Compact convolutional neural networks for classification of asynchronous steady-state visual evoked potentials.
Steady-state visual evoked potentials (SSVEPs) are neural oscillations from the parietal and occipital regions of the brain that are evoked from flickering visual stimuli. SSVEPs are robust signals measurable in the electroencephalogram (EEG) and are commonly used in brain-computer interfaces (BCIs). However, methods for high-accuracy decoding of SSVEPs usually require hand-crafted approaches that leverage domain-specific knowledge of the stimulus signals, such as specific temporal frequencies in the visual stimuli and their relative spatial arrangement. When this knowledge is unavailable, such as when SSVEP signals are acquired asynchronously, such approaches tend to fail. In this paper, we show how a compact convolutional neural network (Compact-CNN), which only requires raw EEG signals for automatic feature extraction, can be used to decode signals from a 12-class SSVEP dataset without the need for user-specific calibration. The Compact-CNN demonstrates across subject mean accuracy of approximately 80%, out-performing current state-of-the-art, hand-crafted approaches using canonical correlation analysis (CCA) and Combined-CCA. Furthermore, the Compact-CNN approach can reveal the underlying feature representation, revealing that the deep learner extracts additional phase- and amplitude-related features associated with the structure of the dataset. We discuss how our Compact-CNN shows promise for BCI applications that allow users to freely gaze/attend to any stimulus at any time (e.g. asynchronous BCI) as well as provides a method for analyzing SSVEP signals in a way that might augment our understanding about the basic processing in the visual cortex.


Task load modulates tDCS effects on brain network for phonological processing.
Motor participation in phonological processing can be modulated by task nature across the speech perception to speech production range. The pars opercularis of the left inferior frontal gyrus (LIFG) would be increasingly active across this range, because of changing motor demands. Here, we investigated with simultaneous tDCS and fMRI whether the task load modulation of tDCS effects translates into predictable patterns of functional connectivity. Findings were analysed under the "multi-node framework", according to which task load and the network structure underlying cognitive functions are modulators of tDCS effects. In a within-subject study, participants (N = 20) performed categorical perception, lexical decision and word naming tasks [which differentially recruit the target of stimulation (LIFG)], which were repeatedly administered in three tDCS sessions (anodal, cathodal and sham). The LIFG, left superior temporal gyrus and their right homologues formed the target network subserving phonological processing. C-tDCS inhibition and A-tDCS excitation should increase with task load. Correspondingly, the larger the task load, the larger the relevance of the target for the task and smaller the room for compensation of C-tDCS inhibition by less relevant nodes. Functional connectivity analyses were performed with partial correlations, and network compensation globally inferred by comparing the relative number of significant connections each condition induced relative to sham. Overall, simultaneous tDCS and fMRI was adequate to show that motor participation in phonological processing is modulated by task nature. Network responses induced by C-tDCS across phonological processing tasks matched predictions. A-tDCS effects were attributed to optimisation of network efficiency.


Prediction of pre-eclampsia in nulliparous women using routinely collected maternal characteristics: a model development and validation study.
Guidelines recommend identifying in early pregnancy women at elevated risk of pre-eclampsia. The aim of this study was to develop and validate a pre-eclampsia risk prediction model for nulliparous women attending routine antenatal care "the Western Sydney (WS) model"; and to compare its performance with the National Institute of Health and Care Excellence (NICE) risk factor-list approach for classifying women as high-risk. This retrospective cohort study included all nulliparous women who gave birth in three public hospitals in the Western-Sydney-Local-Health-District, Australia 2011-2014. Using births from 2011 to 2012, multivariable logistic regression incorporated established maternal risk factors to develop and internally validate the WS model. The WS model was then externally validated using births from 2013 to 2014, assessing its discrimination and calibration. We fitted the final WS model for all births from 2011 to 2014, and compared its accuracy in predicting pre-eclampsia with the NICE approach. Among 12,395 births to nulliparous women in 2011-2014, there were 293 (2.4%) pre-eclampsia events. The WS model included: maternal age, body mass index, ethnicity, multiple pregnancy, family history of pre-eclampsia, autoimmune disease, chronic hypertension and chronic renal disease. In the validation sample (6201 births), the model c-statistic was 0.70 (95% confidence interval 0.65-0.75). The observed:expected ratio for pre-eclampsia was 0.91, with a Hosmer-Lemeshow goodness-of-fit test p-value of 0.20. In the entire study sample of 12,395 births, 374 (3.0%) women had a WS model-estimated pre-eclampsia risk ≥8%, the pre-specified risk-threshold for considering aspirin prophylaxis. Of these, 54 (14.4%) developed pre-eclampsia (sensitivity 18% (14-23), specificity 97% (97-98)). Using the NICE approach, 1173 (9.5%) women were classified as high-risk, of which 107 (9.1%) developed pre-eclampsia (sensitivity 37% (31-42), specificity 91% (91-92)). The final model showed similar accuracy to the NICE approach when using lower risk-threshold of ≥4% to classify women as high-risk for pre-eclampsia. The WS risk model that combines readily-available maternal characteristics achieved modest performance for prediction of pre-eclampsia in nulliparous women. The model did not outperform the NICE approach, but has the advantage of providing individualised absolute risk estimates, to assist with counselling, inform decisions for further testing, and consideration of aspirin prophylaxis.


SoC CMOS UWB Pulse Radar Sensor for Contactless Respiratory Rate Monitoring.
An ultra wideband (UWB) system-on-chip radar sensor for respiratory rate monitoring has been realized in 90 nm CMOS technology and characterized experimentally. The radar testchip has been applied to the contactless detection of the respiration activity of adult and baby. The field operational tests demonstrate that the UWB radar sensor detects the respiratory rate of person under test (adult and baby) associated with sub-centimeter chest movements, allowing the continuous-time non-invasive monitoring of hospital patients and other people at risk of obstructive apneas such as babies in cot beds, or other respiratory diseases.


Agricultural land is the main source of stream sediments after conversion of an African montane forest.
In many parts of Africa, soil erosion is an important problem, which is evident from high sediment yields in tropical montane streams. Previous studies in Kenya pointed to a large contribution from catchments cultivated by smallholder farmers. This led to the hypothesis that unpaved tracks and gullies are the main sediment sources in smallholder agriculture catchments of the highlands of Kenya. The aim of this study was to investigate the sediment sources with sediment fingerprinting to generate the knowledge base to improve land management and to reduce sediment yields. Four main sediment sources (agricultural land, unpaved tracks, gullies and channel banks) and suspended sediments were analysed for biogeochemical elements as potential tracers. To apportion the catchments target sediment to different sources, we applied the MixSIAR un-mixing modelling under a Bayesian framework. Surprisingly, the fingerprinting analysis showed that agricultural land accounted for 75% (95% confidence interval 63-86%) of the total sediment. Channel banks contributed 21% (8-32%), while the smallest contributions to sediment were generated by the unpaved tracks and gullies with 3% (0-12%) and 1% (0-4%), respectively. Erosion management strategies should target agricultural lands with an emphasis on disconnecting unpaved tracks form hillslope source areas to reduce sediment yields to Lake Victoria.


Trajectories of cannabis-related associative memory among vulnerable adolescents: Psychometric and longitudinal evaluations.
Indirect tests of memory associations relevant to cannabis have been shown to be useful in explaining and predicting adolescent cannabis use habits. This study sought to increase the understanding of adolescent cannabis-related associative memory and cannabis use behavior over time. A longitudinal sample of alternative high school students (N = 775) was assessed yearly for 3 years. The study first conducted extensive longitudinal measurement analyses of the cannabis-related word association test (WAT) applying contemporary psychometric models. Second, the study examined the longitudinal trajectories of cannabis-related associative memory and cannabis use and their contemporaneous and longitudinal relationships. Results showed that the cannabis-related WAT provided strong evidence of sound psychometric properties. Longitudinal change in cannabis-related associative memory was best described by modeling either a linearly decreasing trajectory or two separate trajectories: During middle adolescence, levels of cannabis-related associative memory were highest and stable but then gradually decreased toward late adolescence. Moreover, cannabis-related associative memory was contemporaneously predictive of cannabis use within ages 15 to 19 while controlling for the underlying growth process of cannabis use and time-invariant covariates (TICs) of gender and lifetime concurrent use of alcohol and cigarettes. Partial support of longitudinal prediction of cannabis use was also obtained from age 17 to 18 and age 19 to 20 while adjusting for growth in cannabis use and the TICs. These results demonstrated that predictive effects of cannabis-related memory associations on cannabis use were detected within some of the 1-year age spans and were consistent within ages across adolescent years. (PsycINFO Database Record


Tumor Hypoxia Response After Targeted Therapy in EGFR-Mutant Non-Small Cell Lung Cancer: Proof of Concept for FMISO-PET.
Hypoxia is associated with resistance to radiotherapy and chemotherapy. Functional imaging of hypoxia in non-small cell lung cancer (NSCLC) could allow early assessment of tumor response and guide subsequent therapies. Epidermal growth factor receptor (EGFR) inhibition with erlotinib reduces hypoxia in vivo. [18F]-Fluoromisonidazole (FMISO) is a radiolabeled tracer that selectively accumulates in hypoxic cells. We sought to determine whether FMISO positron emission tomography (FMISO-PET) could detect changes in hypoxia in vivo in response to EGFR-targeted therapy. In a preclinical investigation, nude mice with human EGFR-mutant lung adenocarcinoma xenografts underwent FMISO-PET scans before and 5 days after erlotinib or empty vehicle initiation. Descriptive statistics and analysis of variance (ANOVA) tests were used to analyze changes in standardized uptake value (SUV), with pooled analyses for the mice in each group (baseline, postvehicle, and posterlotinib). In a small correlative pilot human study, patients with EGFR-mutant metastatic NSCLC underwent FMISO-PET scans before and 10 to 12 days after erlotinib initiation. Changes in SUV were compared to standard chest computed tomography (CT) scans performed 6 weeks after erlotinib initiation. The mean (±standard error of the mean; SUVmean) of the xenografts was 0.17 ± 0.014, 0.14 ± 0.008, and 0.06 ± 0.004 for baseline, postvehicle, and posterlotinib groups, respectively, with lower SUVmean among the posterlotinib group compared to other groups (P < .05). Changes on preclinical PET imaging were striking, with near-complete disappearance of FMISO uptake after erlotinib initiation. Two patients were enrolled on the pilot study. In the first patient, SUVmean increased by 21% after erlotinib, with progression on 6-week chest CT followed by death after 4.8 months. In the second patient, SUVmean decreased by 7% after erlotinib, with regression on 6-week chest CT accompanied by clinical improvement; the patient had stable disease at 14.5 months. In conclusion, we observed that FMISO-PET can detect changes in hypoxia levels after EGFR-directed therapy in EGFR-mutant NSCLC. Further study is warranted to determine its utility as an imaging biomarker of early response to EGFR-directed therapy.


