Microfluidic device enabled quantitative time-lapse microscopic-photography for phenotyping vegetative and reproductive phases in Fusarium virguliforme, which is pathogenic to soybean.
Time-lapse microscopic-photography allows in-depth phenotyping of microorganisms. Here we report development of such a system using a microfluidic device, generated from polydimethylsiloxane and glass slide, placed on a motorized stage of a microscope for conducting time-lapse microphotography of multiple observations in 20 channels simultaneously. We have demonstrated the utility of the device in studying growth, germination and sporulation in Fusarium virguliforme that causes sudden death syndrome in soybean. To measure the growth differences, we developed a polyamine oxidase fvpo1 mutant in this fungus that fails to grow in minimal medium containing polyamines as the sole nitrogen source. Using this system, we demonstrated that the conidiospores of the pathogen take an average of five hours to germinate. During sporulation, it takes an average of 10.5 h for a conidiospore to mature and get detached from its conidiophore for the first time. Conidiospores are developed in a single conidiophore one after another. The microfluidic device enabled quantitative time-lapse microphotography reported here should be suitable for screening compounds, peptides, micro-organisms to identify fungitoxic or antimicrobial agents for controlling serious plant pathogens. The device could also be applied in identifying suitable target genes for host-induced gene silencing in pathogens for generating novel disease resistance in crop plants.


Turnover intention and coping strategies among older nursing assistants in China: a qualitative study.
With the increasing aging population, older nursing assistants have made significant contributions to institutional eldercare. However, there is a high turnover rate among these workers, and it is crucial to address this issue and find ways to stabilize the workforce. This study aimed to explore the factors influencing turnover intention and coping strategies among older nursing assistants, in order to provide targeted assistance and guidance to reduce their intention to resign and ultimately lower the turnover rate. Qualitative research methods were employed to conduct semi-structured interviews with older nursing assistants in Changsha. The data obtained from these interviews were then analyzed using a phenomenological analysis approach and NVIVO (QSR International, Doncaster, Australia) software version 11.0. It is found that several factors influence turnover intention among older nursing assistants. Which include work pay, work environment, professional identity, external motivation, and work pressure. Additionally, the coping strategies employed by these individuals in relation to their intention to resign include self-regulation, seeking support, self-improvement, and exploring motivation. It is also evident from our study that reducing the turnover intention of older nursing assistants requires a collaborative effort from older adult care institutions, functional departments, and eldercare nursing assistants themselves. By addressing the factors influencing turnover intention and providing support and resources for coping strategies, we can work towards stabilizing the workforce and improving institutional eldercare.


The Variety in the Common Theme of Translation Inhibition by Type II Toxin-Antitoxin Systems.
Type II Toxin-antitoxin (TA) modules are bacterial operons that encode a toxic protein and its antidote, which form a self-regulating genetic system. Antitoxins put a halter on toxins in many ways that distinguish different types of TA modules. In type II TA modules, toxin and antitoxin are proteins that form a complex which physically sequesters the toxin, thereby preventing its toxic activity. Type II toxins inhibit various cellular processes, however, the translation process appears to be their favorite target and nearly every step of this complex process is inhibited by type II toxins. The structural features, enzymatic activities and target specificities of the different toxin families are discussed. Finally, this review emphasizes that the structural folds presented by these toxins are not restricted to type II TA toxins or to one particular cellular target, and discusses why so many of them evolved to target translation as well as the recent developments regarding the role(s) of these systems in bacterial physiology and evolution.


