Aspirations to become an anaesthetist: longitudinal study of historical trends and trajectories of UK-qualified doctors' early career choices and of factors that have influenced their choices.
It is important to inform medical educators and workforce planners in Anaesthesia about early career choices for the specialty, factors that influence them and to elucidate how recent choices of men and women doctors relate to the overall historical trends in the specialty's popularity. We analysed longitudinal data on career choice, based on self-completed questionnaires, from national year-of-qualification cohorts of UK-trained doctors from 1974 to 2012 surveyed one, three and 5 years post-qualification. Career destination data 10 years post-qualification were used for qualifiers between 1993 and 2002, to investigate the association between early choice and later destinations. In years 1, 3 and 5 post-qualification, respectively, 59.9% (37,385), 64.6% (31,473), and 67.2% (24,971) of contactable doctors responded. There was an overall increase, from the early to the later cohorts, in the percentage of medical graduates who wished to enter anaesthesia: for instance year 1 choices rose from 4.6 to 9.4%, comparing the 1974 and 2012 cohorts. Men were more likely than women to express an early preference for a career in anaesthesia: for example, at year 3 after qualification anaesthesia was the choice of 10.1% of men and 7.9% of women. There was a striking increase in the certainty with which women chose anaesthesia as their future career specialty in recent compared to earlier cohorts, not reflected in any trends observed in men choosing anaesthesia. Sixty percent of doctors who were anaesthetists, 10 years after qualifying, had specified anaesthesia as their preferred specialty when surveyed in year 1, 80% in year 3, and 92% in year 5. Doctors working as anaesthetists were less likely than those working in other hospital specialties to have specified, as strong influences on specialty choice, 'experience of the subject' as students, 'inclinations before medical school', and 'what I really want to do'. Men anaesthetists were more influenced in their specialty choice than men in other hospital specialties by 'wanting a career with acceptable hours'; the corresponding difference among women was not significant. We suggest a focus on inspirational teaching of anaesthesia in medical school and on greater exposure to the specialty in the foundation programme. Factors which may discourage women from entering anaesthesia should be explored and addressed.


Gender differences in the association of periodontitis and type 2 diabetes.
THE OBJECTIVE WAS TO INVESTIGATE IF GENDER DIFFERENCES EXIST IN THE ASSOCIATIONS BETWEEN PERIODONTITIS AND TYPE 2 DIABETES. DISPROPORTIONATE DISPARITIES BY GENDER WERE FOUND TO EXIST IN RATES OF BOTH PERIODONTITIS AND DIABETES WITH RESPECT TO DEMOGRAPHICS AND BEHAVIOURAL PREDICTORS THAT CANNOT BE EXPLAINED SOLELY BY THE WELL-ESTABLISHED ASSOCIATION BETWEEN THESE TWO DISEASES. MULTIPLE DATASETS WERE EXTRACTED FROM THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES) 2009-2014, WHICH USED A STRATIFIED MULTISTAGE PROBABILITY SAMPLING TO OBTAIN SAMPLES FROM ALL CIVILIAN NON-INSTITUTIONALISED PEOPLE IN THE USA. BIVARIATE RELATIONSHIPS BETWEEN EACH EXPLANATORY VARIABLE AND PERIODONTITIS LEVEL WERE ASSESSED WITH ODDS RATIOS (OR) AND THEIR 95% CONFIDENCE INTERVALS (CI). A SET OF WEIGHTED LOGISTIC REGRESSION MODELS WAS USED TO INVESTIGATE THE ASSOCIATION DIFFERENTIATIONS BETWEEN PERIODONTITIS AND DIABETES BY GENDER. C-STATISTICS MEASURED THE GOODNESS-OF-FIT OF WEIGHTED LOGISTIC REGRESSION MODELS. THE PREVALENCE OF MODERATE-SEVERE PERIODONTITIS WAS 36.39% AND 22.71% AMONG PARTICIPANTS WITH TYPE 2 DIABETES AND WITHOUT DIABETES, RESPECTIVELY. TYPE 2 DIABETES WAS SIGNIFICANTLY ASSOCIATED WITH MODERATE-SEVERE PERIODONTITIS OR (OR = 1.47, 95% CI: 1.18-1.82) AMONG MALES EVEN AFTER ADJUSTING FOR DEMOGRAPHICS, SOCIOECONOMIC STATUS AND ORAL HEALTH BEHAVIOURS. THE AFOREMENTIONED RELATIONSHIP WAS NOT FOUND IN FEMALES. FURTHERMORE, DIFFERENT RELATIONSHIPS OF MODERATE-SEVERE PERIODONTITIS WITH BODY MASS INDEX AND THE USE OF MOUTHWASH WERE FOUND BETWEEN THE MALES AND FEMALES. THE CURRENT FINDINGS SUGGEST THAT IMPORTANT IMPROVEMENTS IN THE DEVELOPMENT OF GENDER-SPECIFIC STRATEGIES IN PREVENTION, SUCH AS ORAL HOME-CARE, TO REDUCE THE HIGH PREVALENCE OF PERIODONTAL DISEASE AND MAINTAIN GOOD ORAL HEALTH ARE VITAL, AND ARE ESPECIALLY IMPORTANT FOR MALE DIABETIC PATIENTS AND THOSE WHO ARE AT HIGH RISK OF DEVELOPING DIABETES, SUCH AS THOSE WHO ARE OBESE.


Photocatalytic overall water splitting by conjugated semiconductors with crystalline poly(triazine imide) frameworks.
Photocatalytic water splitting is an ideal pathway to produce hydrogen for the future energy supply due to the sustainability of solar energy and the mild reaction conditions. In the past four decades, many inorganic semiconductor photocatalysts have been studied for this purpose. In recent years, conjugated polymers, in particular covalent carbon nitride frameworks, have rapidly emerged as a new family of photocatalysts. However, the use of conjugated photocatalysts in overall water splitting in the absence of sacrificial agents has been much less reported. Herein, we used surface kinetic control to photocatalyze overall water splitting by a covalent carbon nitride semiconductor with a crystalline poly(triazine imide) (PTI) frameworks. Our study demonstrates that the loading of a Pt co-catalyst on the PTI surface plays the key role in inducing overall water splitting. The co-deposition of a cobalt species can effectively increase the photocatalytic activity and adjust the ratio of H2 and O2 produced, as well as enhancing the stability of the photocatalyst. The optimal sample with the dual co-catalysts shows an apparent quantum yield of 2.1% for the overall water splitting reaction.


Pacifier Overuse and Conceptual Relations of Abstract and Emotional Concepts.
This study explores the impact of the extensive use of an oral device since infancy (pacifier) on the acquisition of concrete, abstract, and emotional concepts. While recent evidence showed a negative relation between pacifier use and children's emotional competence (Niedenthal et al., 2012), the possible interaction between use of pacifier and processing of emotional and abstract language has not been investigated. According to recent theories, while all concepts are grounded in sensorimotor experience, abstract concepts activate linguistic and social information more than concrete ones. Specifically, the Words As Social Tools (WAT) proposal predicts that the simulation of their meaning leads to an activation of the mouth (Borghi and Binkofski, 2014; Borghi and Zarcone, 2016). Since the pacifier affects facial mimicry forcing mouth muscles into a static position, we hypothesize its possible interference on acquisition/consolidation of abstract emotional and abstract not-emotional concepts, which are mainly conveyed during social and linguistic interactions, than of concrete concepts. Fifty-nine first grade children, with a history of different frequency of pacifier use, provided oral definitions of the meaning of abstract not-emotional, abstract emotional, and concrete words. Main effect of concept type emerged, with higher accuracy in defining concrete and abstract emotional concepts with respect to abstract not-emotional concepts, independently from pacifier use. Accuracy in definitions was not influenced by the use of pacifier, but correspondence and hierarchical clustering analyses suggest that the use of pacifier differently modulates the conceptual relations elicited by abstract emotional and abstract not-emotional. While the majority of the children produced a similar pattern of conceptual relations, analyses on the few (6) children who overused the pacifier (for more than 3 years) showed that they tend to distinguish less clearly between concrete and abstract emotional concepts and between concrete and abstract not-emotional concepts than children who did not use it (5) or used it for short (17). As to the conceptual relations they produced, children who overused the pacifier tended to refer less to their experience and to social and emotional situations, use more exemplifications and functional relations, and less free associations.


Speciation of nanoscale objects by nanoparticle imprinted matrices.
The toxicity of nanoparticles is not only a function of the constituting material but depends largely on their size, shape and stabilizing shell. Hence, the speciation of nanoscale objects, namely, their detection and separation based on the different species, similarly to heavy metals, is of outmost importance. Here we demonstrate the speciation of gold nanoparticles (AuNPs) and their electrochemical detection using the concept of "nanoparticles imprinted matrices" (NAIM). Negatively charged AuNPs are adsorbed as templates on a conducting surface previously modified with polyethylenimine (PEI). The selective matrix is formed by the adsorption of either oleic acid (OA) or poly(acrylic acid) (PAA) on the non-occupied areas. The AuNPs are removed by electrooxidation to form complementary voids. These voids are able to recognize the AuNPs selectively based on their size. Furthermore, the selectivity could be improved by adsorbing an additional layer of 1-hexadecylamine, which deepened the voids. Interestingly, silver nanoparticles (AgNPs) were also recognized if their size matched those of the template AuNPs. The steps in assembling the NAIMs and the reuptake of the nanoparticles were characterized carefully. The prospects for the analytical use of NAIMs, which are simple, of small dimension, cost-efficient and portable, are in the sensing and separation of nanoobjects.