Handshaking promotes deal-making by signaling cooperative intent.
We examine how a simple handshake-a gesture that often occurs at the outset of social interactions-can influence deal-making. Because handshakes are social rituals, they are imbued with meaning beyond their physical features. We propose that during mixed-motive interactions, a handshake is viewed as a signal of cooperative intent, increasing people's cooperative behavior and affecting deal-making outcomes. In Studies 1a and 1b, pairs who chose to shake hands at the onset of integrative negotiations obtained better joint outcomes. Study 2 demonstrates the causal impact of handshaking using experimental methodology. Study 3 suggests a driver of the cooperative consequence of handshaking: negotiators expected partners who shook hands to behave more cooperatively than partners who avoided shaking hands or partners whose nonverbal behavior was unknown; these expectations of cooperative intent increased negotiators' own cooperation. Study 4 uses an economic game to demonstrate that handshaking increased cooperation even when handshakes were uninstructed (vs. instructed). Further demonstrating the primacy of signaling cooperative intent, handshaking actually reduced cooperation when the action signaled ill intent (e.g., when the hand-shaker was sick; Study 5). Finally, in Study 6, executives assigned to shake hands before a more antagonistic, distributive negotiation were less likely to lie about self-benefiting information, increasing cooperation even to their own detriment. Together, these studies provide evidence that handshakes, ritualistic behaviors imbued with meaning beyond mere physical contact, signal cooperative intent and promote deal-making. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


CT density analysis of the medial cuneiform.
A cannulated lag screw inserted through the medial cuneiform into the base of the second metatarsal is often utilized to reduce the diastasis and aid healing of Lisfranc injuries. Also procedures such as a midfoot or a Lapidus arthrodesis require adequate implant-bone purchase in the medial cuneiform. The medial cuneiform contains cancellous bone of varying density. Knowledge of density variation may be helpful for implant usage and manufacturing of area specific implants. In 60 randomly selected patients, mean computed tomography (CT) intensity in Hounsfield units was measured at 12 sampled locations within the medial cuneiform and served as a proxy for bone density. The patients' age, gender, and race were recorded. An analysis of variance (ANOVA) assessed the effect of age, gender, race, and sample site on bone density. Statistical testing assumed 95% level of confidence. ANOVA showed age, gender, and sample site had significant effects (P < .001) on bone density, though race had no significant effect (P = .28). The distal-dorsal-lateral (DDL) site was significantly denser than all other sites (P < .001) except the middle-dorsal-lateral (MDL) (P = .53). The proximal-plantar-lateral (PPL) site was significantly less dense than all other sites (P < .001) except the middle-plantar-lateral/medial and the proximal-plantar-medial sites (P < .14). A general trend of density increasing in the distal and dorsal directions was evident, and within the dorsal sites there was a trend of increasing density in the lateral direction. This is the first study to date to measure density of the medial cuneiform using living subjects. The sample size of 60 patients was also the largest of any study measuring density of this bone. We conclude that the densest area of the medial cuneiform is the most anterior, dorsal, and lateral portion. The findings of this study may indicate the most optimal area for implant purchase in the medial cuneiform when reducing the diastasis between the base of the second metatarsal and medial cuneiform and for stabilization of the medial column.


Structural basis for homodimerization of the Src-associated during mitosis, 68-kDa protein (Sam68) Qua1 domain.
Sam68 (Src-associated during mitosis, 68 kDa) is a prototypical member of the STAR (signal transducer and activator of RNA) family of RNA-binding proteins. STAR proteins bind mRNA targets and modulate cellular processes such as cell cycle regulation and tissue development in response to extracellular signals. Sam68 has been shown to modulate alternative splicing of the pre-mRNAs of CD44 and Bcl-xL, which are linked to tumor progression and apoptosis. Sam68 and other STAR proteins recognize bipartite RNA sequences and are thought to function as homodimers. However, the structural and functional roles of the self-association are not known. Here, we present the solution structure of the Sam68 Qua1 homodimerization domain. Each monomer consists of two antiparallel alpha-helices connected by a short loop. The two subunits are arranged perpendicular to each other in an unusual four-helix topology. Mutational analysis of Sam68 in vitro and in a cell-based assay revealed that the Qua1 domain and residues within the dimerization interface are essential for alternative splicing of a CD44 minigene. Together, our results indicate that the Qua1 homodimerization domain is required for regulation of alternative splicing by Sam68.


Electromagnetic fields, 5G and health: what about the precautionary principle?
New fifth generation (5G) telecommunications systems, now being rolled out globally, have become the subject of a fierce controversy. Some health protection agencies and their scientific advisory committees have concluded that there is no conclusive scientific evidence of harm. Several recent reviews by independent scientists, however, suggest that there is significant uncertainty on this question, with rapidly emerging evidence of potentially harmful biological effects from radio frequency electromagnetic field (RF-EMF) exposures, at the levels 5G roll-out will entail. This essay identifies four relevant sources of scientific uncertainty and concern: (1) lack of clarity about precisely what technology is included in 5G; (2) a rapidly accumulating body of laboratory studies documenting disruptive in vitro and in vivo effects of RF-EMFs-but one with many gaps in it; (3) an almost total lack (as yet) of high-quality epidemiological studies of adverse human health effects from 5G EMF exposure specifically, but rapidly emerging epidemiological evidence of such effects from past generations of RF-EMF exposure; (4) persistent allegations that some national telecommunications regulatory authorities do not base their RF-EMF safety policies on the latest science, related to unmanaged conflicts of interest. The author, an experienced epidemiologist, concludes that one cannot dismiss the growing health concerns about RF-EMFs, especially in an era when higher population levels of exposure are occurring widely, due to the spatially dense transmitters which 5G systems require. Based on the precautionary principle, the author echoes the calls of others for a moratorium on the further roll-out of 5G systems globally, pending more conclusive research on their safety.


Transparency induced by coupled resonances in disordered metamaterials.
We propose a scheme to induce transparency in one-dimensional disordered multilayers which are composed of negative permittivity and negative permeability metamaterials. First, analytical expressions for transparency condition are derived exactly, providing us a picture that complete tunneling in such kind of multiple-resonance system can be achieved if exponentially growing waves can compensate exponentially decaying waves. Second, a compensating method is used to realize this idea, and both simulations and experiments are performed in the microwave regime to confirm the theoretical analysis. Last, we have a discussion on how the coupling of resonances affects the transport properties of samples.


Lead transport into Bayou Trepagnier wetlands in Louisiana, USA.
Establishment of a petroleum refinery in 1916 near the headwaters of Bayou Trepagnier with subsequent dredging of the bayou resulted in spoil banks containing high levels of Pb. A large swamp abuts the eastern bank of the bayou. Cores were taken from 15 baldcypress [Taxodium distichum (L.) Richard] trees growing in the swamp along a 610-m transect (nine trees) and a 183-m transect (six trees) running perpendicular from the spoil bank. The cores were crossdated, annual rings were measured, and 5-yr segments of the cores were prepared and analyzed for heavy metals. Soil samples were collected along one transect and analyzed for metals. Levels of Pb in Bayou Trepagnier swamp trees were compared to levels in nine baldcypress trees growing along Stinking Bayou, a reference area. During the last 100 yr, Pb in growth rings of swamp baldcypress trees averaged 8.6 mg/kg (SD 4.88) along one transect and 7.9 mg/kg (SD 5.39) along the other. Lead in the soil along the first transect dropped from >2700 mg/kg (spoil bank) to 10 mg/kg at 420 m into the swamp. Baldcypress trees growing near the refinery on the spoil bank along Bayou Trepagnier (covered in an earlier study) averaged 4.5 mg/kg Pb, and trees along Stinking Bayou averaged 2.1 mg/kg. Trees in the swamp soil with 10 to 425 mg/kg Pb concentrated much more Pb than trees growing on the heavily polluted bank. Greater uptake of Pb by trees in the swamp is discussed in terms of soil dynamics and Pb sources.