3D faces are recognized more accurately and faster than 2D faces, but with similar inversion effects.
Recognition of faces typically occurs via holistic processing where individual features are combined to provide an overall facial representation. However, when faces are inverted, there is greater reliance on featural processing where faces are recognized based on their individual features. These findings are based on a substantial number of studies using 2-dimensional (2D) faces and it is unknown whether these results can be extended to 3-dimensional (3D) faces, which have more depth information that is absent in the typical 2D stimuli used in face recognition literature. The current study used the face inversion paradigm as a means to investigate how holistic and featural processing are differentially influenced by 2D and 3D faces. Twenty-five participants completed a delayed face-matching task consisting of upright and inverted faces that were presented as both 2D and 3D stereoscopic images. Recognition accuracy was significantly higher for 3D upright faces compared to 2D upright faces, providing support that the enriched visual information in 3D stereoscopic images facilitates holistic processing that is essential for the recognition of upright faces. Typical face inversion effects were also obtained, regardless of whether the faces were presented in 2D or 3D. Moreover, recognition performances for 2D inverted and 3D inverted faces did not differ. Taken together, these results demonstrated that 3D stereoscopic effects influence face recognition during holistic processing but not during featural processing. Our findings therefore provide a novel perspective that furthers our understanding of face recognition mechanisms, shedding light on how the integration of stereoscopic information in 3D faces influences face recognition processes.


A quantitative method for estimating hepatic blood flow using a dual-input single-compartment model.
The purpose of this study was to investigate the accuracy of a quantitative method for estimating arterial hepatic blood flow and portal hepatic blood flow separately using a dual-input single-compartment model compared with the maximum slope method using computer simulations and clinical data. In computer simulations, the rate constants for the transfer of contrast agent (CA) from the hepatic artery to the liver (K(1a)), from the portal vein to the liver (K(1p)) and from the liver to the blood (k(2)) were estimated from simulated time-density curves with various transit times of CA from the aorta to the liver (tau(a)) and from the portal vein to the liver (tau(p)) using the linear least-squares (LLSQ) method. In clinical studies, dynamic CT data were acquired from 27 patients, and parametric maps of K(1a), K(1p) and k(2) were generated by applying the LLSQ method pixel by pixel. In simulation studies, tau(a) and tau(p) were found to have a large and a small effect on the estimates of K(1a) and K(1p), respectively. In clinical studies, the K(1a) and K(1p) values estimated with the maximum slope method were underestimated by 60+/-29% and 37+/-12%, respectively, compared with those estimated by the LLSQ method. In conclusion, our results suggest that correction of tau(a) is necessary for accurately estimating K(1a) and K(1p). Our method is therefore promising for the evaluation of hepatic blood flow in various liver diseases because it allows us to evaluate arterial hepatic blood flow and portal hepatic blood flow separately and visually.


Encoding of three-dimensional structure-from-motion by primate area MT neurons.
We see the world as three-dimensional, but because the retinal image is flat, we must derive the third dimension, depth, from two-dimensional cues. Image movement provides one of the most potent cues for depth. For example, the shadow of a contorted wire appears flat when the wire is stationary, but rotating the wire causes motion in the shadow, which suddenly appears three-dimensional. The neural mechanism of this effect, known as 'structure-from-motion', has not been discovered. Here we study cortical area MT, a primate region that is involved in visual motion perception. Two rhesus monkeys were trained to fixate their gaze while viewing two-dimensional projections of transparent, revolving cylinders. These stimuli appear to be three-dimensional, but the surface order perceived (front as opposed to back) tends to reverse spontaneously. These reversals occur because the stimulus does not specify which surface is in front or at the back. Monkeys reported which surface order they perceived after viewing the stimulus. In many of the neurons tested, there was a reproducible change in activity that coincided with reversals of the perceived surface order, even though the stimulus remained identical. This suggests that area MT has a basic role in structure-from-motion perception.


Applications of Next-generation Sequencing in Systemic Autoimmune Diseases.
Systemic autoimmune diseases are a group of heterogeneous disorders caused by both genetic and environmental factors. Although numerous causal genes have been identified by genome-wide association studies (GWAS), these susceptibility genes are correlated to a relatively low disease risk, indicating that environmental factors also play an important role in the pathogenesis of disease. The intestinal microbiome, as the main symbiotic ecosystem between the host and host-associated microorganisms, has been demonstrated to regulate the development of the body's immune system and is likely related to genetic mutations in systemic autoimmune diseases. Next-generation sequencing (NGS) technology, with high-throughput capacity and accuracy, provides a powerful tool to discover genomic mutations, abnormal transcription and intestinal microbiome identification for autoimmune diseases. In this review, we briefly outlined the applications of NGS in systemic autoimmune diseases. This review may provide a reference for future studies in the pathogenesis of systemic autoimmune diseases.