Models of poststroke depression and assessments of core depressive symptoms in rodents: How to choose?
Our previous studies have indicated that depression and declined cognition have been involved in some neurodegenerative diseases including Stroke, Parkinson's diseases and Vascular Parkinsonism. Post-stroke depression (PSD) is the most common psychiatric disorder following a stroke and has high morbidity and mortality. Studies on PSD are increasingly common, but the specific mechanisms remain unknown. Current research mainly includes clinical and animal aspects. Questionnaires and peripheral blood examination are two of the most common methods used to study clinical PSD. The results of questionnaires are influenced by multiple factors such as disease history, education background, occupation, economic status, family relationships and social support. There are certain limitations to blood sample testing; for example, it is influenced by cerebrovascular diseases and some other disruptions of the internal environment. It is difficult for either method to fully clarify the pathophysiological mechanism of PSD. Animal models provide alternative methods to further understand the pathophysiological mechanisms of PSD, such as the involvement of neuronal circuits and cytokines. More than ten animal models of PSD have been developed, and new models are constantly being introduced. Therefore, it is important to choose the appropriate model for any given study. In this paper, we will discuss the characteristics of the different models of PSD and comment on the advantages and disadvantages of each model, drawing from research on model innovation. Finally, we briefly describe the current assessment methods for the core symptoms of PSD models, point out the shortcomings, and present the improved sucrose preference test as a rational evaluation of anhedonia.


A reversible wet/dry adhesive inspired by mussels and geckos.
The adhesive strategy of the gecko relies on foot pads composed of specialized keratinous foot-hairs called setae, which are subdivided into terminal spatulae of approximately 200 nm (ref. 1). Contact between the gecko foot and an opposing surface generates adhesive forces that are sufficient to allow the gecko to cling onto vertical and even inverted surfaces. Although strong, the adhesion is temporary, permitting rapid detachment and reattachment of the gecko foot during locomotion. Researchers have attempted to capture these properties of gecko adhesive in synthetic mimics with nanoscale surface features reminiscent of setae; however, maintenance of adhesive performance over many cycles has been elusive, and gecko adhesion is greatly diminished upon full immersion in water. Here we report a hybrid biologically inspired adhesive consisting of an array of nanofabricated polymer pillars coated with a thin layer of a synthetic polymer that mimics the wet adhesive proteins found in mussel holdfasts. Wet adhesion of the nanostructured polymer pillar arrays increased nearly 15-fold when coated with mussel-mimetic polymer. The system maintains its adhesive performance for over a thousand contact cycles in both dry and wet environments. This hybrid adhesive, which combines the salient design elements of both gecko and mussel adhesives, should be useful for reversible attachment to a variety of surfaces in any environment.


Electrochemical characterization of riboflavin-enhanced reduction of trinitrotoluene.
There is great interest in understanding trinitrotoluene (TNT) and dinitrotoluene (DNT) contamination, detection and remediation in the environment due to TNT's negative health effects and security implications. Numerous publications have focused on detecting TNT in groundwater using multiple techniques, including electrochemistry. The main degradation pathway of nitrotoluenes in the environment is reduction, frequently with biological and/or photolytic assistance. Riboflavin has also been noted to aid in TNT remediation in soils and groundwater when exposed to light. This report indicates that adding riboflavin to a TNT or DNT solution enhances redox currents in electrochemical experiments. Here AC voltammetry was performed and peak currents compared with and without riboflavin present. Results indicated that TNT, DNT and riboflavin could be detected using AC voltammetry on modified gold electrodes and the addition of riboflavin affected redox peaks of TNT and DNT. Poised potential experiments indicated that it is possible to enhance reduction of TNT in the presence of riboflavin and light. These results were dramatic enough to explain long term enhancement of bioremediation in environments containing high levels of riboflavin and enhance the limit of detection in electrochemically-based nitrotoluene sensing.


The Molecular Basis of Toxins' Interactions with Intracellular Signaling via Discrete Portals.
An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking. In this review, specific examples of different toxins are emphasized to illustrate the fundamental mechanisms of toxicity at different biochemical, molecular and cellular- levels with particular consideration for the nervous system. The target of primary action has been highlighted and operationally classified into 13 sub-categories. Selected examples of toxins were assigned to each target category, denominated as portal, and the modulation of the different portal's signaling was featured. The first portal encompasses the plasma membrane lipid domains, which give rise to pores when challenged for example with pardaxin, a fish toxin, or is subject to degradation when enzymes of lipid metabolism such as phospholipases A₂ (PLA₂) or phospholipase C (PLC) act upon it. Several major portals consist of ion channels, pumps, transporters and ligand gated ionotropic receptors which many toxins act on, disturbing the intracellular ion homeostasis. Another group of portals consists of G-protein-coupled and tyrosine kinase receptors that, upon interaction with discrete toxins, alter second messengers towards pathological levels. Lastly, subcellular organelles such as mitochondria, nucleus, protein- and RNA-synthesis machineries, cytoskeletal networks and exocytic vesicles are also portals targeted and deregulated by other diverse group of toxins. A fundamental concept can be drawn from these seemingly different toxins with respect to the site of action and the secondary messengers and signaling cascades they trigger in the host. While the interaction with the initial portal is largely determined by the chemical nature of the toxin, once inside the cell, several ubiquitous second messengers and protein kinases/ phosphatases pathways are impaired, to attain toxicity. Therefore, toxins represent one of the most promising natural molecules for developing novel therapeutics that selectively target the major cellular portals involved in human physiology and diseases.


Tofacitinib in the treatment of moderate-to-severe rheumatoid arthritis: a cost-effectiveness analysis compared with adalimumab in Taiwan.
Aims: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis investigated the cost-effectiveness of the second-line treatment with tofacitinib, compared with adalimumab, both plus methotrexate (MTX), in patients with moderate-to-severe RA and an inadequate response to the first-line MTX, from a Taiwan National Health Insurance Administration perspective. Materials and methods: A patient-level simulation model was used to project lifetime costs and quality-adjusted life-years (QALYs). Base-case analysis compared second-line treatment with tofacitinib 5 mg twice daily plus MTX vs adalimumab 40 mg every 2 weeks plus MTX. Patients switched or discontinued treatment due to a lack or loss of effectiveness or a serious adverse event. Efficacy was measured by change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score. HAQ-DI scores were used to predict mortality and resource utilization, and were mapped onto utility values to estimate QALYs. Efficacy and safety data were derived from clinical trials and other secondary sources. Uncertainty in model parameters was explored using one-way deterministic and probabilistic sensitivity analyses. Results: Patients gained 0.09 more QALYs with second-line tofacitinib plus MTX compared with adalimumab plus MTX (5.13 vs 5.04, respectively) at an additional cost of New Taiwan Dollars (NT$) 12,881. The incremental cost-effectiveness ratio was NT$143,122/QALY. One-way sensitivity analysis confirmed the base-case result was robust. Limitations: The lack of available clinical data, particularly for HAQ-DI scores, may introduce some bias in the analysis. No patients were in an early stage of RA, which may limit the generalizability of these results. Base-case results from our study are not necessarily generalizable to countries with healthcare systems that differ considerably from Taiwan. Conclusions: From a payer perspective, second-line treatment with tofacitinib plus MTX is a cost-effective treatment strategy, compared with adalimumab plus MTX, in patients with moderate-to-severe RA in Taiwan.


Toward simpler and faster genome-wide mutagenesis in mice.
Here we describe a practical Cre-loxP and piggyBac transposon-based mutagenesis strategy to systematically mutate coding sequences and/or the vast noncoding regions of the mouse genome for large-scale functional genomic analysis. To illustrate this approach, we first created loxP-containing loss-of-function alleles in the protocadherin alpha, beta and gamma gene clusters (Pcdha, Pcdhb and Pcdhg). Using these alleles, we show that, under proper guidance, Cre-loxP site-specific recombination can mediate efficient trans-allelic recombination in vivo, facilitating the generation of large germline deletions and duplications including deletions of Pcdha, and Pcdha to Pcdhb, simply by breeding (that is, at frequencies of 5.5%-21.6%). The same breeding method can also generate designed germline translocations between nonhomologous chromosomes at unexpected frequencies of greater than 1%. By incorporating a piggyBac transposon to insert and to distribute loxP sites randomly throughout the mouse genome, we present a simple but comprehensive method for generating genome-wide deletions and duplications, in addition to insertional loss-of-function and conditional rescue alleles, again simply by breeding.


A Systematic Review of Discrete-Choice Experiments and Conjoint Analysis Studies in People with Multiple Sclerosis.
Multiple sclerosis (MS) is a chronic disabling, inflammatory, and degenerative disease of the central nervous system that, in most cases, requires long-term disease-modifying treatment (DMT). The drugs used vary in efficacy and adverse effect profiles. Several studies have used attribute-based stated-preference methods, primarily to investigate patient preferences for initiating or escalating DMT. To conduct a systematic review of attribute-based stated-preference studies in people with MS to identify common methods employed and to assess study quality, with reference to the specific challenges of this disease area. We conducted a systematic search for studies related to attribute-based stated-preference and MS in multiple databases, including Cochrane and MEDLINE. Studies were included if they were published in a peer-reviewed journal, were on the topic of MS, and used a survey methodology that measured stated preferences for attributes of a whole. Analysis was conducted using narrative synthesis and summary statistics. Study quality was judged against the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) conjoint analysis checklist. We identified 16 relevant articles reporting 17 separate studies, all but one focusing on DMTs. Most studies were discrete-choice experiments. Study quality was generally high, but we recommend the following: (1) that consideration of sample sizes be improved, (2) that survey design choices be justified and documented, (3) that qualitative approaches for attribute and level selection be incorporated to better involve patients, and (4) that reporting of experimental practice be improved. The effects of DMTs on reproduction and the impact of how risk and uncertainty are presented were identified as neglected research topics. The ISPOR conjoint analysis checklist was found to be unsuitable for the assessment of study quality. Attribute-based stated preference is a useful method with which to examine the preferences of people with MS in their choice of DMT. However, further research embracing the methodological recommendations identified, particularly greater use of qualitative methods in attribute development, is needed.