Does antenatal care make a difference to safe delivery? A study in urban Uttar Pradesh, India.
Evidence to support that antenatal screenings and interventions are effective in reducing maternal mortality has been scanty and studies have presented contradictory findings. In addition, antenatal care utilization is poorly characterized in studies. As an exposure under investigation, antenatal care should be well defined. However, measures typically only account for the frequency and timing of visits and not for care content. We introduce a new measure for antenatal care utilization, comprised of 20 input components covering care content and visit frequency. Weights for each component reflect its relative importance to better maternal and child health, and were derived from a survey of international researchers. This composite measure for antenatal care utilization was studied in a probability sample of 300 low to middle income women who had given birth within the last three years in Varanasi, Uttar Pradesh, India. Results showed that demarcating women's antenatal care status based on a simple indicator--two or more visits versus less--masked a large amount of variation in care received. Logistic regression analyses were conducted to examine the effect of antenatal care utilization on the likelihood of using safe delivery care, a factor known to decrease maternal mortality. After controlling for relevant socio-demographic and maternity history factors, women with a relatively high level of care (at the 75th percentile of the score) had an estimated odds of using trained assistance at delivery that was almost four times higher than women with a low level of care (at the 25th percentile of the score) (OR = 3.97, 95% CI = 1.96, 8.10). Similar results were obtained for women delivering in a health facility versus at home. This strong positive association between level of care obtained during pregnancy and the use of safe delivery care may help explain why antenatal care could also be associated with reduced maternal mortality.


Long-Term Evaluation of a UK Community Pharmacy-Based Weight Management Service.
Obesity increases the risk of cardiovascular disease, type 2 diabetes and cancer, reducing both the quality and quantity of life. Consequently, government healthcare costs are significant. A greater than 5% reduction in weight has been shown to result in significant improvements in type II diabetes, blood pressure and cholesterol levels and therefore effective interventions are required. This paper reports the results from 17 years of delivering a private, individualised very low calorie diet (VLCD) programme in community pharmacy. In line with national guidelines, a community pharmacy-based private weight management service was set up to support individuals over the age of 18. After assessment for clinical suitability, individuals were offered either a flexible weight loss plan or a strict weight loss plan using a very low calorie diet (VLCD). The VLCD was delivered using the protocols of the proprietary programme, Lipotrim™. These individuals followed one or more dieting sequences, defined as at least one week of attendance whilst following the VLCD, without discontinuation, producing at least a start and end weight. Data were recorded weekly and audited for this report including weight and BMI on initial presentation, weight and BMI lost and % weight and BMI loss. A total of 1875 dieting sequences were recorded from 1023 dieters. In 1261 (67.3%) sequences, a medically beneficial weight loss of >5% was achieved. Overall, the cohort demonstrated mean (sd) % weight losses of 10.1% (7.7). Mean (sd) % weight losses seen in people with type 2 diabetes was 10.4% (2.7) and 10.6% (5.9) in hypertension. In total, 555 diet sequences accessed long-term weight maintenance support. In 173 (31%) of these cases, a second weight check post weight loss could not be made. The remaining 382 individuals presenting showed a mean (sd) weight gain of only 1.4kg (4.3) equating to a mean (sd) % weight gain of only 1.8% (4.6) over a mean (sd) number of days post weight-loss of 132 days (179). The results from this long-term review demonstrate that with proper provision of a nutritionally complete VLCD, through private service provision, community pharmacies can make a significant contribution to reducing the obesity epidemic at no cost to state-funded health systems.


Autumn migratory orientation and route choice in early and late dunlins Calidris alpina captured at a stopover site in Alaska.
We investigated the migratory orientation of early and late captured dunlins, Calidris alpina, by recording their migratory activity in circular orientation cages during autumn at a staging site in southwest Alaska and performed route simulations to the wintering areas. Two races of dunlins breeding in Alaska have different wintering grounds in North America (Pacific Northwest), and East Asia. Dunlins caught early in autumn (presumably Calidris alpinapacifica) oriented towards their wintering areas (east-southeast; ESE) supporting the idea that they migrate nonstop over the Gulf of Alaska to the Pacific Northwest. We found no difference in orientation between adult and juveniles, nor between fat and lean birds or under clear and overcast skies demonstrating that age, energetic status and cloud cover did not affect the dunlins' migratory orientation. Later in autumn, we recorded orientation responses towards south-southwest suggesting arrival of the northern subspecies Calidris alpinaarcticola at our site. Route simulations revealed multiple compass mechanisms were compatible with the initial direction of early dunlins wintering in the Pacific Northwest, and for late dunlins migrating to East Asia. Future high-resolution tracking would reveal routes, stopover use including local movements and possible course shifts during migration from Alaska to wintering sites on both sides of the north Pacific Ocean.


Automating Vector Autoregression on Electronic Patient Diary Data.
Finding the best vector autoregression model for any dataset, medical or otherwise, is a process that, to this day, is frequently performed manually in an iterative manner requiring a statistical expertize and time. Very few software solutions for automating this process exist, and they still require statistical expertize to operate. We propose a new application called Autovar, for the automation of finding vector autoregression models for time series data. The approach closely resembles the way in which experts work manually. Our proposal offers improvements over the manual approach by leveraging computing power, e.g., by considering multiple alternatives instead of choosing just one. In this paper, we describe the design and implementation of Autovar, we compare its performance against experts working manually, and we compare its features to those of the most used commercial solution available today. The main contribution of Autovar is to show that vector autoregression on a large scale is feasible. We show that an exhaustive approach for model selection can be relatively safe to use. This study forms an important step toward making adaptive, personalized treatment available and affordable for all branches of healthcare.


Effective interventions for preventing work related physical health complaints in nursing students and novice nurses: A systematic review.
From the start of their career, nursing students and novice nurses are at risk of developing physical health problems due to high physical workload, which may lead to early exit from nursing. To provide an overview of interventions preventing physical health problems in early career, a systematic review was performed. A comprehensive search of the literature was conducted up to December 2017. Primary outcome of interest was education/work dropout. Secondary outcomes were musculoskeletal symptoms. Independent authors selected studies, appraised quality and extracted data. After screening 7111 titles and abstracts, eleven studies were included. Seven studies evaluated interventions for moving/handling training. Four evaluated other interventions. None focused on our primary outcome education/work dropout. All studies reported on physical complaints among student nurses only. Overall, risk of bias was high and clinical heterogeneity prohibited pooling of data. Intervention effects were small and inconsistent. In conclusion, evidence for the effectiveness of interventions in the nursing curricula for the prevention/treatment of physical complaints is scarce and where available conflicting. We recommend high quality research on dropout due to physical health problems, as well as on the prevention/treatment of physical complaints.


Complex diel cycles of gene expression in coral-algal symbiosis.
Circadian regulation of plant-animal endosymbioses is complicated by a diversity of internal and external cues. Here, we show that stress-related genes in corals are coupled to the circadian clock, anticipating major changes in the intracellular milieu. In this regard, numerous chaperones are "hard-wired" to the clock, effectively preparing the coral for the consequences of oxidative protein damage imposed by symbiont photosynthesis (when O(2) > 250% saturation), including synexpression of antioxidant genes being light-gated. Conversely, central metabolism appears to be regulated by the hypoxia-inducible factor system in coral. These results reveal the complexity of endosymbiosis as well as the plasticity regulation downstream of the circadian clock.


Modulation of Fgfr1a signaling in zebrafish reveals a genetic basis for the aggression-boldness syndrome.
Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.


Platinum-mediated B-H methoxylation of bis(pyrazolyl)borate.
A new bis(pyrazolyl)dihydridoborato diphenylplatinum(ii) complex was found to react with methanol to form H2 and a new diphenylplatinum(ii) complex supported by bis(pyrazolyl)dimethoxyborate. When performed in CD3OD, in addition to the expected installation of OCD3 fragments on the B-center and concomitant formation of H-D, deuteration of PtII(C6H5)2 fragments was observed. In contrast, dissolution of the bis(pyrazolyl)dimethoxyborato diphenylplatinum(ii) complex in CD3OD led to neither deuteration of PtII(C6H5)2 fragments nor substitution of B-bound methoxy fragments. A mechanism discussing the role of the PtII-center is presented.


INFLIXIMAB THERAPY IN PATIENTS WITH NONINFECTIOUS INTERMEDIATE UVEITIS RESISTANT TO CONVENTIONAL IMMUNOMODULATORY THERAPY.
To examine the efficacy and safety of infliximab therapy in the treatment for noninfectious intermediate uveitis resistant to conventional immunomodulatory therapy. Forty-four eyes of 23 patients with resistant noninfectious intermediate uveitis who were treated with infliximab infusions for a minimum period of 3 months were included. Demographic data, clinical data, and fluorescein angiography and optical coherence tomography findings were collected from the Massachusetts Eye Research and Surgery Institution database between August 2005 and February 2014. Clinical response, improvement in ancillary test findings, and major side effects were evaluated. Nineteen patients (82.6%) achieved remission. The mean duration of treatment to induce remission was 3.99 ± 3.06 months (range, 2-14.7). Cystoid macular edema was the only complication observed during the course of the treatment in 1 eye (2.27%). One patient (4.3%) developed major side effects. None of the patients developed central or peripheral demyelinating neuropathies or multiple sclerosis. At 6 months after remission, logarithm of the minimum angle of resolution visual acuity (P = 0.006) and central macular thickness (P = 0.03) showed significant improvement in patients who achieved remission. A significant number of patients achieved remission on infliximab therapy. The incidence of major side effects in our cohort was low.


