involved in flower and fruit development. The observed increase of total peroxidase activity during development was actually correlated with the induction of only a few class III peroxidase genes which supports the existence of a functional specialization of these proteins. We identified peroxidase genes that are predominantly expressed in one development stage and are probable components of the complex gene networks involved in the reproductive phase. An attempt has been made to gain insight into plausible functions of these genes by collecting and analyzing the expression data of different studies in plants. Peroxidase activity was additionally observed in situ in the silique dehiscence zone known to be involved in pod shattering. Because treatment with a peroxidase inhibitor delayed pod shattering, we subsequently studied mutants of transcription factors (TF) controlling this mechanism. Three peroxidases genes -AtPrx13, AtPrx30 and AtPrx55- were altered by the TFs involved in pod shatter. Our data illustrated the problems caused by linking only an increase in total peroxidase activity to any specific development stage or function. The activity or involvement of specific class III peroxidase genes needs to be assessed. Several genes identified in our study had not been linked to any particular development stage or function until now. Notably AtPrx13, which is one of the peroxidase genes not present on commercially available microarrays. A systematic survey of class III peroxidase genes expression is necessary to reveal specific class III peroxidase gene functions and the regulation and evolution of this key multifunctional enzyme family. The approach used in this study highlights key individual genes that merit further investigation.


Long-term variability in artificially and naturally fluoridated water supplies in England.
To understand the potential impact of exposure misclassification on water fluoridation studies in England, this paper aims to describe the long-term variation in water fluoride concentrations in both artificially and naturally fluoridated water supplies. Water fluoridation dose monitoring data were requested from all five English public water suppliers who artificially fluoridate their water, as well as from one water company that supplies naturally fluoridated water. Descriptive statistics were calculated, including annual means, standard deviations, minimum-maximum and absolute and relative frequencies. Data were made available by two of the five English water companies who supply artificially fluoridated water and one water company that supplies naturally fluoridated water (40 398 individual samples). The data for fluoridated water spanned 18-35 years, whilst the data on naturally fluoridated water spanned 14 years. The artificially fluoridated samples showed wide variation in fluoride dose control, both between different water treatment works and over time. Mean fluoride concentrations in the artificially fluoridated supplies ranged from 0.53 (SD 0.47) to 0.93 (SD 0.22) mg F/L and were within the optimal range of 0.7-1.0 mg F/L in 27.7%-77.8% of samples. The naturally fluoridated supplies had a higher mean fluoride concentration of 1.06 (SD 0.18) and 1.15 (SD 0.16) mg F/L than the artificially fluoridated supplies, with lower variation over time. The naturally fluoridated supplies were above the optimal range in 75.5% and 53% of samples. Assumptions that populations living in areas with a water fluoridation scheme have received optimally fluoridated water (0.7-1.0 mg F/L) are invalid. To support future research endeavours, as well as to provide 'external control' and facilitation of optimal dosing, it is recommended that a quarterly record of water fluoride concentrations (mean, standard deviation and minimum and maximum) are made available for every water supply in England, in a format that can be mapped against residential postcodes.


Plant-Based Cannabinoids for the Treatment of Chronic Neuropathic Pain.
Chronic neuropathic pain is a prevalent condition that places a heavy burden on individuals and the healthcare system. Current medications have limitations and new approaches are needed, particularly given the current opioid crisis. There is some clinical evidence that the plant Cannabis sativa produces relief from neuropathic pain. However, current meta-analyses suggest that this efficacy is limited and there are problems with side effects. Most of this clinical research has examined whole cannabis, the psychoactive phytocannabinoid 9-tetrahydrocannabinol (THC), and nabiximols, which are a mixture of THC and the non-psychoactive phytocannabinoid cannabidiol. In the past, there has been little evidence based, preclinical animal research to guide clinical studies on phytocannabinoids. Recent animal studies indicate that while THC and high dose nabiximols are effective in animal neuropathic pain models, significant pain relief is only achieved at doses that produce substantial side effects. By contrast, cannabidiol and low dose nabiximols have moderate pain relieving efficacy, but are devoid of cannabinoid-like side effects. This animal data suggests that cannabidiol and low dose nabiximols warrant consideration for clinical studies, at least as adjuvants to current drugs. Preclinical research is also required to identify other phytocannabinoids that have therapeutic potential.