Effects of exercise training and detraining on atheromatous matrix metalloproteinase activity in mice.
Exercise training (ET) helps treat atherosclerosis. However, many patients stop regular ET for various reasons. The effect of detraining on atherosclerosis is not well studied. We examined the effects of ET vs. short-term detraining on atheromatous matrix-metalloproteinase (MMP) activity in preexisting plaque and circulating cytokines/lipids. Eighteen-week-old apolipoprotein-E-/- mice (n = 56) on a Western diet underwent: 1) ET for 6-weeks (ET5+1), 2) ET for 5-weeks and detraining for 1-week (ET5+0), 3) ET for the last 1-week (ET0+1), or 4) no treadmill ET at all for 6-weeks (ET0+0). Atheromatous MMP-activity was visualized using molecular imaging with an MMP-2/9-activatable near-infrared-fluorescent probe. Compared with no ET (ET0+0), regular ET (ET5+1) decreased carotid atheromatous MMP activity, but this protective effect was significantly blunted by short-term detraining (ET5+0). Short-term detraining after longer-term ET showed a reduction in MMP-activity similar to short-term ET (ET0+1). Blood levels of lipids and cytokines paralleled the molecular imaging results: exercise caused higher levels of high-density lipoprotein, adiponectin, and interleukin-10 and lower levels of vascular cell adhesion molecule, monocyte chemoattractant protein-1, interleukin-1β, and low-density lipoprotein. However, this beneficial effect was short-lived, with the ET5+0 group being similar to the ET0+0 group, and the ET0+1 group being similar to the ET5+1 group. The effect of exercise can be modeled with an exponential-decay of the protective factor of about 15%/day. Even short-term detraining reduces atheroprotective effects, and tips the balance towards atherosclerosis. This suggests that ET, to be effective, needs to be prolonged and regular, and that detraining should be avoided.


Comparison of Social Interaction between Cochlear-Implanted Children with Normal Intelligence Undergoing Auditory Verbal Therapy and Normal-Hearing Children: A Pilot Study.
A cochlear implant is a device that helps hearing-impaired children by transmitting sound signals to the brain and helping them improve their speech, language, and social interaction. Although various studies have investigated the different aspects of speech perception and language acquisition in cochlear-implanted children, little is known about their social skills, particularly Persian-speaking cochlear-implanted children. Considering the growing number of cochlear implants being performed in Iran and the increasing importance of developing near-normal social skills as one of the ultimate goals of cochlear implantation, this study was performed to compare the social interaction between Iranian cochlear-implanted children who have undergone rehabilitation (auditory verbal therapy) after surgery and normal-hearing children. This descriptive-analytical study compared the social interaction level of 30 children with normal hearing and 30 with cochlear implants who were conveniently selected. The Raven test was administered to the both groups to ensure normal intelligence quotient. The social interaction status of both groups was evaluated using the Vineland Adaptive Behavior Scale, and statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 21. After controlling age as a covariate variable, no significant difference was observed between the social interaction scores of both the groups (p > 0.05). In addition, social interaction had no correlation with sex in either group. Cochlear implantation followed by auditory verbal rehabilitation helps children with sensorineural hearing loss to have normal social interactions, regardless of their sex.


Characterization of human Sertoli cells in vitro.
The Sertoli cell is thought to play a significant role in the hormonal regulation of spermatogenesis within the rat testis. Little, however, is known about Sertoli cell function in man, largely because of the difficulties associated with the isolation of pure cell populations from human tissue. We have now developed a rapid and reproducible technique for establishing a human Sertoli cell monolayer culture. This has involved mechanical separation of the tissue, sequential trypsin and collagenase enzyme digestion, and final disruption of tubules by passage through a wire mesh grid. Using this technique, primary cultures can be maintained for up to 45 days. Ultrastructural studies of these cells have demonstrated the presence of the perinucleolar spheres, cell to cell junctional complexes, abundant lipid droplets, and smooth endoplasmic reticulum, all characteristic of Sertoli cells. Furthermore, biochemical markers of animal Sertoli cells, androgen-binding protein and gamma-glutamyl transpeptidase, have also been identified in these human cells. Concentrated media electrophoresed on nondenaturing gels containing 2 nM [3H]dihydrotestosterone produced a single peak of bound activity which coelectrophoresed with rat androgen-binding protein. This binding activity persisted despite media changes, thus ruling out contamination by serum binding proteins; fresh media lacked demonstrable binding activity. Using a colorimetric assay, these cells were also found to contain significant gamma-glutamyl transpeptidase activity compared to human foreskin fibroblasts and Leydig cells. Enzyme activity increased in a characteristic dose-response fashion in the presence of FSH (0.05-0.5 microgram/ml) and dibutyryl cAMP (0.1-1 microgram/ml), but not with LH or testosterone. These data offer the first demonstration of human Sertoli cells in monolayer culture and their production of a marker specifically regulated by FSH.


Pharmacokinetics and systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator (rt-PA) in humans.
The pharmacokinetics of recombinant human tissue-type plasminogen activator (rt-PA) were studied in 20 subjects during and after its i.v. infusion at three different rates (5.6, 8.3, and 10 micrograms/kg/min). Steady-state plasma concentrations of 0.9 to 1.6 micrograms/ml were reached. The plasma disappearance curves of rt-PA (both antigen and activity) after cessation of infusion were approximated by a sum of two exponential terms and the turnover of rt-PA was represented by a two-compartment mammillary model with peripheral (liver) elimination. The fractional efflux rate constant from the central compartment was 0.10 per min and the fractional catabolic rate constant about 0.02 per min. After cessation of infusion the initial half-life of the drug in plasma was 6 min. Fibrinogen levels were measured by a clotting rate assay and by sodium sulfite precipitation. Infusion of rt-PA at 10 micrograms/kg/min for 30 min did not cause systemic fibrinogen breakdown. Infusion of 5.6 micrograms/kg/min for 90 min was associated with a decrease of fibrinogen to 62% of the preinfusion value (4.5 g/l) as measured with the clotting rate assay, but only 2% was recovered as incoagulable fibrinogen-fibrin degradation products. Infusion of 8.3 micrograms/kg/min for 90 min resulted in a decrease of fibrinogen to 45% of the preinfusion level (2.5 g/l) and generation of 8.5% fibrinogen-fibrin degradation products. Fibrinogen assays with the sodium sulfite method showed a much less extensive decrease of fibrinogen. This extent of systemic fibrinolytic activation and fibrinogen breakdown at high infusion rates and prolonged durations is compatible with that anticipated from the kinetic parameters of the activation of plasminogen by rt-PA.


Simultaneous structure and texture image inpainting.
An algorithm for the simultaneous filling-in of texture and structure in regions of missing image information is presented in this paper. The basic idea is to first decompose the image into the sum of two functions with different basic characteristics, and then reconstruct each one of these functions separately with structure and texture filling-in algorithms. The first function used in the decomposition is of bounded variation, representing the underlying image structure, while the second function captures the texture and possible noise. The region of missing information in the bounded variation image is reconstructed using image inpainting algorithms, while the same region in the texture image is filled-in with texture synthesis techniques. The original image is then reconstructed adding back these two sub-images. The novel contribution of this paper is then in the combination of these three previously developed components, image decomposition with inpainting and texture synthesis, which permits the simultaneous use of filling-in algorithms that are suited for different image characteristics. Examples on real images show the advantages of this proposed approach.


Cost-effectiveness of 13-valent pneumococcal conjugate vaccine in Switzerland.
The 7-valent pneumococcal conjugate vaccine (PCV7) has been shown to be highly cost-effective. The 13-valent pneumococcal conjugate vaccine (PCV13) offers seroprotection against six additional serotypes. A decision-analytic model was constructed to estimate direct medical costs and clinical effectiveness of PCV13 vaccination on invasive pneumococcal disease (IPD), pneumonia, and otitis media relative to PCV7 vaccination. The option with an one-dose catch-up vaccination in children of 15-59 months was also considered. Assuming 83% vaccination coverage and considering indirect effects, 1808 IPD, 5558 pneumonia and 74,136 otitis media cases could be eliminated from the entire population during a 10-year modelling period. The PCV13 vaccination programme would lead to additional costs (+€26.2 Mio), but saved medical costs of -€77.1 Mio due to cases averted and deaths avoided, overcompensate these costs (total cost savings -€50.9 Mio). The national immunisation programmes with PCV13 can be assumed cost saving when compared with the current vaccine PCV7 in Switzerland.


An observational study to evaluate the safety and efficacy of telbivudine in adults with chronic hepatitis B.
to assess the safety and efficacy of telbivudine therapy in adult patients with CHB in Indonesia. the study design was prospective cohort study. Multicenter study of adult CHB patients requiring oral antiviral therapy in daily practice setting. All patients received 600 mg of telbivudine daily for one year. Recruitment and decision to start telbivudine therapy was based on clinical indication as assessed by the participating physicians. The primary end-point was patient safety (adverse event or serious adverse events); while the secondary end-points were HBeAg seroconversion, changes of serum HBV DNA levels and serum ALT normalization. Patients were assessed at week-24 and week-52 of treatment. a total of 176 cases were eligible for analysis, comprising 104 (59.8%) HBeAg-positive and 70 (40.2%) HBeAg-negative patients. Adverse events were reported in 7 (4.0%) patients, most of them were mild. HBeAg loss and seroconversion rate was 28.8% and 14.14% at week-52 respectively. Undetectable HBV DNA (PCR negativity) was 51.8% at week-24 and 62.7% at week-52. Median HBV DNA levels were significantly reduced from baseline to week-24 and week-52 treatment (both p<0.001; Wilcoxon's signed-rank test). Normalization of serum ALT activity occurred in 85 (73.28%) patients at week-52. Telbivudine therapy is generally safe and well tolerated among adult Indonesian patients with chronic hepatitis B. Treatment efficacy in terms of HBeAg loss and seroconversion, changes of HBV DNA levels and serum ALT normalization were similar to previous reported studies.


E-mailed standardized cognitive behavioural treatment of work-related stress: a randomized controlled trial.
The aim of this study was to assess the effects of a 7-week standardized cognitive behavioural treatment of work-related stress conducted via e-mail. A total of 342 people applied for treatment in reaction to a newspaper article. Initial screening reduced the sample to a heterogeneous (sub)clinical group of 239 participants. Participants were assigned randomly to a waiting list condition (n = 62), or to immediate treatment (n = 177). A follow-up was conducted 3 years after inception of the treatment. The outcome measures used were the Depression Anxiety Stress Scales (DASS-42) and the Emotional Exhaustion scale of the Maslach Burnout Inventory - General Survey (MBI-GS). Fifty participants (21%) dropped out. Both groups showed statistically significant improvements. Intention-to-treat analysis of covariance (ANCOVAs) revealed that participants in the treatment condition improved significantly more than those in the waiting control condition (0.001<p < or = 0.025). In the treatment group, the effects were large to moderate (0.9 (stress) > or = d > or = 0.5 (anxiety)). The between-group effects ranged from d = 0.6 (stress) to d = 0.1 (anxiety). At follow-up, the effects were more pronounced, but this result requires replication in view of high attrition at follow-up. The results warrant further research on Internet-driven standardized cognitive behavioural therapy for work-related stress. Such research should include the direct comparison of this treatment with face-to-face treatment, and should address the optimal level of therapist contact in Internet-driven treatment.