N-terminal deletions and His-tag fusions dramatically affect expression of cytochrome p450 2C2 in bacteria.
The expression of mutants with deletions in the N-terminal signal-anchor sequence of cytochrome P450 2C2 and His-tag fusions was examined in Escherichia coli to determine the influence of N-terminal sequences on expression of the protein. Two mutants predicted to be translocated across the membrane inhibited bacterial growth. In other mutants, deletion of the N-terminal transmembrane domain (residues 2-20) reduced expression of functional P450 by about 75% and further deletion of the following linker sequence (residues 21-27) resulted in a modest further decrease. Expression of the mutant with residues 2-27 deleted contrasts with the lack of expression of functional protein if only the linker was deleted, which suggests that the linker sequence is critical for expression only if the protein is inserted into the membrane by the transmembrane domain. Fusion proteins of green fluorescent protein with full-length P450 2C2 and 2C2(Delta2-20) were predominantly membrane-associated in vivo as determined by fluorescence microscopy. Subcellular fractionation of bacteria expressing these proteins and extraction of the proteins from the membrane by high salt or alkaline buffer demonstrated that P450 2C2 was an integral membrane protein while 2C2(Delta2-20) was a peripheral membrane protein that associated with the membrane mainly by hydrophobic interactions. Residues 1-27 of P450 2C2 fused to green fluorescent protein resulted in a redistribution of fluorescence from cytosol to membrane, which, with the deletion studies, indicates that the P450 signal-anchor is both necessary and sufficient for normal membrane targeting and is the sole transmembrane domain of cytochrome P450 2C2 in bacteria. Addition of a His-tag at the N-terminus completely restored wild-type expression levels to the 2C2(Delta2-20) mutants in bacteria. In insect cells, functional 2C2(Delta2-20) was not expressed but an N-terminal His-tag also restored full expression. The increase in expression may be related to decreased association with the membrane mediated by the His-tag.


Myotoxicity and neurotoxicity during clozapine treatment.
Some recent studies have shown that clozapine (CLZ) has myopathic side effects and causes alterations in motor force control. The aim of this study was to evaluate the neurologic and electrophysiologic characteristics of patients with schizophrenia who are undergoing long-term CLZ treatment. Ninety-four patients with schizophrenia treated with CLZ for 18.2 +/- 15.5 months were studied retrospectively and prospectively (40% and 60%, respectively) for serum creatine kinase (CK) levels before and after initiation of CLZ treatment. An electrodiagnostic study was performed on patients with CK elevation above normal limits, complained of general weakness or muscle pains, and/or had abnormal clinically significant findings. In 13 patients (13.8%), abnormal CK levels were found. Six patients complained of some muscular weakness. In two patients, clinical assessment revealed mild general muscular weakness; one revealed decreased tendon reflexes and, in both, CK levels were above 1,750 IU/L. On electrophysiologic examinations performed in the six patients with abnormal neurologic findings, the motor and sensory nerve conduction velocity were within normal range in all but one patient, who exhibited some prolongation of distal latency in the lower limbs. In two patients, the electromyography demonstrated a myopathic pattern. In 2.1% of medically healthy patients with schizophrenia treated with clozapine on a long-term basis, signs of myotoxicity were found. It seems warranted to discontinue CLZ therapy in patients who exhibit abnormal CK levels and myopathic features during treatment. Further studies are needed to provide more objective data on the impact of CLZ treatment on muscle tissue.


Analgesic effect of mineral cream containing natural spa minerals for use on the skin.
Previous studies have shown that dissolved substances in some natural hot springs have analgesic/anti-nociceptive and anti-inflammatory actions. However, the mechanisms underlying how such dissolved substances exert these actions are not fully understood. In the present study on mice, we examined the analgesic/anti-nociceptive and anti-inflammatory properties of a mineral cream containing natural hot spring ingredients. The anti-nociceptive effects of the mineral cream were assessed by using the von Frey test. Application of the mineral cream to the hind paw of mice produced a significant anti-nociceptive effect compared to control. The anti-nociceptive effects of the mineral cream were also assessed following the injection of complete Freund's adjuvant (CFA) into the hind paws of mice after pre-treatment for one or four weeks with the mineral cream. Histological experiments with light microscopy showed that the mineral cream did not reduce inflammation caused by the CFA treatment. In addition, the mineral cream did not inhibit oxidative stress as evidenced by increased levels of oxidative metabolites (d-ROMs) and biological anti-oxidant potential (BAP). These results suggest that the mineral cream does not exert a protective effect against inflammation, and that the constituents of the mineral cream may produce their anti-nociceptive effects transdermally via different mechanisms including the nervous system.


Molecular mechanisms of N-acetylcysteine actions.
Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.


High-resolution delineation of chlorinated volatile organic compounds in a dipping, fractured mudstone: Depth- and strata-dependent spatial variability from rock-core sampling.
Synthesis of rock-core sampling and chlorinated volatile organic compound (CVOC) analysis at five coreholes, with hydraulic and water-quality monitoring and a detailed hydrogeologic framework, was used to characterize the fine-scale distribution of CVOCs in dipping, fractured mudstones of the Lockatong Formation of Triassic age, of the Newark Basin in West Trenton, New Jersey. From these results, a refined conceptual model for more than 55years of migration of CVOCs and depth- and strata-dependent rock-matrix contamination was developed. Industrial use of trichloroethene (TCE) at the former Naval Air Warfare Center (NAWC) from 1953 to 1995 resulted in dense non-aqueous phase liquid (DNAPL) TCE and dissolved TCE and related breakdown products, including other CVOCs, in underlying mudstones. Shallow highly weathered and fractured strata overlie unweathered, gently dipping, fractured strata that become progressively less fractured with depth. The unweathered lithology includes black highly fractured (fissile) carbon-rich strata, gray mildly fractured thinly layered (laminated) strata, and light-gray weakly fractured massive strata. CVOC concentrations in water samples pumped from the shallow weathered and highly fractured strata remain elevated near residual DNAPL TCE, but dilution by uncontaminated recharge, and other natural and engineered attenuation processes, have substantially reduced concentrations along flow paths removed from sources and residual DNAPL. CVOCs also were detected in most rock-core samples in source areas in shallow wells. In many locations, lower aqueous concentrations, compared to rock core concentrations, suggest that CVOCs are presently back-diffusing from the rock matrix. Below the weathered and highly fractured strata, and to depths of at least 50 meters (m), groundwater flow and contaminant transport is primarily in bedding-plane-oriented fractures in thin fissile high-carbon strata, and in fractured, laminated strata of the gently dipping mudstones. Despite more than 18 years of pump and treat (P&T) remediation, and natural attenuation processes, CVOC concentrations in aqueous samples pumped from these deeper strata remain elevated in isolated intervals. DNAPL was detected in one borehole during coring at a depth of 27 m. In contrast to core samples from the weathered zone, concentrations in core samples from deeper unweathered and unfractured strata are typically below detection. However, high CVOC concentrations were found in isolated samples from fissile black carbon-rich strata and fractured gray laminated strata. Aqueous-phase concentrations were correspondingly high in samples pumped from these strata via short-interval wells or packer-isolated zones in long boreholes. A refined conceptual site model considers that prior to P&T remediation groundwater flow was primarily subhorizontal in the higher-permeability near surface strata, and the bulk of contaminant mass was shallow. CVOCs diffused into these fractured and weathered mudstones. DNAPL and high concentrations of CVOCs migrated slowly down in deeper unweathered strata, primarily along isolated dipping bedding-plane fractures. After P&T began in 1995, using wells open to both shallow and deep strata, downward transport of dissolved CVOCs accelerated. Diffusion of TCE and other CVOCs from deeper fractures penetrated only a few centimeters into the unweathered rock matrix, likely due to sorption of CVOCs on rock organic carbon. Remediation in the deep, unweathered strata may benefit from the relatively limited migration of CVOCs into the rock matrix. Synthesis of rock core sampling from closely spaced boreholes with geophysical logging and hydraulic testing improves understanding of the controls on CVOC delineation and informs remediation design and monitoring.


Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness.
Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.


Building Community Well-being by Leveraging the Economic Impact of Health Systems.
Local communities face systematically deepening disparities in economic, health, and well-being outcomes. Nurses are increasingly leading initiatives to positively impact the social determinants of health in local communities. This article describes how to use the enormous economic impact of hospitals and health systems as anchor institutions embedded in local communities. By leveraging the everyday business practices of hospitals and health systems, such as hiring, purchasing, and investing, nurses can help to transform the economic and consequent health well-being of socioeconomically disadvantaged individuals and neighborhoods. Hiring, purchasing, and investing in nearby neighborhoods build community wealth through both gainful employment and subsequent recirculation of money locally. Improving the economic viability of the local community positively impacts concomitant social determinants of health. Nurses, with their experience and expertise in collaboration and communication with diverse stakeholder and with their high ranking as the most trusted profession, are natural leaders to build community networks and partnerships that promote community transformation for well-being.


Developmental defects of lymphoid cells in Jak3 kinase-deficient mice.
Jak3 is a tyrosine kinase mediating cytokine receptor signaling through the association with the common gamma chain of the cytokine receptors such as IL-2, IL-4, IL-7, IL-9, and IL-15. Unlike other members of the Jak family, the expression of Jak3 is highly restricted in hematopoietic cells. To elucidate in vivo function of Jak3, Jak3-deficient mice were generated by homologous recombination. Mice homozygous for Jak3 null mutation showed severe defects, specifically in lymphoid cells. B cell precursors in bone marrow, thymocytes, and both T and B cells in the spleen drastically decreased, although these defects were significantly recovered as aging occurred. Peripheral lymph nodes, NK cells, dendritic epidermal T cells, and intestinal intraepithelial gamma delta T cells were absent. Normal number of hematopoietic stem cells in bone marrow from Jak3-deficient mice and the similar capability to generate myeloid and erythroid colonies as wild-type mice indicated specific defects in lymphoid stem cells. Furthermore, the abnormal architecture of lymphoid organs suggested the involvement of Jak3 in the function of epithelial cells. T cells developed in the mutant mice did not respond to either IL-2, IL-4, or IL-7. These findings establish the crucial role of Jak3 in the development of lymphoid cells.