Preoperative assessment of trigeminal neuralgia and hemifacial spasm using constructive interference in steady state-three-dimensional Fourier transformation magnetic resonance imaging.
Results of microvascular decompression (MVD) for trigeminal neuralgia (TN) and hemifacial spasm (HFS) may be improved by accurate preoperative assessment of neurovascular relationships at the root entry/exit zone (REZ). Constructive interference in steady state (CISS)-three-dimensional Fourier transformation (3DFT) magnetic resonance (MR) imaging was evaluated for visualizing the neurovascular relationships at the REZ. Fourteen patients with TN and eight patients with HFS underwent MR imaging using CISS-3DFT and 3D fast inflow with steady-state precession (FISP) sequences. Axial images of the cerebellopontine angle (CPA) obtained by the two sequences were reviewed to assess the neurovascular relationships at the REZ of the trigeminal and facial nerves. Eleven patients subsequently underwent MVD. Preoperative MR imaging findings were related to surgical observations and results. CISS MR imaging provided excellent contrast between the cranial nerves, small vessels, and cerebrospinal fluid (CSF) in the CPA. CISS was significantly better than FISP for delineating anatomic detail in the CPA (trigeminal and facial nerves, petrosal vein) and abnormal neurovascular relationships responsible for TN and HFS (vascular contact and deformity at the REZ). Preoperative CISS MR imaging demonstrated precisely the neurovascular relationships at the REZ and identified the offending artery in all seven patients with TN undergoing MVD. CISS MR imaging has high resolution and excellent contrast between cranial nerves, small vessels, and CSF, so can precisely and accurately delineate normal and abnormal neurovascular relationships at the REZ in the CPA, and is a valuable preoperative examination for MVD.


Neurotoxicity mechanisms of thioether ecstasy metabolites.
3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, alpha-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-alpha-MeDA and alpha-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity.


Characteristics of ARG-carrying plasmidome in the cultivable microbial community from wastewater treatment system under high oxytetracycline concentration.
Studies on antibiotic production wastewater have shown that even a single antibiotic can select for multidrug resistant bacteria in aquatic environments. It is speculated that plasmids are an important mechanism of multidrug resistance (MDR) under high concentrations of antibiotics. Herein, two metagenomic libraries were constructed with plasmid DNA extracted from cultivable microbial communities in a biological wastewater treatment reactor supplemented with 0 (CONTROL) or 25 mg/L of oxytetracycline (OTC-25). The OTC-25 plasmidome reads were assigned to 72 antibiotic resistance genes (ARGs) conferring resistance to 13 types of antibiotics. Dominant ARGs, encoding resistance to tetracycline, aminoglycoside, sulfonamide, and multidrug resistance genes, were enriched in the plasmidome under 25 mg/L of oxytetracycline. Furthermore, 17 contiguous multiple-ARG carrying contigs (carrying ≥ 2 ARGs) were discovered in the OTC-25 plasmidome, whereas only nine were found in the CONTROL. Mapping of the OTC-25 plasmidome reads to completely sequenced plasmids revealed that the conjugative IncU resistance plasmid pFBAOT6 of Aeromonas caviae, carrying multidrug resistance transporter (pecM), tetracycline resistance genes (tetA, tetR), and transposase genes, might be a potential prevalent resistant plasmid in the OTC-25 plasmidome. Additionally, two novel resistant plasmids (containing contig C301682 carrying multidrug resistant operon mexCD-oprJ and contig C301632 carrying the tet36 and transposases genes) might also be potential prevalent resistant plasmids in the OTC-25 plasmidome. This study will be helpful to better understand the role of plasmids in the development of MDR in water environments under high antibiotic concentrations.


Complications of apheresis.
In general, therapeutic apheresis is a relatively safe procedure with the most commonly seen complications caused by citrate-induced hypocalcemia and urticarial reactions to the protein-containing replacement fluid. Depletion coagulopathy and immunoglobulin depletion must be anticipated when albumin is used as the replacement fluid and becomes more profound as the number of treatment increases. The most serious complications are seen when there is an anaphylactoid reaction to the multiple units of fresh frozen plasma required when used as the replacement fluid. The overall incidence of death is 0.05%, but many of these deaths were in patients with severe preexisting conditions in which the apheresis procedure, itself, may not have been the precipitating cause. As with all extracorporeal treatments requiring large bore vascular access, catheter-related trauma, clotting, infection, and bleeding may also occur.