Effects on skeletal muscle glutathione status of ischemia and reperfusion following abdominal aortic aneurysm surgery.
Glutathione (GSH) is an important endogenous scavenger against reactive oxygen species. Elective abdominal surgery without ischemia and reperfusion leads to decreased muscle GSH concentrations 4-72 hr postoperatively without altering GSH redox status. In the present study, we investigated to what extent muscle GSH status was affected during and following elective abdominal aortic aneurysm repair. From patients (n = 10) undergoing abdominal aortic repair, thigh muscle specimens were taken preoperatively, at maximal ischemia, and at 10 min and 4, 24, and 48 hr of reperfusion. Specimens were analyzed for GSH, amino acids, and energy-rich compounds. At maximal ischemia, phosphocreatine decreased by 37% (p < 0.05) and lactate and creatine increased by 274% and 57% (p < 0.001 and 0.05), respectively, indicating ischemia during the clamping of aorta. Adenosine triphosphate, on the other hand, remained unaltered during the entire study period. Total GSH (tGSH) decreased by 46% at 24 hr and by 43% at 48 hr of reperfusion (p < 0.001), while reduced GSH decreased by 48% at 24 hr and by 44% at 48 hr (p < 0.001). The redox status (GSH/tGSH) of GSH and oxidized GSH remained unaltered. Among the constituent amino acids of GSH, glycine and cysteine remained unaltered while glutamine and glutamate decreased by 55% and 55%, respectively (p < 0.001). Abdominal aortic aneurysm repair induces metabolic alterations characteristic for ischemia. The antioxidative capacity in terms of muscle levels of GSH was decreased. However, the oxidative stress during reperfusion did not change GSH status more than what has been reported following abdominal surgery without ischemia and reperfusion. The results indicate that the oxidative stress elicited by elective abdominal aortic aneurysm repair is outbalanced by a compensated GSH metabolism not giving rise to an increased amount of oxidized GSH or an altered GSH redox status.


Macrolides versus placebo for chronic asthma.
Asthma is a chronic disease in which inflammation of the airways causes symptomatic wheezing, coughing and difficult breathing. Macrolides are antibiotics with antimicrobial and anti-inflammatory activities that have been explored for the long-term control of asthma symptoms. To assess the effects of macrolides compared with placebo for managing chronic asthma. We searched the Cochrane Airways Group Specialised Register up to March 2021. We also manually searched bibliographies of previously published reviews and conference proceedings and contacted study authors. We included records published in any language in the search. We included randomised controlled clinical trials (RCTs) involving both children and adults with asthma treated with macrolides versus placebo for four or more weeks. Primary outcomes were exacerbation requiring hospitalisation, severe exacerbations (exacerbations requiring emergency department (ED) visits or systemic steroids, or both), symptom scales, asthma control questionnaire (ACQ, score from 0 totally controlled, to 6 severely uncontrolled), Asthma Quality of Life Questionnaire (AQLQ, with score from 1 to 7 with higher scores indicating better QoL), rescue medication puffs per day, morning and evening peak expiratory flow (PEF; litres per minutes), forced expiratory volume in one second (FEV1; litres), bronchial hyperresponsiveness, and oral corticosteroid dose. Secondary outcomes were adverse events (including mortality), withdrawal, blood eosinophils, sputum eosinophils, eosinophil cationic protein (ECP) in serum, and ECP in sputum. Two review authors independently examined all records identified in the searches then reviewed the full text of all potentially relevant articles before extracting data in duplicate from all included studies. As per protocol, we used a fixed-effect model. We conducted a sensitivity analysis for analyses with high heterogeneity (I2 greater than 30%). GRADE was used to assess the certainty of the body of evidence. Twenty-five studies met the inclusion criteria, randomising 1973 participants to receive macrolide or placebo for at least four weeks. Most of the included studies reported data from adults (mean age 21 to 61 years) with persistent or severe asthma, while four studies included children. All participants were recruited in outpatient settings. Inclusion criteria, interventions and outcomes were highly variable. The evidence suggests macrolides probably deliver a moderately sized reduction in exacerbations requiring hospitalisations compared to placebo (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.20 to 1.12; studies = 2, participants = 529; moderate-certainty evidence). Macrolides probably reduce exacerbations requiring ED visits and/or treatment with systemic steroids (rate ratio (RaR) 0.65, 95% CI 0.53 to 0.80; studies = 4, participants = 640; moderate-certainty evidence). Macrolides may reduce symptoms (as measured on symptom scales) (standardised mean difference (SMD) -0.46, 95% CI -0.81 to -0.11; studies = 4, participants = 136 ; very low-certainty evidence). Macrolides may result in a little improvement in ACQ (SMD -0.17, 95% CI -0.31 to -0.03; studies = 5, participants = 773; low-certainty evidence). Macrolides may have little to no effect on AQLQ (mean difference (MD) 0.24, 95% CI 0.12 to 0.35; studies = 6, participants = 802; very low-certainty evidence). For both the ACQ and the AQLQ the suggested effect of macrolides versus placebo did not reach a minimal clinically important difference (MCID, 0.5 for ACQ and AQLQ) (ACQ: low-certainty evidence; AQLQ: very low-certainty evidence). Due to high heterogeneity (I2 > 30%), we conducted sensitivity analyses on the above results, which reduced the size of the suggested effects by reducing the weighting on the large, high quality studies. Macrolides may result in a small effect compared to placebo in reducing need for rescue medication (MD -0.43 puffs/day, 95% CI -0.81 to -0.04; studies = 4, participants = 314; low-certainty evidence). Macrolides may increase FEV1, but the effect is almost certainly below a level discernible to patients (MD 0.04 L, 95% CI 0 to 0.08; studies = 10, participants = 1046; low-certainty evidence). It was not possible to pool outcomes for non-specific bronchial hyperresponsiveness or lowest tolerated oral corticosteroid dose (in people requiring oral corticosteroids at baseline). There was no evidence of a difference in severe adverse events (including mortality), although less than half of the studies reported the outcome (OR 0.80, 95% CI 0.49 to 1.31; studies = 8, participants = 854; low-certainty evidence). Reporting of specific adverse effects was too inconsistent across studies for a meaningful analysis. Existing evidence suggests an effect of macrolides compared with placebo on the rate of exacerbations requiring hospitalisation. Macrolides probably reduce severe exacerbations (requiring ED visit and/or treatment with systemic steroids) and may reduce symptoms. However, we cannot rule out the possibility of other benefits or harms because the evidence is of very low quality due to heterogeneity among patients and interventions, imprecision and reporting biases. The results were mostly driven by a well-designed, well powered RCT, indicating that azithromycin may reduce exacerbation rate and improve symptom scores in severe asthma. The review highlights the need for researchers to report outcomes accurately and according to standard definitions. Macrolides can reduce exacerbation rate in people with severe asthma. Future trials could evaluate if this effect is sustained across all the severe asthma phenotypes, the comparison with newer biological drugs, whether effects persist or wane after treatment cessation and whether effects are associated with infection biomarkers.


Porphyrins as theranostic agents from prehistoric to modern times.
Long before humans roamed the planet, porphyrins in blood were serving not only as indispensable oxygen carriers, but also as the bright red contrast agent that unmistakably indicates injury sites. They have proven valuable as whole body imaging modalities have emerged, with endogenous hemoglobin porphyrins being used for new approaches such as functional magnetic resonance imaging and photoacoustic imaging. With the capability for both near infrared fluorescence imaging and phototherapy, porphyrins were the first exogenous agents that were employed with intrinsic multimodal theranostic character. Porphyrins have been used as tumor-specific diagnostic fluorescence imaging agents since 1924, as positron emission agents since 1951, and as magnetic resonance (MR) contrast agents since 1987. Exogenous porphyrins remain in clinical use for photodynamic therapy. Because they can chelate a wide range of metals, exogenous porphyrins have demonstrated potential for use in radiotherapy and multimodal imaging modalities. Going forward, intrinsic porphyrin biocompatibility and multimodality will keep new applications of this class of molecules at the forefront of theranostic research.


Intraspecific eye color variability in birds and mammals: a recent evolutionary event exclusive to humans and domestic animals.
Human populations and breeds of domestic animals are composed of individuals with a multiplicity of eye (= iris) colorations. Some wild birds and mammals may have intraspecific eye color variability, but this variation seems to be due to the developmental stage of the individual, its breeding status, and/or sexual dimorphism. In other words, eye colour tends to be a species-specific trait in wild animals, and the exceptions are species in which individuals of the same age group or gender all develop the same eye colour. Domestic animals, by definition, include bird and mammal species artificially selected by humans in the last few thousand years. Humans themselves may have acquired a diverse palette of eye colors, likewise in recent evolutionary time, in the Mesolithic or in the Upper Paleolithic. We posit two previously unrecognized hypotheses regarding eye color variation: 1) eye coloration in wild animals of every species tends to be a fixed trait. 2) Humans and domestic animal populations, on the contrary, have eyes of multiple colors. Sexual selection has been invoked for eye color variation in humans, but this selection mode does not easily apply in domestic animals, where matings are controlled by the human breeder. Eye coloration is polygenic in humans. We wish to investigate the genetics of eye color in other animals, as well as the ecological correlates. Investigating the origin and function of eye colors will shed light on the reason why some species may have either light-colored irises (e.g., white, yellow or light blue) or dark ones (dark red, brown or black). The causes behind the vast array of eye colors across taxa have never been thoroughly investigated, but it may well be that all Darwinian selection processes are at work: sexual selection in humans, artificial selection for domestic animals, and natural selection (mainly) for wild animals.