Microscopy image resolution improvement by deconvolution of complex fields.
Based on truncated inverse filtering, a theory for deconvolution of complex fields is studied. The validity of the theory is verified by comparing with experimental data from digital holographic microscopy (DHM) using a high-NA system (NA=0.95). Comparison with standard intensity deconvolution reveals that only complex deconvolution deals correctly with coherent cross-talk. With improved image resolution, complex deconvolution is demonstrated to exceed the Rayleigh limit. Gain in resolution arises by accessing the objects complex field - containing the information encoded in the phase - and deconvolving it with the reconstructed complex transfer function (CTF). Synthetic (based on Debye theory modeled with experimental parameters of MO) and experimental amplitude point spread functions (APSF) are used for the CTF reconstruction and compared. Thus, the optical system used for microscopy is characterized quantitatively by its APSF. The role of noise is discussed in the context of complex field deconvolution. As further results, we demonstrate that complex deconvolution does not require any additional optics in the DHM setup while extending the limit of resolution with coherent illumination by a factor of at least 1.64.


Tigecycline: a review of properties, applications, and analytical methods.
Tigecycline is a new glycylcycline with an expanded broad-spectrum antibiotic, including inhibition of Gram-positive, Gram-negative, atypical, anaerobic, and antibiotic-resistant organisms. Trials have demonstrated that tigecycline is noninferior to the comparators for the treatment of complicated skin and skin structure infections as well as complicated intra-abdominal infections. Tigecycline is only available as an intravenous preparation and analytical methods to its quantitation in pharmaceutical products has not been published to date. This review examined tigecycline characteristics, the spectrum and mechanism of action, pharmacokinetics, applications, and, mainly, the instrumental conditions of published chromatographic methods used to measure tigecycline, its metabolites, and some analogs in clinical and biologic research.


Management of recurrent epithelial ovarian cancer.
Epithelial ovarian cancer is the fifth most common cancer in women. It is usually diagnosed at an advanced stage and is the leading cause of death from gynecologic cancers in women. The overall survival rate at five years is 50% and its treatment is still poor. We need new treatments for patients with recurrent ovarian cancer who are incurable with current management. We review the effectiveness of new biological agents and morbidity and mortality of cytoreductive surgery. Since the hyperthermic increases the effectiveness of chemotherapy and the chance of survival, hyperthermic intraperitoneal chemotherapy has been proven to be a promising option, however it still requires further study to be the standard treatment.


Reamed intramedullary nailing of the femur: 551 cases.
The care of the patient with the fractured femur entails a multiple surgical team approach. Healing of the fracture and expediency in the operating room are both important. We sought to determine the results of the treatment of fractures of the femoral shaft with interlocking femoral nails inserted with closed techniques, and to compare the outcomes of fractures nailed by using a fracture table with those stabilized with the leg draped free on a radiolucent table. Eight hundred eighty-two consecutive patients with fractures of the femoral shaft treated with a first-generation intramedullary nail at the authors' institution during the years 1986 to 1996 were identified. Five hundred fifty-one fractures in 515 patients met the inclusion criteria. Treatment with an intramedullary nail led to a union rate of 98.9%. There were six infections, all occurring in closed fractures. Thirty-eight percent of the fractures had hardware removed, most commonly because of pain. One nail and 13 locking bolts broke. Four hundred eighteen fractures had adequate radiographs available to assess fracture alignment. No fracture healed with more than 10 degrees of angulation in either plane. Forty-four fractures healed with more than 5 degrees of angulation. A distal third fracture was found to be associated with an increased incidence of malalignment. There were no differences in outcomes between fractures stabilized with or without a fracture table. Reamed intramedullary nailing of femoral shaft fractures results in a low rate of nonunion, malunion, infection, and hardware failure. There is no difference in the outcomes of fractures treated with and without the use of a fracture table. This is particularly useful in the patient with multiple injuries for whom transfer to a fracture table may not be time effective.


RTI v medical ethics: some questions arising from the recent decision of the Chief Information Commissioner under the RTI Act.
Medical ethics attaches the utmost priority to the confidentiality of medical records. Hence, the decision of the Chief Information Commissioner (CIC) rendered on April 10, 2015 in Case No: CIC/KY/A/2014/001348SA Ms Jyoti Jeena v. PIO, Institute of Human Behaviour & Allied Science (hereinafter referred to as Jyoti Jeena), that the wife-applicant is entitled to get copies of the medical records of her estranged husband has raised many eyebrows.


Community mobilization to modify harmful gender norms and reduce HIV risk: results from a community cluster randomized trial in South Africa.
Community mobilization (CM) is increasingly recognized as critical to generating changes in social norms and behaviours needed to achieve reductions in HIV. We conducted a CM intervention to modify negative gender norms, particularly among men, in order to reduce associated HIV risk. Twenty two villages in the Agincourt Health and Socio-Demographic Surveillance Site in rural Mpumalanga, South Africa were randomized to either a theory-based, gender transformative, CM intervention or no intervention. Two cross-sectional, population-based surveys were conducted in 2012 (pre-intervention, n = 600 women; n = 581 men) and 2014 (post-intervention, n = 600 women; n = 575 men) among adults ages 18 to 35 years. We used an intent-to-treat (ITT) approach using survey regression cluster-adjusted standard errors to determine the intervention effect by trial arm on gender norms, measured using the Gender Equitable Mens Scale (GEMS), and secondary behavioural outcomes. Among men, there was a significant 2.7 point increase (Beta Coefficient 95% CI: 0.62, 4.78, p = 0.01) in GEMS between those in intervention compared to control communities. We did not observe a significant difference in GEMS scores for women by trial arm. Among men and women in intervention communities, we did not observe significant differences in perpetration of intimate partner violence (IPV), condom use at last sex or hazardous drinking compared to control communities. The number of sex partners in the past 12 months (AOR 0.29, 95% CI 0.11 to 0.77) were significantly lower in women in intervention communities compared to control communities and IPV victimization was lower among women in intervention communities, but the reduction was not statistically significant (AOR 0.53, 95% CI 0.24 to 1.16). Community mobilization can reduce negative gender norms among men and has the potential to create environments that are more supportive of preventing IPV and reducing HIV risk behaviour. Nevertheless, we did not observe that changes in attitudes towards gender norms resulted in desired changes in risk behaviours suggesting that more time may be necessary to change behaviour or that the intervention may need to address behaviours more directly. ClinicalTrials.gov NCT02129530.


A double-blind randomized controlled study to evaluate the efficacy of low-dose oral interferon-alpha in preventing hepatitis C relapse.
Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500 IU/day (n=59), 1,500 IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4-1.7, relapse occurred in 1/12 (8.3%) 500 IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500 IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500 IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500 IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy.


Animal welfare consequences in England and Wales of the 2001 epidemic of foot and mouth disease.
The ethical issues surrounding slaughter as a means of control of a disease epidemic are discussed and the use of this method as at least one component of the eradication of foot and mouth disease (FMD) is justified. The Royal Society for the Prevention of Cruelty to Animals received numerous complaints of suffering at slaughter during the FMD epidemic in the United Kingdom in 2001 but none led to prosecution because of lack of evidence. Movement restrictions imposed as part of the disease control strategy caused major welfare problems on farms which were unaffected by disease. These issues are detailed. Significant breaches of transport regulations appear to have occurred.


A universal strategy for proteomic studies of SUMO and other ubiquitin-like modifiers.
Post-translational modification by the conjugation of small ubiquitin-like modifiers is an essential mechanism to affect protein function. Currently, only a limited number of substrates are known for most of these modifiers, thus limiting our knowledge of their role and relevance for cellular physiology. Here, we report the development of a universal strategy for proteomic studies of ubiquitin-like modifiers. This strategy involves the development of stable transfected cell lines expressing a double-tagged modifier under the control of a tightly negatively regulated promoter, the induction of the expression and conjugation of the tagged modifier to cellular proteins, the tandem affinity purification of the pool of proteins covalently modified by the tagged modifier, and the identification of the modified proteins by LC and MS. By applying this methodology to the proteomic analysis of SUMO-1 and SUMO-3, we determined that SUMO-1 and SUMO-3 are stable proteins exhibiting half-lives of over 20 h, demonstrated that sumoylation with both SUMO-1 and SUMO-3 is greatly stimulated by MG-132 and heat shock treatment, demonstrated the preferential usage of either SUMO-1 or SUMO-3 for some known SUMO substrates, and identified 122 putative SUMO substrates of which only 27 appeared to be modified by both SUMO-1 and SUMO-3. This limited overlapping in the subset of proteins modified by SUMO-1 and SUMO-3 supports that the SUMO paralogues are likely to be functionally distinct. Three of the novel putative SUMO substrates identified, namely the polypyrimidine tract-binding protein-associated splicing factor PSF, the structural microtubular component alpha-tubulin, and the GTP-binding nuclear protein Ran, were confirmed as authentic SUMO substrates. The application of this universal strategy to the identification of the pool of cellular substrates modified by other ubiquitin-like modifiers will dramatically increase our knowledge of the biological role of the different ubiquitin-like conjugations systems in the cell.


Post hoc analyses of the impact of previous medication on the efficacy of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in a randomized, controlled trial.
Following the approval of lisdexamfetamine dimesylate (LDX) in several European countries for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with an inadequate response to methylphenidate (MPH) treatment, the aim of the present analysis was to establish the response to LDX in subgroups of patients with different ADHD medication histories. This was a post hoc subgroup analysis of data from a 7-week, European, double-blind, dose-optimized, Phase III study. Patients aged 6-17 years were randomized 1:1:1 to LDX, placebo, or osmotic-release oral system methylphenidate (OROS-MPH). OROS-MPH was included as a reference arm rather than as a direct comparator. Efficacy was assessed in patients categorized according to their ADHD medication history using the ADHD Rating Scale IV and Clinical Global Impressions-Improvement (CGI-I) scores. The difference between active drug and placebo in least-squares mean change from baseline to endpoint in ADHD Rating Scale IV total score (95% confidence interval) was similar between the overall study population (n=317; LDX, -18.6 [-21.5, -15.7]; OROS-MPH, -13.0 [-15.9, -10.2]) and treatment-naïve individuals (n=147; LDX, -15.1 [-19.4, -10.9]; OROS-MPH, -12.7 [-16.8, -8.5]) or patients previously treated with any ADHD medication (n=170; LDX, -21.5 [-25.5, -17.6]; OROS-MPH, -14.2 [-18.1, -10.3]). In addition, similar proportions of patients receiving active treatment were categorized as improved based on CGI-I score (CGI-I of 1 or 2) in the overall study population and among treatment-naïve individuals or patients previously treated with any ADHD medication. In these post hoc analyses, the response to LDX treatment, and to the reference treatment OROS-MPH, was similar to that observed for the overall study population in subgroups of patients categorized according to whether or not they had previously received ADHD medication.