The gut microbiota of insects - diversity in structure and function.
Insect guts present distinctive environments for microbial colonization, and bacteria in the gut potentially provide many beneficial services to their hosts. Insects display a wide range in degree of dependence on gut bacteria for basic functions. Most insect guts contain relatively few microbial species as compared to mammalian guts, but some insects harbor large gut communities of specialized bacteria. Others are colonized only opportunistically and sparsely by bacteria common in other environments. Insect digestive tracts vary extensively in morphology and physicochemical properties, factors that greatly influence microbial community structure. One obstacle to the evolution of intimate associations with gut microorganisms is the lack of dependable transmission routes between host individuals. Here, social insects, such as termites, ants, and bees, are exceptions: social interactions provide opportunities for transfer of gut bacteria, and some of the most distinctive and consistent gut communities, with specialized beneficial functions in nutrition and protection, have been found in social insect species. Still, gut bacteria of other insects have also been shown to contribute to nutrition, protection from parasites and pathogens, modulation of immune responses, and communication. The extent of these roles is still unclear and awaits further studies.


LINC01118 Modulates Paclitaxel Resistance of Epithelial Ovarian Cancer by Regulating miR-134/ABCC1.
BACKGROUND Epithelial ovarian cancer (EOC) has a high mortality rate and is a common malignant tumor of women, seriously impairing health. Chemoresistance is one of the major causes of poor prognosis. Therefore, analyzing the molecular mechanism of paclitaxel resistance has great significance. MATERIAL AND METHODS We analyzed aberrantly expressed lncRNAs in chemoresistant EOC cells by microarray and confirmed LINC01118 expression by real-time PCR. The paclitaxel sensitivity alternation was analyzed by MTS, flow cytometry, and Transwell assay, while wound healing assays were performed to assess apoptosis, migration, and invasion in vitro. The interaction between LINC01118 and miR-134 was confirmed by luciferase assay. RESULTS LINC01118 was highly expressed in EOC tissues and chemoresistant cells. Biological function experiments showed LINC01118 could facilitate paclitaxel resistance and promote migration and invasion while inhibiting apoptosis of EOC cells. Moreover, LINC01118 targets miR-134 and then affects ABCC1 expression. CONCLUSIONS LINC01118 acted as an oncogene and modulated EOC paclitaxel sensitivity by regulating miR-134/ABCC1.


In vitro effect of a corrosive hostile ocular surface on candidate biomaterials for keratoprosthesis skirt.
Keratoprosthesis (KPro) devices are prone to long-term corrosion and microbiological assault. The authors aimed to compare the inflammatory response and material dissolution properties of two candidate KPro skirt materials, hydroxyapatite (HA) and titania (TiO(2)) in a simulated in vitro cornea inflammation environment. Lipopolysaccharide-stimulated cytokine secretions were evaluated with human corneal fibroblasts on both HA and TiO(2). Material specimens were subjected to electrochemical and long-term incubation test with artificial tear fluid (ATF) of various acidities. Topography and surface roughness of material discs were analysed by scanning electron microscopy and atomic force microscopy. There were less cytokines secreted from human corneal fibroblasts seeded on TiO(2) substrates as compared with HA. TiO(2) was more resistant to the corrosion effect caused by acidic ATF in contrast to HA. Moreover, the elemental composition of TiO(2) was more stable than HA after long-term incubation with ATF. TiO(2) is more resistant to inflammatory degradation and has a higher corrosion resistance as compared with HA, and in this regard may be a suitable material to replace HA as an osteo-odonto-keratoprosthesis skirt. This would reduce resorption rates for KPro surgery.


Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.
Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.


Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1beta converting enzyme cDNA.
We report here that a cancer gene therapy protocol using a combination of IL-12, pro-IL-18, and IL-1beta converting enzyme (ICE) cDNA expression vectors simultaneously delivered via gene gun can significantly augment antitumor effects, evidently by generating increased levels of bioactive IL-18 and consequently IFN-gamma. First, we compared the levels of IFN-gamma secreted by mouse splenocytes stimulated with tumor cells transfected with various test genes, including IL-12 alone; pro-IL-18 alone; pro-IL-18 and ICE; IL-12 and pro-IL-18; and IL-12, pro-IL-18, and ICE. Among these treatments, the combination of IL-12, pro-IL-18, and ICE cDNA resulted in the highest level of IFN-gamma production from splenocytes in vitro, and similar results were obtained when these same treatments were delivered to the skin of a mouse by gene gun and IFN-gamma levels were measured at the skin transfection site in vivo. Furthermore, the triple gene combinatorial gene therapy protocol was the most effective among all tested groups at suppressing the growth of TS/A (murine mammary adenocarcinoma) tumors previously implanted intradermally at the skin site receiving DNA transfer by gene gun on days 6, 8, 10, and 12 after tumor implantation. Fifty percent of mice treated with the combined three-gene protocol underwent complete tumor regression. In vivo depletion experiments showed that this antitumor effect was CD8(+) T cell-mediated and partially IFN-gamma-dependent. These results suggest that a combinatorial gene therapy protocol using a mixture of IL-12, pro-IL-18, and ICE cDNAs can confer potent antitumor activities against established TS/A tumors via cytotoxic CD8(+) T cells and IFN-gamma-dependent pathways.