Red cell transfusion for the management of upper gastrointestinal haemorrhage.
Upper gastrointestinal haemorrhage affects 50 to 150 per 100,000 adults per year, with a high mortality. Red blood cell transfusions are frequently given, but their impact on rebleeding rates and mortality is unknown. To assess the effects of red blood cell (RBC) transfusion in adults with upper gastrointestinal haemorrhage. For this update, we re-ran the initial search strategies from the last issue/month searched until March 2010.We previously searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register to February 2008, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 1), MEDLINE (1950 to February 2008), EMBASE (1974 to February 2008), the Systematic Review Initiative database of randomised controlled trials (RCTs), haematology and gastroenterology conference proceedings, and reference lists of articles. Randomised and quasi-randomised studies comparing RBC transfusion and standard care with other intravenous fluid and standard care regimens in haemodynamically stable and haemodynamically unstable adults with upper gastrointestinal haemorrhage. Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. Three trials involving 126 patients were included, with complete data available for 93 patients. The participants were heterogeneous, none of the three studies examined exactly the same interventions or measured the same outcomes. Only two trials reported mortality data and the summary relative risk for mortality of the intervention was 5.4 (95% CI 0.27 to 107.09). One trial reported increased coagulation times in the transfused group, and reported these patients to have increased rates of rebleeding. None of the studies reported adverse events directly related to RBC transfusion. Methodological deficiencies, including allocation concealment, generation of random sequences and blinding, simply compound the uncertainty surrounding analysis. None of the studies were appropriately powered and in the largest study fewer than half the participants were included in the final analysis.One RCT of restrictive versus liberal RBC transfusion aims to recruit 860 patients but has yet to be completed. There were more deaths and more rebleeding in the transfusion arms of the combined studies, but the small numbers of participants and large volume of missing data limit the significance of the findings. The studies in this review do not provide useful data regarding outcomes following red blood cell transfusion for acute upper gastrointestinal haemorrhage. They appear to exclude large survival benefit. Large, well-concealed RCTs of sufficient power are urgently needed.


Dynamic oscillatory processes governing cued orienting and allocation of auditory attention.
In everyday listening situations, we need to constantly switch between alternative sound sources and engage attention according to cues that match our goals and expectations. The exact neuronal bases of these processes are poorly understood. We investigated oscillatory brain networks controlling auditory attention using cortically constrained fMRI-weighted magnetoencephalography/EEG source estimates. During consecutive trials, participants were instructed to shift attention based on a cue, presented in the ear where a target was likely to follow. To promote audiospatial attention effects, the targets were embedded in streams of dichotically presented standard tones. Occasionally, an unexpected novel sound occurred opposite to the cued ear to trigger involuntary orienting. According to our cortical power correlation analyses, increased frontoparietal/temporal 30-100 Hz gamma activity at 200-1400 msec after cued orienting predicted fast and accurate discrimination of subsequent targets. This sustained correlation effect, possibly reflecting voluntary engagement of attention after the initial cue-driven orienting, spread from the TPJ, anterior insula, and inferior frontal cortices to the right FEFs. Engagement of attention to one ear resulted in a significantly stronger increase of 7.5-15 Hz alpha in the ipsilateral than contralateral parieto-occipital cortices 200-600 msec after the cue onset, possibly reflecting cross-modal modulation of the dorsal visual pathway during audiospatial attention. Comparisons of cortical power patterns also revealed significant increases of sustained right medial frontal cortex theta power, right dorsolateral pFC and anterior insula/inferior frontal cortex beta power, and medial parietal cortex and posterior cingulate cortex gamma activity after cued versus novelty-triggered orienting (600-1400 msec). Our results reveal sustained oscillatory patterns associated with voluntary engagement of auditory spatial attention, with the frontoparietal and temporal gamma increases being best predictors of subsequent behavioral performance.


A new and simple method for delivering clamped nitric oxide concentrations in the physiological range: application to activation of guanylyl cyclase-coupled nitric oxide receptors.
The signaling molecule nitric oxide (NO) could engage multiple pathways to influence cellular function. Unraveling their relative biological importance has been difficult because it has not been possible to administer NO under the steady-state conditions that are normally axiomatic for analyzing ligand-receptor interactions and downstream signal transduction. To address this problem, we devised a chemical method for generating constant NO concentrations, derived from balancing NO release from a NONOate donor with NO consumption by a sink. On theoretical grounds, 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO) was selected as the sink. The mixture additionally contained urate to convert an unwanted product of the reaction (NO2) into nitrite ions. The method enabled NO concentrations covering the physiological range (0-100 nM) to be formed within approximately 1 s. Moreover, the concentrations were sufficiently stable over at least several minutes to be useful for biological purposes. When applied to the activation of guanylyl cyclase-coupled NO receptors, the method gave an EC50 of 1.7 nM NO for the protein purified from bovine lung, which is lower than estimated previously using a biological NO sink (red blood cells). The corresponding values for the alpha1beta1 and alpha2beta1 isoforms were 0.9 nM and 0.5 nM, respectively. The slopes of the concentration-response curves were more shallow than before (Hill coefficient of 1 rather than 2), questioning the need to consider the binding of more than one NO molecule for receptor activation. The discrepancies are ascribable to limitations of the earlier method. Other biological problems can readily be addressed by adaptations of the new method.


The protective effect of farm animal exposure on childhood allergy is modified by NPSR1 polymorphisms.
Little is known about the asthma candidate gene neuropeptide S receptor 1 (NPSR1) in relation to environmental exposures, but recent evidences suggest its role as an effect modifier. To explore the interaction between NPSR1 polymorphisms and environmental exposures related to farming lifestyle and to study the in vitro effects of lipopolysaccharide (LPS) stimulation on NPSR1 expression levels. We studied 3113 children from PARSIFAL, a European cross-sectional study on environmental/lifestyle factors and childhood allergy, partly focused on children brought up on a farm. Information on exposures and outcomes was primarily obtained from parental questionnaires. Seven tagging polymorphisms were analysed in a conserved haplotype block of NPSR1. Multivariate logistic regression was used to evaluate a multiplicative model of interaction. NPSR1 protein and messenger RNA (mRNA) levels in monocytes were measured after LPS stimulation by fluorescence activated cell sorting (FACS) and quantitative real-time polymerase chain reaction (PCR). A strong interaction was seen between current regular contact to farm animals and several NPSR1 polymorphisms, particularly rs323922 and rs324377 (p<0.005), with respect to allergic symptoms. Considering the timing of initiation of such current regular farm animal contact, significant interactions with these and two additional polymorphisms (SNP546333, rs740347) were revealed. In response to LPS, NPSR1-A protein levels in monocytes were upregulated (p = 0.002), as were NPSR1-A mRNA levels (p = 0.02). The effect of farm animal contact on the development of allergic symptoms in children is modified by NPSR1 genetic background.


Aberrant planar cell polarity induced by urinary tract obstruction.
Flow sensing by primary cilia of the epithelial cells is involved in cystogenesis in polycystic kidney disease. We investigate whether a similar mechanism applies to the pathogenesis of cyst-like tubular dilatation induced by ureteral obstruction in mice. Robust proliferation occurs in the obstructed tubules when urine flow is interrupted as well as in the repairing tubules when urine flow is reestablished after relief of the obstruction, suggesting a urine flow-independent mechanism of proliferation. In the urothelium, proliferation is only detected above the obstruction, although urine flow ceased both above and below the obstruction. Our results support mechanical strain- rather than flow-mediated proliferation in obstructive uropathy. To understand the mechanism of cell proliferation leading to increased tubular diameter in cyst-like tubular dilatation, we examine planar cell polarity (PCP), which is necessary for oriented cell division and maintenance of tubular diameter. In dilated tubules, the orientation of cell division is randomized, atypical PKC (aPKC) is mislocalized, and the pattern of the expression of a core PCP protein, Frizzled3 (Fz3), is altered. In addition, the level of Fz3 expression is increased. These results indicate that aberrant PCP may contribute to cyst-like tubular dilatation in obstructive uropathy. Interestingly, the orientation of cell division, localization of aPKC, and Fz3 expression return to normal when obstruction is relieved, which suggest a role of normal PCP signaling in tubular repair.


Magnetically Actuated Protease Sensors for in Vivo Tumor Profiling.
Targeted cancer therapies require a precise determination of the underlying biological processes driving tumorigenesis within the complex tumor microenvironment. Therefore, new diagnostic tools that capture the molecular activity at the disease site in vivo are needed to better understand tumor behavior and ultimately maximize therapeutic responses. Matrix metalloproteinases (MMPs) drive multiple aspects of tumorigenesis, and their activity can be monitored using engineered peptide substrates as protease-specific probes. To identify tumor specific activity profiles, local sampling of the tumor microenvironment is necessary, such as through remote control of probes, which are only activated at the tumor site. Alternating magnetic fields (AMFs) provide an attractive option to remotely apply local triggering signals because they penetrate deep into the body and are not likely to interfere with biological processes due to the weak magnetic properties of tissue. Here, we report the design and evaluation of a protease-activity nanosensor that can be remotely activated at the site of disease via an AMF at 515 kHz and 15 kA/m. Our nanosensor was composed of thermosensitive liposomes containing functionalized protease substrates that were unveiled at the target site by remotely triggered heat dissipation of coencapsulated magnetic nanoparticles (MNPs). This nanosensor was combined with a unique detection assay to quantify the amount of cleaved substrates in the urine. We applied this spatiotemporally controlled system to determine tumor protease activity in vivo and identified differences in substrate cleavage profiles between two mouse models of human colorectal cancer.