Targeted cloning of cytotoxic T cells specific for minor histocompatibility antigens restricted by HLA class I molecules of interest.
T cells specific for minor histocompatibility antigens (mHAgs) play a major role in both graft-versus-host disease and the graft-versus-tumor effect after HLA-identical bone marrow transplantation (BMT). However, characterization of individual T-cell responses to mHAgs is difficult and has generally involved extensive screening of T-cell clones isolated from bulk T-cell cultures generated from BMT recipients. In this report, we describe a new approach that permits both direct visualization of CD8 T-cell responses to mHAgs and cloning of T cells reacting with mHAgs presented by individual HLA alleles of interest. Panels of Epstein-Barr virus-transformed B-cell lines (B-LCL) expressing retrovirally transduced HLA cDNA were used as stimulator cells in an enzyme-linked immunospot (ELISPOT) assay to identify CD8 T cells reacting with mHAgs in cultures generated from postBMT recipient peripheral blood. T cells specific for mHAgs presented by selected HLA alleles could then be captured and cloned using an interferon-gamma secretion assay and magnetic bead selection. A majority of T-cell clones thus isolated exhibited cytolytic activity against the same HLA-transfected B-cell lines used for the ELISPOT assay. The ELISPOT assay was useful for identification of the HLA alleles presenting mHAgs recognized by individual T-cell lines. This approach for isolating mHAgs-specific CD8 T-cell clones should assist in characterizing responses restricted by HLA alleles of interest, which are common in a certain ethnic group.


Topography of the lunar poles from radar interferometry: a survey of cold trap locations.
Detailed topographic maps of the lunar poles have been obtained by Earth-based radar interferometry with the 3.5-centimeter wavelength Goldstone Solar System Radar. The interferometer provided maps 300 kilometers by 1000 kilometers of both polar regions at 150-meter spatial resolution and 50-meter height resolution. Using ray tracing, these digital elevation models were used to locate regions that are in permanent shadow from solar illumination and may harbor ice deposits. Estimates of the total extent of shadowed areas poleward of 87.5 degrees latitude are 1030 and 2550 square kilometers for the north and south poles, respectively.


Correlates of Residual Limb Pain: From Residual Limb Length and Usage to Metabolites and Activity in Secondary Somatosensory Cortex.
Most recent studies attribute residual limb pain to peripheral pathological changes of the stump. However, in this paper, we focus on its associations with the residual limb length, usage, as well as the metabolic and functional alterations of the brain. The secondary somatosensory cortex (S2), one important area involved in pain intensity discrimination, was selected as the region of interest. Twenty-two upper-limb amputees were recruited and divided into two groups, i.e., amputees with residual limb pain (9/22) and without residual limb pain (13/22). The residual limb length, usage, as well as the metabolite concentration, resting-state activity and BOLD responses to the tactile stimulation in the contralateral S2, were compared between the two groups and correlated with the pain intensity. The amputees with residual limb pain showed significantly shorter length and less usage of the residual limb than the amputees without residual limb pain, and the pain intensity was significantly negatively correlated with the residual limb length and usage. In addition, the pain intensity was significantly correlated with the tNAA/tCr ratio, resting-state fALFF in the slow-4 band, and BOLD response to the tactile stimulation in the contralateral S2, although there were no significant group differences. Regression analysis suggested that residual limb pain is associated with shorter residual limb length and less residual limb usage.


Model to assess muscle protein turnover: domain of validity using amino acyl-tRNA vs. surrogate measures of precursor pool.
Current models to measure protein turnover across muscle bed are based on many surrogate measures of amino acyl-tRNA. We measured muscle protein turnover based on tracer-to-tracee ratios of the stable isotopes of leucine, phenylalanine, and ketoisocaproate (KIC) in artery and vein and muscle amino acyl-tRNA and muscle tissue fluid (TF) in 26 healthy subjects. A three-compartment model calculation based on arteriovenous and tRNA measurements was first performed and its domain of validity assessed. The results were then compared with those using simpler approaches based on surrogate measures of tRNA such as those of TF and KIC and a one-compartment model based on arteriovenous amino acids. In 96% of cases, the model using tRNA was applicable, but only in a lower percentage of cases were the results using surrogate measures applicable. Protein breakdown, protein synthesis, and shunting of amino acids from artery to vein were consistently underestimated, and fluxes of amino acid from artery to intracellular compartment and from intracellular compartment to vein were overestimated, when surrogate measures were used. The one-compartment model also underestimated protein breakdown and synthesis. Measurements using tissue fluid gave results closer to those based on tRNA. In conclusion, a three-compartment model using arteriovenous samples and amino acyl-tRNA provides measurements of muscle protein turnover of acceptable precision in 96% of cases. The precision was unacceptable in a substantial percentage of cases, and the accuracy of the estimation of protein fluxes was significantly affected when surrogate measures were used.


Mutations at amino acid positions 63, 189, and 396 of human immunodeficiency virus type 1 reverse transcriptase (RT) partially restore the DNA polymerase activity of a Trp229Tyr mutant RT.
Trp229 is part of the nonnucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket of HIV-1 reverse transcriptase (RT). It is also an important constituent of the so-called "primer grip." Using a recombinant virus assay, we tried to obtain recombinant virus containing a Trp229Phe or a Trp229Tyr mutation in its RT. Previous studies already established the very low DNA polymerase activities of both the Trp229Phe and the Trp229Tyr mutant RT enzymes. We were able to obtain a Trp229Tyr but not a Trp229Phe mutant virus. However, in addition to the Trp229Tyr mutation this mutant virus also contained an Ile63Met, a Val189Ile, and a Glu396Gly mutation in its RT. When we evaluated the quadruple mutant virus for sensitivity/resistance against a variety of NNRTIs, no significant difference with the sensitivity/resistance profile of the single Trp229Tyr mutant RT enzyme could be observed. We found that the three additional mutations partly restored the low RNA- and DNA-dependent DNA polymerase activities of the Trp229Tyr mutant enzyme. Kinetic analysis revealed that both template/primer binding and dNTP incorporation are affected by the Trp229Tyr mutation. Our findings demonstrate that a mutation at position 229 is unlikely to occur under NNRTI drug pressure due to the poor catalytic activity of the singly mutated RT and the favorable drug sensitivity profile of the mutated enzyme/viruses in both the absence and the presence of the compensatory mutations. Therefore, amino acid position 229 may be regarded as an excellent amino acid target within the NNRTI pocket for rational drug design.


Dehydroepiandrosterone, Its Sulfate and Cognitive Functions.
To present a review of cross-sectional and longitudinal studies that investigate the relationship between the hormones Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S) and cognition. The cognition items included in this review were global cognitive function, memory, attention, executive function, intelligence, perception and visuospatial ability. A systematic review was proceeded using three databases: PubMed, ISI Web of Science, and PsycINFO. Two thousand fifty five references about cognition and hormones were found; 772 duplicated references were excluded, resulting in 1.283 references to be evaluated. According to exclusion and inclusion criteria, 25 references were selected. A positive correlation between DHEA-S blood levels and global cognition was found in women and men. Other positive correlations between DHEA-S and working memory, attention and verbal fluency were found only in women. The DHEA effect on cognition is limited to one study conducted among young men with high-doses.


Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial.
To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help seeking young people deemed to be at risk for serious conditions such as schizophrenia. Multisite single blind randomised controlled trial. Diverse services at five UK sites. 288 participants aged 14-35 years (mean 20.74, SD 4.34 years) at high risk of psychosis: 144 were assigned to cognitive therapy plus monitoring of mental state and 144 to monitoring of mental state only. Participants were followed-up for a minimum of 12 months and a maximum of 24 months. Cognitive therapy (up to 26 (mean 9.1) sessions over six months) plus monitoring of mental state compared with monitoring of mental state only. Primary outcome was scores on the comprehensive assessment of at risk mental states (CAARMS), which provides a dichotomous transition to psychosis score and ordinal scores for severity of psychotic symptoms and distress. Secondary outcomes included emotional dysfunction and quality of life. Transition to psychosis based on intention to treat was analysed using discrete time survival models. Overall, the prevalence of transition was lower than expected (23/288; 8%), with no significant difference between the two groups (proportional odds ratio 0.73, 95% confidence interval 0.32 to 1.68). Changes in severity of symptoms and distress, as well as secondary outcomes, were analysed using random effects regression (analysis of covariance) adjusted for site and baseline symptoms. Distress from psychotic symptoms did not differ (estimated difference at 12 months -3.00, 95% confidence interval -6.95 to 0.94) but their severity was significantly reduced in the group assigned to cognitive therapy (estimated between group effect size at 12 months -3.67, -6.71 to -0.64, P=0.018). Cognitive therapy plus monitoring did not significantly reduce transition to psychosis or symptom related distress but reduced the severity of psychotic symptoms in young people at high risk. Most participants in both groups improved over time. The results have important implications for the at risk mental state concept. Current Controlled Trials ISRCTN56283883.