The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease.
Growing evidence has shown that the p75 neurotrophin receptor (p75NTR) may play important roles in controlling neuronal survival or cell apoptosis within the central nervous system in development, and in pathological or neural injury. Recent studies have further revealed that p75NTR acts as a "molecular signal switch" that determines cell death or survival by three processes. First, pro-nerve growth factor (proNGF) triggers cell apoptosis by its high affinity binding to p75NTR, while NGF induces neuronal survival with low-affinity binding. Second, p75NTR mediates cell death by combining with co-receptor sortilin, whereas it promotes neuronal survival through combination with proNGF. Third, release of the intracellular domain chopper or cleavaged "short p75NTR" can independently initiate neuronal apoptosis. We have identified the cell self-destructive proNGF-p75NTR-sortilin signalling apparatus assembled in ventral tier dopamine neurons of the substantia nigra pars compacta, suggesting that p75NTR signalling might be involved in selective cell death mechanisms of substantia nigra neurons or disease progression of Parkinson's disease (PD). In addition, experimental manipulation of p75NTR benefited cell survival of cholinergic or motor neurons and improved disease progression of the neurodegenerative diseases Alzheimer's disease and Amyotrophic lateral sclerosis. The proNGF-p75NTR-sortilin signalling complex may thus provide new target for neuroprotection of substantia nigra neurons and the therapeutic treatment of PD.


A descriptive study of the experiences of lesbian, gay and transgender parents accessing health services for their children.
To explore the experiences of lesbian, gay and transgender families accessing health care for their children. Although lesbian, gay and transgender families are becoming more common, little is known about their health-seeking experiences. These families may be fearful about disclosing their sexual orientation or gender identity to health professionals. As a result, lesbian, gay and transgender parents may not be receiving optimal care for their children. Descriptive qualitative study. Data were collected through semi-structured interviews with 11 lesbian, gay and transgender parents in Australia. Three themes were generated from the data: 'managing health care experiences', 'attitudes' and 'transforming bureaucracies'. Negative experiences included encountering homophobia or transphobia and being required to educate health professionals. Positive experiences occurred when both parents were acknowledged as having an equal say in their child's health care. Many health professionals lack the skill or knowledge to meet the needs of lesbian, gay and transgender families. Health services are required to ensure that all policies and procedures are inclusive of all family constellations and that staff receive relevant and up-to-date sensitivity training and create an environment that is respectful of all family groups. Adopting a philosophy of family centred care can enable health providers and health professionals to provide lesbian, gay and transgender families with inclusive non-discriminatory care.


Topical nitroglycerin for the treatment of intraoperative microsurgical vasospasm.
Papaverine remains a popular agent to treat intraoperative microsurgical vasospasm. However, the recent shortage has forced surgeons to trial antispasmodic agents unproven in microsurgery, but commonly used in other areas. During this shortage we have trialed topical nitroglycerin to break intraoperative vasospasm. This study aims to analyze the outcomes of this medication on flap complications compared with papaverine. All consecutive free flaps performed for breast reconstruction at a single institution were reviewed. Data collected included patient demographics, co-morbidities, complications and type of antispasmodic agent. Rates of re-exploration, complications and flap salvage were compared between patients receiving nitroglycerin and papaverine. Over 10 years, 991 flaps were treated with antispasmodics: 18 of which were treated with topical nitroglycerin. Patients treated with nitroglycerin tended to have higher BMI (32.1 vs. 27.9, P < 0.01), higher rates of pre-operative chemotherapy (83.3% vs. 51.3%, P < 0.01) and shorter follow-up duration (735 vs. 1691 days, P < 0.01). However, no differences in complications were observed, including: unplanned return to the operating room, flap loss, fat necrosis, infection, hematoma, or seroma. Subgroup analysis with a time-matched cohort of papaverine patients revealed minimal difference in comorbidities and no difference in complications. Substituting topical nitroglycerin for papaverine to treat vasospasm during the shortage did not demonstrate an increased rate of flap loss or return to the operating room, making these medications a safe alternative to papaverine.