Variation in the dielectric properties of freshly excised colorectal cancerous tissues at different tumor stages.
The study was designed to identify differences in the dielectric properties of ex vivo colorectal cancerous tissues at different tumor stages. To date, 130 freshly excised colorectal cancerous specimens underwent measurement of both relative permittivity and conductivity on the serosal and mucosal surfaces of the carcinoma nidus, and the mucosa of the surgical resection margin ranging from 50 to 500 MHz at the Larmor frequencies. Tumor node metastasis staging was determined according to pathological reports for each patient. There were statistically significant differences in the relative permittivity of both colorectal cancerous serosa and mucosa among stages ≤I, II, III, and IV and between stages ≤II and ≥III (P < 0.05) at most frequencies under 300 MHz; statistically significant differences in conductivity were also observed for most of the measured frequencies (P < 0.05). The significant differences in dielectric characteristics among tumor stages, especially between early and advanced stages, have value for selecting appropriate surgical strategies. The presented ex vivo data provide important information for magnetic resonance electrical properties tomography in vivo system because the frequencies of 64 MHz (1.5T) and 128 MHz (3T) are usually used in clinical settings. Bioelectromagnetics. 38:522-532, 2017. © 2017 Wiley Periodicals, Inc.


Learning effect of short-wavelength automated perimetry in patients with ocular hypertension.
To evaluate the learning effect of short-wavelength automated perimetry (SWAP) on a group of patients with ocular hypertension experienced with standard automated perimetry (SAP). Thirty patients with ocular hypertension underwent 5 full-threshold SWAP tests at intervals of 7+/-2 days. The parameters investigated to detect a learning effect were duration, the perimetric indices, and the number of points with a P of <5% and 1% in the total and pattern deviation maps. Differences in learning effect were also evaluated by comparing the sensitivities of central, paracentral, and peripheral areas, hemifields and quadrants. Learning effects were demonstrated for mean defect (P<0.0001, analysis of variance), duration (P=0.0001), the number of points with P<5% in the pattern deviation map (P=0.003), and short fluctuations (P=0.03). The effect was greater in the peripheral than in central areas (P=0.04). Mean defect was the most sensitive parameter, for which the learning effect was statistically significant between the first and the fifth test. The results of this study demonstrate a significant learning effect at full-threshold SWAP. This may limit the efficacy of this kind of perimetry in detecting early glaucoma, and should therefore be carefully considered when creating normative databases for new SWAP strategies.


Dysfunctional HDL as a Therapeutic Target for Atherosclerosis Prevention.
Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction.


Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation.
The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and β2-microglobulin (β2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts < 100 × 109/L, Scr level ≥ 177 μmol/L, serum β2-MG ≥ 5.5 μmol/L, serum calcium (Ca) ≥ 2.75 mmol/L, and thalidomide use were associated with both OS and PFS in MM patients. Age ≥ 60 was associated with OS and Ig isotype was associated with PFS in MM patients. Moreover, blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival.


Economic impact of medication error: a systematic review.
Medication error is a significant source of morbidity and mortality among patients. Clinical and cost-effectiveness evidence are required for the implementation of quality of care interventions. Reduction of error-related cost is a key potential benefit of interventions addressing medication error. The aim of this review was to describe and quantify the economic burden associated with medication error. PubMed, Cochrane, Embase, CINAHL, EconLit, ABI/INFORM, Business Source Complete were searched. Studies published 2004-2016 assessing the economic impact of medication error were included. Cost values were expressed in Euro 2015. A narrative synthesis was performed. A total of 4572 articles were identified from database searching, and 16 were included in the review. One study met all applicable quality criteria. Fifteen studies expressed economic impact in monetary terms. Mean cost per error per study ranged from €2.58 to €111 727.08. Healthcare costs were used to measure economic impact in 15 of the included studies with one study measuring litigation costs. Four studies included costs incurred in primary care with the remaining 12 measuring hospital costs. Five studies looked at general medication error in a general population with 11 studies reporting the economic impact of an individual type of medication error or error within a specific patient population. Considerable variability existed between studies in terms of financial cost, patients, settings and errors included. Many were of poor quality. Assessment of economic impact was conducted predominantly in the hospital setting with little assessment of primary care impact. Limited parameters were used to establish economic impact. Copyright © 2017 John Wiley & Sons, Ltd.