Clinicopathological features and the value of differential Cytokeratin 7 and 20 expression in resolving diagnostic dilemmas of ovarian involvement by colorectal adenocarcinoma and vice-versa.
The distinction between metastasis from a colorectal adenocarcinoma into the ovary and an ovarian adenocarcinoma is vital, but challenging at times, due to overlapping morphological features. Similarly, a distinction between an ovarian metastasis into the colorectum and a colorectal adenocarcinoma, although rare; is important and can be daunting. We report an analysis of 20 cases of ovarian involvement by metastatic colorectal adenocarcinomas and colorectal involvement by metastatic ovarian adenocarcinomas, including the value of differential expression of cytokeratins 7 & 20 by immunohistochemistry (IHC), in these cases. Nine cases (45%) were identified as colorectal adenocarcinomas metastatic to the ovary. On biopsy, all these cases showed a 'garland-like' tumor necrosis, with desmoplasia and predominantly exhibited a tubuloalveolar pattern (67% cases). On IHC, all 8 of 9 such cases, where staining for cytokeratin 20 was performed, displayed strong positivity and 7 cases, where staining for carcinoembryogenic antigen (CEA) was performed, revealed positivity for this marker (100%). Other 11 cases (55%) were ovarian adenocarcinomas, metastatic to the colorectum. These showed metachronous presentations, with the ovarian tumor preceding the colorectal tumor deposits. Morphologically, psammomatous calcification was noted in 73% of these cases, whereas 'garland-like' necrosis was absent in all. The chief morphological subtype was serous papillary cystadenocarcinoma (55% cases). On IHC, CK7 and CA 125 were positive in all 6 of 11 such cases, whereas CK 20 was negative in all these cases.In cases of complex presentations like an ovarian involvement by a metastatic colorectal adenocarcinoma and vice-versa, certain clinicopathological features are useful. Differential expression of CK 7 and CK20 is vital in resolving these dilemmas. CK20 positivity and CK7 negativity is associated with a colorectal adenocarcinoma. Markers like CEA and CA-125 have an added value.


Physical activity, watching television, and the risk of obesity in students, Texas, 2004-2005.
The epidemic of childhood obesity has been well-documented. Prevalence of obesity among students in Texas is higher than the US prevalence. Our objective was to understand the combined influence of physical activity and television viewing on weight status of students in Texas. Students in grades 4, 8, and 11 participated in the School Physical Activity and Nutrition survey during the 2004-2005 academic year. Multinomial logistic regression tested the associations between both being overweight and obese (vs underweight/normal weight) and the combined influence of physical activity and watching television, adjusting for age, grade, race/ethnicity, language spoken at home, and percentage of economically disadvantaged students in the school. We used 5 physical activity indicators to describe students' physical activity. Girls who participated in less than 3 days of exercise per week to strengthen or tone muscles and watched 2 hours or less per day of television had increased odds of being obese (adjusted odds ratio, 1.8; 95% confidence interval, 1.1-3.0) compared with girls who participated in 3 or more days per week of exercise to strengthen or tone muscles and watched 2 hours or less per day of television. Boys in our study who watched 3 or more hours per day of television and did not meet physical activity recommendations had increased odds of being obese in all of our 5 physical activity indicators. Although results varied by physical activity indicator and sex, our findings provide further evidence for the combined effect of high television watching and low physical activity engagement on the risk for obesity in children and adolescents.


Comprehensive understanding of nano-sized particle separation processes using nanoparticle tracking analysis.
The understanding of nano-sized particle separation processes has been limited by difficulties of nanoparticle characterization. In this study, nanoparticle tracking analysis (NTA) was deployed to evaluate the absolute particle size distributions in laboratory scale flocculation and filtration experiments with silver nanoparticles. The results from NTA were consistent with standard theories of particle destabilization and transport. Direct observations of changes in absolute particle size distributions from NTA enhance both qualitative and quantitative understanding of particle separation processes of nano-sized particles.


Oligodendrogliomas in children.
Oligodendrogliomas are rare central nervous system (CNS) tumors in children. The purpose of this study was to identify prognostic factors for progression free survival (PFS) and overall survival (OS) in pediatric patients with oligodendrogliomas. We retrospectively analyzed clinical data on 37 pediatric patients with oligodendroglial tumors treated at Washington University. Kaplan-Meier method was used to calculate survival rates. Log-rank was used to detect the difference between survival curves. The median age was 11.1 years (range 10 months-18 years), and median follow-up was 4.5 years (range 2 months-30.5 years). The 5-year PFS and OS were 66.4 and 93.4%, respectively. Mixed histology was associated with worse OS compared to patients with pure oligodendroglioma, 5-year OS 77.6 versus 100% (P < 0.01). Patients who underwent gross total resection (GTR) experienced an improved 5-year PFS of 100% compared to 28.8% (P = 0.03) in patients treated with subtotal resection (STR) or biopsy alone. Age >3 years at diagnosis correlated with improved 5-year PFS, 33.3 versus 69.8% (P = 0.01). Neither post-operative chemotherapy nor radiation therapy correlated with improved outcome. GTR and age >3 years at diagnosis remained significant for improved PFS on multivariate analysis. There were no factors correlated with improved overall survival on multivariate analysis. Pediatric oligodendroglial tumors are associated with excellent OS; however, a third of patients developed progressive disease. Our data demonstrate that patients with less than GTR and <3 years at diagnosis are at increased risk for progression and may benefit from more aggressive therapy.


Evaluation of plasma-free endocannabinoids and their congeners in abstinent cocaine addicts seeking outpatient treatment: impact of psychiatric co-morbidity.
Cocaine is associated with serious health problems including psychiatric co-morbidity. There is a need for the identification of biomarkers for the stratification of cocaine-addicted subjects. Several studies have evaluated circulating endocannabinoid-related lipids as biomarkers of inflammatory, metabolic and mental disorders. However, little is known in substance use disorders. This study characterizes both free N-acyl-ethanolamines (NAEs) and 2-acyl-glycerols in abstinent cocaine addicts from outpatient treatment programs who were diagnosed with cocaine use disorder (CUD; n = 88), and age-/gender-/body mass-matched healthy control volunteers (n = 46). Substance and mental disorders that commonly occur with substance abuse were assessed by the semi-structured interview 'Psychiatric Research Interview for Substance and Mental Diseases' according to the 'Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision' (DSM-IV-TR) and plasma-free acyl derivatives were quantified by a liquid chromatography-tandem mass spectrometry system. The results indicate that plasma acyl derivatives are altered in abstinent cocaine-addicted subjects with CUD (CUD subjects). While NAEs were found to be increased, 2-acyl-glycerols were decreased in CUD subjects compared with controls. Multivariate predictive models based on these lipids as explanatory variables were developed to distinguish CUD subjects from controls providing high discriminatory power. However, these alterations were not influenced by the DSM-IV-TR criteria for cocaine abuse and dependence as cocaine trait severity measure. In contrast, we observed that some free acyl derivatives in CUD subjects were found to be affected by the diagnosis of some co-morbid psychiatric disorders. Thus, we found that the monounsaturated NAEs were significantly elevated in CUD subjects diagnosed with mood [N-oleoyl-ethanolamine and N-palmitoleoyl-ethanolamine (POEA)] and anxiety (POEA) disorders compared with non-co-morbid CUD subjects. Interestingly, the coexistence of alcohol use disorders did not influence the circulating levels of these free acyl derivatives. In summary, we have identified plasma-free acyl derivatives that might serve as reliable biomarkers for CUD. Furthermore, we found that monounsaturated NAE levels are also enhanced by co-morbid mood and anxiety disorders in cocaine addicts. These findings open the way for the development of new strategies for cocaine addiction diagnosis and treatment.


Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism.
c-Myc is frequently deregulated in human cancers. Although deregulated c-Myc leads to tumor growth, it also triggers apoptosis in partnership with tumor suppressors such as ARF and p53. Apoptosis induced by c-Myc is a critical fail-safe mechanism for the cell to protect against unrestrained proliferation. Despite the plethora of information on c-Myc, the molecular mechanism of how c-Myc induces both transformation and apoptosis is unclear. Oncogenic c-Myc can indirectly induce the expression of the tumor suppressor ARF, which leads to apoptosis through the stabilization of p53, but both c-Myc and ARF have apoptotic activities that are independent of p53. In cells without p53, ARF directly binds to c-Myc protein and inhibits c-Myc-induced hyperproliferation and transformation with a concomitant inhibition of canonical c-Myc target gene induction. However, ARF is an essential cofactor for p53-independent c-Myc-induced apoptosis. Here we show that ARF is necessary for c-Myc to drive transcription of a unique noncanonical target gene, Egr1. In contrast, c-Myc induces another family member, Egr2, through a canonical mechanism that is inhibited by ARF. We further demonstrate that Egr1 is essential for p53-independent c-Myc-induced apoptosis, but not ARF-independent c-Myc-induced apoptosis. Therefore, ARF binding switches the inherent activity of c-Myc from a proliferative to apoptotic protein without p53 through a unique noncanonical transcriptional mechanism. These findings also provide evidence that cofactors can differentially regulate specific transcriptional programs of c-Myc leading to different biological outcomes.