Planetary health and the role of community health workers.
In this era, grand challenges lies in biodiversity loss, climate change, and global noncommunicable diseases signify that planet and humanity are in crisis. Scholarly evidence from human and animal kingdom suggest that there is an optimism in planetary health which can provide a unique and novel concept where efforts toward survival and remediation can be made. With accurate navigation, the current challenges can be mitigated leading to a new reality, one in which the core value is the well-being of all. This paper discusses the drivers of planetary health and the role of community health workers (CHWs) in making health-care system more resilient that can produce multiple benefits to community and overall planetary health. A web-based international database such as Google, Google Scholar, SCOPUS/MEDLINE/PubMed, and JSTOR was searched relevant to a planetary health framework. The study findings suggest that CHWs can offer health care interventions through environmental health cobenefits across the spectrum of health effects of climate change cause and effects. These actions have been divided into four major categories (i. health care promotion and prevention, ii. health care strengthening, iii. advocacy, and iv. education and research) that CHWs perform through a variety of roles and functions they are engaged in protecting planetary health. CHWs contribute toward achieving sustainable development goals such as planetary health and focus on environment sustainability and well-being of entire mankind.


Hemorrhage and thrombus formation in early experimental osteonecrosis.
The aim of the current study was to test the hypothesis that the induction of an underlying immunologic condition in rabbits may enhance the development of steroid-induced osteonecrosis. Thirty-five adult rabbits were divided into four groups. Group I: 10 rabbits were immunized at 15-day intervals for 2 months by murine antibodies to deoxyribonucleic acid autoantibodies. Four weeks after the end of the immunization, the animals received injections of methylprednisolone for 7 days and then prednisolone per os for 8 months. Group II: 10 animals only received immunizations according to the protocol used in Group I. Group III: 10 animals only were treated with corticosteroids according to the protocol used in Group I. Group IV: five animals were used as controls. Various changes were observed in the proximal metaphysis and diaphysis of the femur in eight of 10 animals in Group I (80%) and in five of 10 animals in Group II (50%) when compared with the animals in Group III and Group IV. The most common feature was evidence of new and old hemorrhage through the sinusoids, exudative reaction and thrombus formation in veins and small arteries. Focal necrotic areas of bone marrow showed an accumulation of cell debris, residue of hemorrhage, and disappearance of marrow elements. These findings suggest that (1) corticosteroids may potentiate the effects of a preexisting condition to increase the risk of osteonecrosis; (2) immunologic reaction may be an important factor in the pathogenesis of necrotic lesions; and (3) repeated intramedullary hemorrhage and thrombus formation may represent early major pathologic findings in bone necrosis.


Effect of Immediate vs Delayed Pushing on Rates of Spontaneous Vaginal Delivery Among Nulliparous Women Receiving Neuraxial Analgesia: A Randomized Clinical Trial.
It is unclear whether the timing of second stage pushing efforts affects spontaneous vaginal delivery rates and reduces morbidities. To evaluate whether immediate or delayed pushing results in higher rates of spontaneous vaginal delivery and lower rates of maternal and neonatal morbidities. Pragmatic randomized clinical trial of nulliparous women at or beyond 37 weeks' gestation admitted for spontaneous or induced labor with neuraxial analgesia between May 2014 and December 2017 at 6 US medical centers. The interim analysis suggested futility for the primary outcome and recruitment was terminated with 2414 of 3184 planned participants. Follow-up ended January 4, 2018. Randomization occurred when participants reached complete cervical dilation. Immediate group participants (n = 1200) began pushing immediately. Delayed group participants (n = 1204) were instructed to wait 60 minutes. The primary outcome was spontaneous vaginal delivery. Secondary outcomes included total duration of the second stage, duration of active pushing, operative vaginal delivery, cesarean delivery, postpartum hemorrhage, chorioamnionitis, endometritis, perineal lacerations (≥second degree), and a composite outcome of neonatal morbidity that included neonatal death and 9 other adverse outcomes. Among 2414 women randomized (mean age, 26.5 years), 2404 (99.6%) completed the trial. The rate of spontaneous vaginal delivery was 85.9% in the immediate group vs 86.5% in the delayed group, and was not significantly different (absolute difference, -0.6% [95% CI, -3.4% to 2.1%]; relative risk, 0.99 [95% CI, 0.96 to 1.03]). There was no significant difference in 5 of the 9 prespecified secondary outcomes reported, including the composite outcome of neonatal morbidity (7.3% for the immediate group vs 8.9% for the delayed group; between-group difference, -1.6% [95% CI, -3.8% to 0.5%]) and perineal lacerations (45.9% vs 46.4%, respectively; between-group difference, -0.4% [95% CI, -4.4% to 3.6%]). The immediate group had significantly shorter mean duration of the second stage compared with the delayed group (102.4 vs 134.2 minutes, respectively; mean difference, -31.8 minutes [95% CI, -36.7 to -26.9], P < .001), despite a significantly longer mean duration of active pushing (83.7 vs 74.5 minutes; mean difference, 9.2 minutes [95% CI, 5.8 to 12.6], P < .001), lower rates of chorioamnionitis (6.7% vs 9.1%; between-group difference, -2.5% [95% CI, -4.6% to -0.3%], P = .005), and fewer postpartum hemorrhages (2.3% vs 4.0%; between-group difference, -1.7% [95% CI, -3.1% to -0.4%], P = .03). Among nulliparous women receiving neuraxial anesthesia, the timing of second stage pushing efforts did not affect the rate of spontaneous vaginal delivery. These findings may help inform decisions about the preferred timing of second stage pushing efforts, when considered with other maternal and neonatal outcomes. ClinicalTrials.gov Identifier: NCT02137200.


Magnetoencephalography shows atypical sensitivity to linguistic sound sequences in autism spectrum disorder.
Neuroscientific evidence points toward atypical auditory processing in individuals with autism spectrum disorders (ASD), and yet, the consequences of this for receptive language remain unclear. Using magnetoencephalography and a passive listening task, we test for cascading effects on speech sound processing. Children with ASD and age-matched control participants (8-12 years old) listened to nonce linguistic stimuli that either did or did not conform to the phonological rules that govern consonant sequences in English (e.g. legal 'vimp' vs. illegal 'vimk'). Beamformer source analysis was used to isolate evoked responses (0.1-30 Hz) to these stimuli in the left and the right auditory cortex. Right auditory responses from participants with ASD, but not control participants, showed an attenuated response to illegal sequences relative to legal sequences that emerged around 330 ms after the onset of the critical phoneme. These results suggest that phonological processing is impacted in ASD, perhaps because of cascading effects from disrupted initial acoustic processing.


VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation.
Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unclear. Here, we showed that midbrain LepR neurons overlap with a subset of dopaminergic, GABAergic and glutamatergic neurons. Specific removal of vesicular monoamine transporter 2 (VMAT2) in midbrain LepR neurons (KO mice) disrupted DA accumulation in vesicles, but failed to cause a significant change in the evoked release of either glutamate or GABA to downstream neurons. While KO mice showed no differences on chow, they presented a reduced high-fat diet (HFD) intake and resisted to HFD-induced obesity. Specific activation of midbrain LepR neurons promoted VMAT2-dependent feeding on chow and HFD. When tested with an intermittent access to HFD where first 2.5-h HFD eating (binge-like) and 24-h HFD feeding were measured, KO mice exhibited more binge-like, but less 24-h HFD feeding. Interestingly, leptin inhibited 24-h HFD feeding in controls but not in KO mice. Thus, VMAT2-mediated neurotransmission from midbrain LepR neurons contributes to both binge-like eating and HFD feeding regulation.


Establishing key components of yoga interventions for reducing depression and anxiety, and improving well-being: a Delphi method study.
Previous research suggests benefits of yoga in reducing depression and anxiety. However, common concerns in reviews of the research include lack of detail, rationale and consistency of approach of interventions used. Issues related to heterogeneity include amount, types and delivery of yoga interventions. This study aims to document consensus-based recommendations for consistency of yoga interventions for reducing depression and anxiety. The Delphi method was used to establish consensus from experienced yoga teachers. Thirty-three eligible teachers were invited to participate, from four different countries. Two rounds of an online survey were sent to participants. The first round sought initial views. The second round sought consensus on a summary of those views. Survey questions related to frequency and duration (dosage) of the yoga, approaches and techniques to be included or avoided, and training and experience for yoga teachers. Twenty-four teachers agreed to participate. Eighteen completed the second round (n = 18). General consensus (>75% of participants in agreement) was achieved on parameters of practice (dosage): an average of 30 to 40 minutes, to be done 5 times per week, over a period of 6 weeks. Numerous recommendations for yoga techniques to include or avoid were collected in the first round. The second round produced a consensus statement on those recommendations. Breath regulation and postures were considered very important or essential for people with depression; and relaxation, breath regulation and meditation being very important or essential for people with anxiety. Other recommended components also achieved consensus. There was also general consensus that it is very important or essential for teachers to have a minimum of 500 training hours over 2 years, at least 2 years teaching experience, training in developing personalised yoga practices, training in yoga for mental health, and professional supervision or mentoring. The Delphi process has achieved a consensus statement on the application of yoga for reducing anxiety and depression. This consensus provides a checklist for identification of commonalities and evaluation of past research. Future research can proceed to develop and evaluate consensus-based yoga intervention protocols for the reduction of anxiety and depression, and improvements in well-being.


Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis.
Myasthenia gravis is usually caused by autoantibodies to the acetylcholine receptor (AChR). The AChR is clustered and anchored in the postsynaptic membrane of the neuromuscular junction (NMJ) by a cytoplasmic protein called rapsyn. We previously showed that resistance to experimental autoimmune myasthenia gravis (EAMG) in aged rats correlates with increased rapsyn concentration at the NMJ. It is possible, therefore, that endogenous rapsyn expression may be an important determinant of AChR loss and neuromuscular transmission failure in the human disease, and that upregulation of rapsyn expression could be used therapeutically. To examine first a potential therapeutic application of rapsyn upregulation, we induced acute EAMG in young rats by passive transfer of AChR antibody, mAb 35, and used in vivo electroporation to over-express rapsyn unilaterally in one tibialis anterior. We looked at the compound muscle action potentials (CMAPs) in the tibialis anterior, at rapsyn and AChR expression by quantitative radioimmunoassay and immunofluorescence, and at the morphology of the NMJs, comparing the electroporated and untreated muscles, as well as the control and EAMG rats. In control rats, transfected muscle fibres had extrasynaptic rapsyn aggregates, as well as slightly increased rapsyn and AChR concentrations at the NMJ. In EAMG rats, despite deposits of the membrane attack complex, the rapsyn-overexpressing muscles showed no decrement in the CMAPs, no loss of AChR, and the majority had normal postsynaptic folds, whereas endplates of untreated muscles showed typical AChR loss and morphological damage. These data suggest not only that increasing rapsyn expression could be a potential treatment for selected muscles of myasthenia gravis patients, but also lend support to the hypothesis that individual differences in innate rapsyn expression could be a factor in determining disease severity.