Transforming-growth factor beta1 Leu10Pro polymorphism and breast cancer morbidity.
TGF-beta1 has a dual role in carcinogenesis. In this gene, a leucine to proline substitution in codon 10 leads to higher circulating levels of TGF-beta1. This variant has been studied in relationship to the risk for breast cancer yielding contradicting results. We aim to unravel the relationship of this polymorphism and the risk of breast cancer. Women participating in the Rotterdam Study including 143 patients with incident breast cancer were genotyped for this polymorphism. We carried out a logistic regression and a survival analysis using age as the time variable. The logistic regression analysis showed an increased risk of breast cancer for Proline carriers (OR=1.4; 95% confidence interval (CI)=1.1-2.0) versus non-carriers. The survival analysis showed that carriers of the same allele had an increased risk of breast cancer (HR=1.4, 95% CI=1.1-2.0) against non-carriers. Our data suggest that the TGF-beta1 Leu10Pro polymorphism might play a role in breast cancer risk.


Exploration of cost effectiveness of active vaccination in the control of a school outbreak of hepatitis A in a deprived community in the United Kingdom.
In January 2006, an outbreak of hepatitis A occurred in a socio-economically deprived area of Liverpool, in the United Kingdom (UK), where extensive community outbreaks of hepatitis had previously occurred. A total of nine cases were confirmed. Five of these were linked within a primary school. The outbreak initially occurred among a close social contact group, but there was evidence of subsequent person-to-person transmission within a local primary school. The school was attended by 221 pupils (age range 4-12 years) with a total of 37 teaching and other staff (age range 22-71 years). Following local risk assessment, mass hepatitis A virus (HAV) vaccination was offered to all staff and pupils, as all were judged to be likely to have been in close contact with the affected pupils. A total of 188 of 217 eligible children (87%), and 33 of 37 staff (89%) were vaccinated. A salivary seroprevalence survey was conducted at the same time as vaccination to assess the benefit of this intervention in the school population. The survey confirmed high levels of susceptibility to hepatitis A in this setting (97.8%, 95% CI 91.6 to 99.62). The direct costs of intervention were estimated as euro5,000. The cost effectiveness of intervention varies widely (euro60.50 to euro2,099 per case avoided) depending on the expected attack rate, which is difficult to estimate due to heterogeneity in published studies.


Nitroimidazoles, part 2: Synthesis, antiviral and antitumor activity of new 4-nitroimidazoles.
A series of 5-alkylamino and 5-alkylsulfanyl derivatives of 1-aryl-2-alkyl-4-nitro-1H-imidazoles 12-21, 31, and 34 were synthesized by a simple method with the aim to develop novel HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs). All the new compounds were tested against HIV-1 and HIV-2 in MT-4 cells. Compound 21, with an arylsulfanyl group at C(5) of the 4-nitro-1H-imidazole backbone showed an EC(50) value of 0.22 microg/ml against HIV-1 with a therapeutic index of 13. This means that compound 21 was cytotoxic to MT-4 cells at a CC(50) value of 2.57 microg/ml; also compounds 8, 22-25, 28, and 29 were cytotoxic to MT-4 cells within the 0.4-4 microg/ml concentration range. Compounds 8, and 12-21 were evaluated, as a rule, but found inactive at non-toxic concentrations against hepatitis C virus, herpes simplex type 1 and 2, cytomegalovirus (CMV), varicella-zoster virus (VZV), vaccinia virus, and vesicular stomatitis virus, and a number of other viruses. Yet, the therapeutic index of compounds 17 and 21 for CMV and VZV approached the tenfold cut-off point. Compounds 8 and 21 exhibited some cytostatic activity against leukemia and melanoma cell lines.


Predictors of Physical Activity for Preschool Children With and Without Disabilities From Socioeconomically Disadvantaged Settings.
The purpose of this study was to examine differences in motor competence, perceived motor competence (PMC), body mass index, and physical activity (PA) and to assess factors that predict PA behaviors of preschool children with and without disabilities. A total of 59 children with (n = 28) and without (n = 31) disabilities participated in the study. Results revealed that children with disabilities had significantly greater amounts of PA than peers without disabilities. There were no significant differences for motor competence, PMC, and body mass index for children with or without a disability. Although age and body mass index were controlled, both disability and PMC significantly predicted PA. Future intervention studies should consider maintaining high levels of PMC, as it is a significant predictor of PA.