Swimming and persons with mild persistant asthma.
The aim of our study was to analyze the effect of recreational swimming on lung function and bronchial hyperresponsiveness (BHR) in patients with mild persistent asthma. This study included 65 patients with mild persistent asthma, who were divided into two groups: experimental group A (n = 45) and control group B (n = 20). Patients from both groups were treated with low doses of inhaled corticosteroids (ICS) and short-acting beta2 agonists salbutamol as needed. Our program for patients in group A was combined asthma education with swimming (twice a week on a 1-h basis for the following 6 months). At the end of the study, in Group A, we found a statistically significant increase of lung function parameters FEV1 (forced expiratory volume in 1 sec) (3.55 vs. 3.65) (p < 0.01), FVC (forced vital capacity) (4.27 vs. 4.37) (p < 0.05), PEF (peak expiratory flow) (7.08 vs. 7.46) (p < 0.01), and statistically significant decrease of BHR (PD20 0.58 vs. 2.01) (p < 0.001). In Group B, there was a statistically significant improvement of FEV1 3.29 vs. 3.33 (p < 0.05) and although FVC, FEV1/FVC, and PEF were improved, it was not significant. When Groups A and B were compared at the end of the study, there was a statistically significant difference of FVC (4.01 vs. 4.37), FEV1 (3.33 vs. 3.55), PEF (6.79 vs.7.46), and variability (p < 0.001), and statistically significantly decreased BHR in Group A (2.01 vs. 1.75) (p < 0.001). Engagement of patients with mild persistent asthma in recreational swimming in nonchlorinated pools, combined with regular medical treatment and education, leads to better improvement of their parameters of lung function and also to more significant decrease of their airway hyperresponsiveness compared to patients treated with traditional medicine.


Depressive symptoms and physical activity in adolescent girls.
To evaluate the relationship between depressive symptoms and physical activity in a geographically and ethnically diverse sample of sixth-grade adolescent girls. The Trial of Activity for Adolescent Girls (TAAG) baseline measurement included a random sample (N = 1721) of sixth-grade girls in 36 schools at six field sites. Measurements were accelerometry and the 3-d Physical Activity Recall (3DPAR) for physical activity, and the Center for Epidemiological Studies-Depression scale (CES-D) for depressive symptoms. Girls with complete data (N = 1397), mean age 12 yr, had an average CES-D score of 14.7 (SD = 9.25) and engaged in an average of about 460 min of sedentary activity, < 24 min of moderate to vigorous physical activity (MVPA), and < 6 min of vigorous physical activity (VPA) in an 18-h day. Thirty-minute segments of MVPA ranged in number from 3.9 to 1.2, and METS for these segments ranged from > 3.0 to > 6.5. Mixed-model regression indicated no relationship between depressive symptoms and physical activity; however, a significant but modest inverse relationship between sedentary activity and depressive symptoms was observed. A sufficient sample size, standardized procedures, and validated instruments characterized this study; however, a relationship between depressive symptoms and physical activity was not observed for sixth-grade girls from diverse geographic locations. The average CES-D score was lower than is considered clinically meaningful for either adolescents or adults, and MET-minutes of sedentary activity were high. This combination of data may be different from other studies and could have contributed to the unexpected finding. This unexpected finding is informative, however, because it shows the need for additional research that includes a wider range of possible combinations of data, especially with young adolescent girls.


Visual topography in primate V2: multiple representation across functional stripes.
The second visual cortical area (V2) of the primate is composed of repeating thin, pale, and thick cytochrome oxidase stripes containing primarily color-selective, broad-band oriented, and disparity-selective cells, respectively. We have now examined topography in V2 with respect to these functional subdivisions. Our data suggest that there are multiple, interleaved visual maps in V2, one for each of the color, orientation, and disparity domains. The same region of visual space is re-represented by each stripe within a stripe cycle, resulting in discontinuities or "jumps back" in representation at stripe borders. Adjacent stripe cycles represent adjacent regions of space such that the visual map is continuous from one stripe to the next like stripe. Receptive field size and scatter are significantly larger for thin stripes than for thick stripes. Unexpectedly, our data suggest two types of pale stripes within each stripe cycle, one with scatter similar to thin stripes and another to thick stripes. Some evidence also suggests the presence of multiple maps within individual stripes in V2. Consistent with functional clustering within single stripes (Ts'o et al., 1990b), we have recorded re-representations and topographic discontinuities coincident with functional borders within single stripes. These results suggest that multiple and interleaved mapping may be a common organizational strategy for representing multiple functional domains within a single cortical area.


The sbv IMPROVER Systems Toxicology Computational Challenge: Identification of Human and Species-Independent Blood Response Markers as Predictors of Smoking Exposure and Cessation Status.
Cigarette smoking entails chronic exposure to a mixture of harmful chemicals that trigger molecular changes over time, and is known to increase the risk of developing diseases. Risk assessment in the context of 21st century toxicology relies on the elucidation of mechanisms of toxicity and the identification of exposure response markers, usually from high-throughput data, using advanced computational methodologies. The sbv IMPROVER Systems Toxicology computational challenge (Fall 2015-Spring 2016) aimed to evaluate whether robust and sparse (≤40 genes) human (sub-challenge 1, SC1) and species-independent (sub-challenge 2, SC2) exposure response markers (so called gene signatures) could be extracted from human and mouse blood transcriptomics data of current (S), former (FS) and never (NS) smoke-exposed subjects as predictors of smoking and cessation status. Best-performing computational methods were identified by scoring anonymized participants' predictions. Worldwide participation resulted in 12 (SC1) and six (SC2) final submissions qualified for scoring. The results showed that blood gene expression data were informative to predict smoking exposure (i.e. discriminating smoker versus never or former smokers) status in human and across species with a high level of accuracy. By contrast, the prediction of cessation status (i.e. distinguishing FS from NS) remained challenging, as reflected by lower classification performances. Participants successfully developed inductive predictive models and extracted human and species-independent gene signatures, including genes with high consensus across teams. Post-challenge analyses highlighted "feature selection" as a key step in the process of building a classifier and confirmed the importance of testing a gene signature in independent cohorts to ensure the generalized applicability of a predictive model at a population-based level. In conclusion, the Systems Toxicology challenge demonstrated the feasibility of extracting a consistent blood-based smoke exposure response gene signature and further stressed the importance of independent and unbiased data and method evaluations to provide confidence in systems toxicology-based scientific conclusions.


Treatment for primary postpartum haemorrhage.
Primary postpartum haemorrhage (PPH) is one of the top five causes of maternal mortality in both developed and developing countries. To assess the effectiveness and safety of any intervention used for the treatment of primary PPH. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013). Randomised controlled trials comparing any interventions for the treatment of primary PPH. We assessed studies for eligibility and quality and extracted data independently. We contacted authors of the included studies to request more information. Ten randomised clinical trials (RCTs) with a total of 4052 participants fulfilled our inclusion criteria and were included in this review.Four RCTs (1881 participants) compared misoprostol with placebo given in addition to conventional uterotonics. Adjunctive use of misoprostol (in the dose of 600 to 1000 mcg) with simultaneous administration of additional uterotonics did not provide additional benefit for our primary outcomes including maternal mortality (risk ratio (RR) 6.16, 95% confidence interval (CI) 0.75 to 50.85), serious maternal morbidity (RR 0.34, 95% CI 0.01 to 8.31), admission to intensive care (RR 0.79, 95% CI 0.30 to 2.11) or hysterectomy (RR 0.93, 95% CI 0.16 to 5.41). Two RCTs (1787 participants) compared 800 mcg sublingual misoprostol versus oxytocin infusion as primary PPH treatment; one trial included women who had received prophylactic uterotonics, and the other did not. Primary outcomes did not differ between the two groups, although women given sublingual misoprostol were more likely to have additional blood loss of at least 1000 mL (RR 2.65, 95% CI 1.04 to 6.75). Misoprostol was associated with a significant increase in vomiting and shivering.Two trials attempted to test the effectiveness of estrogen and tranexamic acid, respectively, but were too small for any meaningful comparisons of pre-specified outcomes.One study compared lower segment compression but was too small to assess impact on primary outcomes.We did not identify any trials evaluating surgical techniques or radiological interventions for women with primary PPH unresponsive to uterotonics and/or haemostatics. Clinical trials included in the current review were not adequately powered to assess impact on the primary outcome measures. Compared with misoprostol, oxytocin infusion is more effective and causes fewer side effects when used as first-line therapy for the treatment of primary PPH. When used after prophylactic uterotonics, misoprostol and oxytocin infusion worked similarly. The review suggests that among women who received oxytocin for the treatment of primary PPH, adjunctive use of misoprostol confers no added benefit.The role of tranexamic acid and compression methods requires further evaluation. Furthermore, future studies should focus on the best way to treat women who fail to respond to uterotonic therapy.


Orphons: dispersed genetic elements derived from tandem repetitive genes of eucaryotes.
We have discovered in animal cells a novel class of dispersed, solitary genetic elements derived from tandem multigene families. We refer to such displaced elements as orphons. Orphons arise from both protein-coding and non-protein-coding structural gene families, including those of histone and ribosomal genes. Southern transfer hybridization experiments, on DNA digested with enzymes that do not cut the major repeat unit of the family of genes of interest, reveal histone gene orphons in the sea urchin (Lytechinus pictus), ribosomal gene orphons in yeast (Saccharomyces cerevisiae) and ribosomal and H3 histone gene orphons in Drosophila melanogaster. There are more than 50 histone gene orphons in each sea urchin genome. Each of the five histone-coding regions has a number of orphons (5--20), in addition to the several hundred copies in the clusters that are not cut by Bam HI. Most such orphons appear to contain only one coding region. Nearly all sea urchin histone gene orphon loci are polymorphic in the population; no two individuals have the same sets of histone orphons for any coding region. An H3-coding orphon, pLpH30-1, was isolated from the genome of L. pictus. The H3 region homologous to the histone gene clusters is 1200 bases long and includes the complete early H3 gene and some surrounding histone DNA. THe orphon is flanked by at least 1.7 kb of 5' and 3 kb of 3' nonhistone DNA. These flanking sequences are each moderately repetitive in the genome and are not homologous to each other. The orphon differs less than 2% in base sequence from the analogous region of pLpC and only slightly more from pLpA (the major histone gene clones). DNA sequence analysis of the junctions between the H3 region and the immediate flanking nonhistone DNA reveals no evidence of repetitive or palindromic sequences.