Hydrogen-rich saline attenuates lung ischemia-reperfusion injury in rabbits.
Hydrogen gas, an antioxidant agent, was found to protect against cerebral and myocardial ischemia-reperfusion (I/R) injury. In the present study, we investigated the effect of hydrogen-rich saline (HRS) on the I/R-induced lung injury. Left lung of male New Zealand White rabbits rendered normothermic ischemia for 60 min and reperfused for up to 240 min. Treated animals received intraperitoneal injection of 5 mL/kg HRS or the same volume of normal saline 10 min before the start of reperfusion. Blood and lung tissue samples were obtained for blood gas and biochemical analyses. The tissues obtained from lower lobe of left lung were used for histologic examination. After 240 min of reperfusion, intraperitoneal administration of HRS increased PaO2/FiO2 ratio and superoxide dismutase activities, and decreased malondialdehyde contents, proinflammatory cytokines expression, and myeloperoxidase activities, along with reduced wet/dry ratio and histologic injury scores (P < 0.05 versus I/R group). These results suggest that intraperitoneal administration of HRS before reperfusion protects the lung from I/R injury. The protective effect seems to be closely related to regulating oxidative damage and antioxidant enzyme activities and neutrophil infiltration.


Synthesis and structure determination of the adducts formed by electrochemical oxidation of the potent carcinogen dibenzo[a,I]pyrene in the presence of nucleosides.
Because dibenzo[a,l]pyrene (DBP) is the most potent known carcinogenic aromatic hydrocarbon, reference adducts formed by reaction of deoxyribonucleosides with electrophilic intermediates of DBP are essential for identifying the structures of adducts formed in biological systems. Electrochemical oxidation of DBP in the presence of nucleosides leads to adducts from DBP.+. When 6.8 equiv of charge are consumed, three adducts are formed with dG: 7-(DBP-10-yl)Gua (89%), 8-(DBP-10-yl)dG (2%), and 8-(DBP-10-yl)Gua (2%). With 10 equiv of charge, however, only two adducts are formed: 7-(DBP-10-yl)Gua (89%) and 8-(DBP-10-yl)Gua (4%). Anodic oxidation of 8-(DBP-10-yl)dG yields 8-(DBP-10-yl)Gua. Anodic oxidation of DBP in the presence of G produces 7-(DBP-10-yl)Gua (27%) and 8-(DBP-10-yl)G (9%). Anodic oxidation of DBP in the presence of dA affords two adducts, N6-(DBP-10-yl)dA (28%) and 7-(DBP-10-yl)Ade (12%), whereas anodic oxidation in the presence of A produces only N6-(DBP-10-yl)A (24%). The structures of the adducts were elucidated by using UV, NMR, and MS. Formation of these adducts demonstrates that DBP.+ reacts at C-10 with nucleophiles. The most reactive nucleophilic groups for the Gua moiety are the N-7 and C-8, whereas for the Ade moiety they are N-7 and the 6-amino group.


Study of the cutaneous electric potentials and the perception threshold to an electric stimulus in diabetic patients with and without clinical neuropathy.
Clinical heterogeneity of diabetic peripheral neuropathy could express a neurophysiological and electrophysiological heterogeneity possibly related with the dissociated metabolic susceptibility of the difference types of nerve fibres and endings. To evaluate the functional status of the skin autonomous nervous system and of the deep pain sensitivity system in diabetics we studied two electrophysiological parameters skin electrical potential (using Digital Multimeter 3466 Hewlet Packard, USA) and the perception threshold (microA) at an electrical stimulus (spike wave, 0.5 m sec duration) 1 cm deeply applied through 2 acupuncture needles placed 30 cm distance each other, in 3 groups: Ia-18 diabetic patients with clinical signs of neuropathy (12 M, 6 F, aged 55 +/- 17 yrs); Ib - 17 diabetic patients without clinical signs of diabetic neuropathy (12 M, 5 F, aged 57 +/- 16 yrs); I1 - 10 age and sex matched non-diabetic controls. Our data show: a higher mean value of the potential in the acupuncture points as against neighbour areas, both in non-diabetic control (- 111 +/- 25 mV v.s. -81 +/- 29 mV, p less than 0.05) and in diabetics (-85 +/- 43 mV v.s. -58 +/- 25 mV, p less than 0.01); a lower mean value of the electrical potentials in diabetic with clinical signs of neuropathy as against in those without clinical signs of neuropathy (-66 +/- 29 mV v.s. -108 +/- 43 mV, p less than 0.01): a higher mean value of the perception threshold in diabetics with clinical signs of neuropathy as against in diabetics without clinical signs of neuropathy (213 +/- 82 microA. v.s. 102 +/- 40 microA, p less than 0.01); a significant correlation (r = -0.81) between the perception threshold and the electrical potentials of the studied points.


Radiological Evaluation of Newly Diagnosed Non-Brainstem Pediatric High-Grade Glioma in the HERBY Phase II Trial.
The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data. Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS). One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Total/near-total resection occurred in 44 of 68 (65%) Cerebral cases but in only 5 of 45 (11%) Midline cases (P < 0.05). Leptomeningeal metastases (27 cases, 13 with subependymal spread) at relapse were more frequent in Midline (17/45) than in Cerebral tumors (10/68, P < 0.05). Mean OS (14.1 months) and EFS (9.0 months) in Midline tumors were significantly lower than mean OS (20.7 months) and EFS (14.9 months) in Cerebral tumors (P < 0.05). Pseudoprogression occurred in 8 of 111 (6.2%) cases. This study has shown that the poor outcome of midline tumors (compared with cerebral) may be related to (1) lesser surgical resection, (2) H3 K27M histone mutations, and (3) higher leptomeningeal dissemination.


Neonatal Outcomes of Very Preterm or Very Low Birth Weight Triplets.
To compare the neonatal outcomes of very preterm triplets with those of matched singletons using a large international cohort. A retrospective matched-cohort study of preterm triplets and singletons born between 2007 and 2013 in the International Network for Evaluation of Outcomes in neonates database countries and matched by gestational age, sex, and country of birth was conducted. The primary outcome was a composite of mortality or severe neonatal morbidity (severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia). Unadjusted and adjusted odds ratios with 95% confidence intervals (CIs) were calculated for model 1 (maternal hypertension and birth weight z score) and model 2 (variables in model 1, antenatal steroids, and mode of birth). Models were fitted with generalizing estimating equations and random effects modeling to account for clustering. A total of 6079 triplets of 24 to 32 weeks' gestation or 500 to 1499 g birth weight and 18 232 matched singletons were included. There was no difference in the primary outcome between triplets and singletons (23.4% vs 24.0%, adjusted odds ratio: 0.91, 95% CI: 0.83-1.01 for model 1 and 1.00, 95% CI: 0.90-1.11 for model 2). Rates of severe neonatal morbidities did not differ significantly between triplets and singletons. The results were also similar for a subsample of the cohort (1648 triplets and 4944 matched singletons) born at 24 to 28 weeks' gestation. No significant differences were identified in mortality or major neonatal morbidities between triplets who were very low birth weight or very preterm and matched singletons.


The contribution of the two hemispheres to lexical decision in different languages.
Both reading words and text in Arabic is slower than in other languages, even among skilled native Arabic speakers Previously we have shown that the right hemisphere (RH) had difficulty in matching Arabic letters, and suggested that it cannot contribute to word recognition in Arabic. In this study we tested this finding directly. We used the Divided Visual Field (DVF) lexical decision (LD) paradigm to assess hemispheric function during reading. The experiment had two conditions (unilateral and bilateral). In the unilateral condition, the target stimulus was presented unilaterally to the left or the right visual field. In the bilateral condition two stimuli were presented simultaneously, and participants were cued as to which one was the target. Three groups of participants were tested: Arabic speakers, Hebrew speakers, and English speakers. Each group was tested in their native language. For Hebrew and English speakers, performance in both visual fields was significantly better in the unilateral than in the bilateral condition. For Arabic speakers, performance in the right visual field (RVF, where stimuli are presented directly to the left hemisphere) did not change in the two conditions. Performance in the LVF (when stimuli are presented directly to the right hemisphere) was at chance level in the bilateral condition, but not in the unilateral condition. We interpret these data as supporting the hypothesis that in English and Hebrew, both hemispheres are involved in LD, whereas in Arabic, the right hemisphere is not involved in word recognition.


Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation.
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.


High-intensity interval training and moderate-intensity continuous training in adults with Crohn's disease: a pilot randomised controlled trial.
This study assessed the feasibility and acceptability of two common types of exercise training-high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT)-in adults with Crohn's disease (CD). In this mixed-methods pilot trial, participants with quiescent or mildly-active CD were randomly assigned 1:1:1 to HIIT, MICT or usual care control, and followed up for 6 months. The HIIT and MICT groups were offered three exercise sessions per week for the first 12 weeks. Feasibility outcomes included rates of recruitment, retention, outcome completion, and exercise attendance. Data were collected on cardiorespiratory fitness (e.g., peak oxygen uptake), disease activity, fatigue, quality of life, adverse events, and intervention acceptability (via interviews). Over 17 months, 53 patients were assessed for eligibility and 36 (68%) were randomised (47% male; mean age 36.9 [SD 11.2] years); 13 to HIIT, 12 to MICT, and 11 to control. The exercise session attendance rate was 62% for HIIT (288/465) and 75% for MICT (320/429), with 62% of HIIT participants (8/13) and 67% of MICT participants (8/12) completing at least 24 of 36 sessions. One participant was lost to follow-up. Outcome completion rates ranged from 89 to 97%. The mean increase in peak oxygen uptake, relative to control, was greater following HIIT than MICT (2.4 vs. 0.7 mL/kg/min). There were three non-serious exercise-related adverse events, and two exercise participants experienced disease relapse during follow-up. The findings support the feasibility and acceptability of the exercise programmes and trial procedures. A definitive trial is warranted. Physical exercise remains a potentially useful adjunct therapy in CD. [ID: ISRCTN13021107].


Diacidic motifs influence the export of transmembrane proteins from the endoplasmic reticulum in plant cells.
In yeast and mammals, amino acid motifs in the cytosolic tails of transmembrane domains play a role in protein trafficking by facilitating export from the endoplasmic reticulum (ER). However, little is known about ER export signals of membrane proteins in plants. Therefore, we investigated the role of diacidic motifs in the ER export of Golgi-localized membrane proteins. We show that diacidic motifs perform a significant function in the export of transmembrane proteins to the Golgi apparatus, as mutations of these signals impede the efficient anterograde transport of multispanning, type II, and type I proteins. Furthermore, we demonstrate that diacidic motifs instigate the export of proteins that reside in the ER due to the lengths of their transmembrane domains. However, not all of the diacidic motifs in the cytosolic tails of the proteins studied were equally important in ER export. Transport of Golgi proteins was disrupted only by mutagenesis of specific diacidic signals, suggesting that the protein environment of these signals affects their function. Our findings indicate that diacidic ER export motifs are present and functional in plant membrane proteins and that they are dominant over transmembrane domain length in determining the export of proteins from the ER in plant cells.


Adaptive plasticity in female mate choice dampens sexual selection on male ornaments in the lark bunting.
Theory on the evolution of ornamental male traits by sexual selection assumes consistency in selection over time. Temporal variation in female choice could dampen sexual selection, but scant information exists on the degree to which individual female preferences are flexible. Here we show that in lark buntings sexual selection on male traits varied dramatically across years and, in some cases, exhibited reversals in the direction of selection for a single trait. We show that these shifts are probably because of flexibility in mate choice by individual females and that they parallel shifts in the male traits that predict female reproductive success in a given year. Plasticity in choice and concomitant reversals in mating patterns across time may weaken the strength of sexual selection and could maintain genetic variation underlying multiple sexual ornaments.


The use of indocyanine green angiography in arterialized-venous free flaps: Case report and insight into flap vascular physiology.
Arterialized venous flaps (AVFs) are an innovative option in hand reconstruction. Their exact vascular physiology and survival mechanisms remain unclear. We report on two hand reconstruction cases with AVFs. Indocyanine green laser angiography was used to assess vascular perfusion of the flaps. A notable change in flap perfusion was seen by 48 h post-operatively with normalization of shunting and progression to a diffuse perfusion pattern resembling traditional flaps. Flap survival was attributed to reversed shunting at the microvascular level occurring within the first 48 h post-operatively.


Correction scheme for close-range lidar returns.
Because of the effect of defocusing and incomplete overlap between the laser beam and the receiver field of view, elastic lidar systems are unable to fully capture the close-range backscatter signal. Here we propose a method to empirically estimate and correct such effects, allowing to retrieve the lidar signal in the region of incomplete overlap. The technique is straightforward to implement. It produces an optimized numerical correction by the use of a simple geometrical model of the optical apparatus and the analysis of two lidar acquisitions taken at different elevation angles. Examples of synthetic and experimental data are shown to demonstrate the validity of the technique.


In search of the active metabolites of an anticancer piperazinedione, TW01003, in rats.
TW01003, a piperazinedione derivative designed as an antimitotic agent, exhibited potent anticancer and antiangiogenesis activities in mice. However, oral administration of this compound in rats led to poor systemic bioavailability which suggested that in vivo efficacy might come from its metabolites. This report describes the identification of TW01003 metabolites in pig and Wistar rats. Following intravenous administration of TW01003, pig urine samples were subjected to sulfatase and glucuronidase treatment to monitor the biotransformation products. Rats were given TW01003 both intravenously and orally, and blood samples were collected and then analyzed by HPLC to quantitatively determine the metabolic transformation of TW01003 to its metabolite. A sulfate conjugate, TW01003 sulfate, was identified as the major metabolite for TW01003 after intravenous injection in both pig and rats. However, in rats, the glucuronide conjugate became major metabolite 30 min after TW01003 oral dosing. Pharmacokinetic analysis after intravenous administration of TW01003 indicated that TW01003 sulfate had a systemic bioavailability 2.5 times higher, volume of distribution three times higher, residence time seven times longer, and clearance rate 2.3 times lower compared to TW01003. Our results indicate that the potent anticancer and antiangiogenesis activities of TW01003 might not come from TW01003 per se but from its metabolites TW01003 sulfate.


Tear lipocalin and lysozyme in Sjögren and non-Sjögren dry eye.
To evaluate the concentration of tear lipocalin, lysozyme, and total protein in Sjögren's Syndrome (SS), non-Sjögren's keratoconjunctivitis sicca (KCS), and non-dry-eyed (NDE) individuals. Seventy-six subjects were recruited for this study: 25 SS subjects; 25 KCS subjects, and 26 NDE individuals. Symptoms were measured with a visual analogue scale. Tear flow was measured by the Schirmer I test without anesthesia. Tears were collected using an eye wash technique. Total tear protein was quantified using the DC Protein Assay Kit. Tear lipocalin and lysozyme were quantified via Western blotting performed on a Phast System. By definition, the SS and KCS groups both had significantly lower mean Schirmer scores (5.12 +/- 5.96 mm and 7.84 +/- 7.35 mm) compared with the NDE group (23.83 +/- 7.85 mm; p < 0.0001). There was no difference in mean Schirmer scores between SS and KCS groups (p = 0.19). The tear film of the SS group was characterized by significantly reduced (p < 0.0001) total protein and lipocalin concentrations compared with both KCS and NDE groups. No difference between the KCS and NDE groups was found in total protein (p = 0.92) or lipocalin (p = 0.19) concentration. In contrast, the concentration of tear film lysozyme was found to be statistically similar in all three groups examined. No statistically significant correlation was found in any group between mean Schirmer values compared with total protein, lipocalin or lysozyme concentration. Our data demonstrate a biochemical distinction between the Sjögren's group compared with both KCS and control groups, in that both tear lipocalin and total tear protein were significantly reduced. Although correlations were not found between protein measurements and tear flow, a combination of tests including Schirmer I and quantitation of tear film biomarkers may allow for the identification of SS patients without the need for invasive testing.


The durability of endoscopic third ventriculostomy and ventriculoperitoneal shunts in children with hydrocephalus following posterior fossa tumor resection: a systematic review and time-to-failure analysis.
OBJECTIVE Up to one-third of patients with a posterior fossa brain tumor (PFBT) will experience persistent hydrocephalus mandating permanent CSF diversion. The optimal hydrocephalus treatment modality is unknown; the authors sought to compare the durability between endoscopic third ventriculostomy (ETV) and ventriculoperitoneal shunt (VPS) therapy in the pediatric population. METHODS The authors conducted a systematic review of articles indexed in PubMed between 1986 and 2016 describing ETV and/or VPS treatment success/failure and time-to-failure rate in patients < 19 years of age with hydrocephalus related to a PFBT. Additionally, the authors conducted a retrospective review of their institutional series of PFBT patients requiring CSF diversion. Patient data from the systematic review and from the institutional series were aggregated and a time-to-failure analysis was performed comparing ETV and VPS using the Kaplan-Meier method. RESULTS A total of 408 patients were included from 12 studies and the authors' institutional series: 284 who underwent ETV and 124 who underwent VPS placement. The analysis included uncontrolled studies with variable method and timing of CSF diversion and were subject to surgeon bias. No significant differences between cohorts were observed with regard to age, sex, tumor grade or histology, metastatic status, or extent of resection. The cumulative failure rate of ETV was 21%, whereas that of VPS surgery was 29% (p = 0.105). The median time to failure was earlier for ETV than for VPS surgery (0.82 [IQR 0.2-1.8] vs 4.7 months [IQR 0.3-5.7], p = 0.03). Initially the ETV survival curve dropped sharply and then stabilized around 2 months. The VPS curve fell gradually but eventually crossed below the ETV curve at 5.7 months. Overall, a significant survival advantage was not demonstrated for one procedure over the other (p = 0.21, log-rank). However, postoperative complications were higher following VPS (31%) than ETV (17%) (p = 0.012). CONCLUSIONS ETV failure occurred sooner than VPS failure, but long-term treatment durability may be higher for ETV. Complications occurred more commonly with VPS than with ETV. Limited clinical conclusions are drawn using this methodology; the optimal treatment for PFBT-related hydrocephalus warrants investigation through prospective studies.


Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults.
Alzheimer's disease (AD) is the most common cause of cognitive dysfunction in older adults. The pathological hallmarks of AD such as beta amyloid (Aβ) aggregation and neurometabolic change, as indicated by altered myo-inositol (mI) and N-acetylaspartate (NAA) levels, typically precede the onset of cognitive dysfunction by years. Furthermore, cerebrovascular disease occurs early in AD, but the interplay between vascular and neurometabolic brain change is largely unknown. Thirty cognitively normal older adults (age = 70 ± 5.6 years, Mini-Mental State Examination = 29.2 ± 1) received 11-C-Pittsburgh Compound B positron emission tomography for estimating Aβ-plaque density, 7 Tesla fluid-attenuated inversion recovery magnetic resonance imaging for quantifying white matter hyperintensity volume as a marker of small vessel cerebrovascular disease and high-resolution magnetic resonance spectroscopic imaging at 7 Tesla, based on free induction decay acquisition localized by outer volume suppression to investigate tissue-specific neurometabolism in the posterior cingulate and precuneus. Aβ (β = 0.45, p = 0.018) and white matter hyperintensities (β = 0.40, p = 0.046) were independently and interactively (β = -0.49, p = 0.026) associated with a higher ratio of mI over NAA (mI/NAA) in the posterior cingulate and precuneus gray matter but not in the white matter. Our data suggest that cerebrovascular disease and Aβ burden are synergistically associated with AD-related gray matter neurometabolism in older adults.