Human Resources for Health in Haryana, India: What can be Done Better?
Health systems in developing countries suffers from both input and productivity issues. We examined the status of three domains of human resources for health, i.e., availability and distribution, capacity and productivity, and motivation and job-satisfaction, of the health-care workforce employed in the public health system of Haryana, a North Indian state. The primary data were collected from 377 public health facilities and 1749 healthcare providers across 21 districts. The secondary data were obtained from government reports in the public domain. Bivariate and multivariate statistical techniques were used for evaluating district performances, making inter-district comparisons and identifying determinants of motivation and job-satisfaction of the clinical cadres. We found 3.6 core health-care workers (doctors, staff nurses, and auxiliary nurses-midwives) employed in the public health-care system per 10,000 population, ranging from 1.35 in Faridabad district to 6.57 in Panchkula district. Around 78% of the sanctioned positions were occupied. A number of inpatient hospitalizations per doctor/nurses per month were 17 at the community health center level and 29 at the district hospital level; however, significant differences were observed among districts. Motivation levels of community health workers (85%) were higher than clinical workforce (78%), while health system administrators had lowest motivation and job satisfaction levels. Posting at primary healthcare facility, contractual employment, and co-habitation with family at the place of posting were found to be the significant motivating factors. A revamp of governance strategies is required to improve health-care worker availability and equitable distribution in the public health system to address the observed geographic variations. Efforts are also needed to improve the motivation levels of health system administrators, especially in poorly performing districts and reduce the wide gap with better-off districts.


Reinforcing adherence to antihypertensive medications.
This pilot study evaluated a reinforcement intervention to improve adherence to antihypertensive therapy. Twenty-nine participants were randomized to standard care or standard care plus financial reinforcement for 12 weeks. Participants in the reinforcement group received a cell phone to self-record videos of adherence, for which they earned rewards. These participants sent videos demonstrating on-time adherence 97.8% of the time. Pill count adherence differed significantly between the groups during treatment, with 98.8%±1.5% of pills taken during treatment in the reinforcement condition vs 92.6%±9.2% in standard care (P<.002). Benefits persisted throughout a 3-month follow-up, with 93.8%±9.3% vs 78.0%±18.5% of pills taken (P<.001). Pill counts correlated significantly (P<.001) with self-reports of adherence, which also differed between groups over time (P<.01). Systolic blood pressure decreased modestly over time in participants overall (P<.01) but without significant time-by-group effects. These results suggest that reinforcing medication adherence via cellular phone technology and financial reinforcement holds potential to improve adherence.


The prevalence of ACPA is lower in rheumatoid arthritis patients with an older age of onset but the composition of the ACPA response appears identical.
Rheumatoid arthritis (RA) consists of two syndromes, one autoantibody-positive and one autoantibody-negative. Existing data on the relation between age of onset and prevalence of autoantibodies were conflicting. Therefore this multicohort study assessed the age of onset in relation to the presence of autoantibodies. The association with characteristics of the anti-citrullinated protein antibodies (ACPA) response was also explored. The 1987 criteria-positive RA patients included in the Leiden EAC, BARFOT, ESPOIR, Umeå and Lund cohorts (n = 3321) were studied at presentation for age of onset and the presence of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies. Logistic regression analyses were performed; effect sizes were summarized in inverse-weighted meta-analyses. Within ACPA-positive RA, ACPA level was studied in all cohorts; ACPA isotypes, ACPA fine specificity and ACPA avidity index and clinical characteristics were studied in the Leiden EAC. From the age of 50 onward, the proportion of ACPA-negative RA patients increased with age in the five cohorts. Similar observations were made for RF and anti-CarP. The composition of the ACPA response did not change with increasing age of onset with respect to titer, isotype distribution, fine specificity and avidity index. With increasing age of onset, RA patients smoked less often, had higher acute phase reactants and more often had a sub(acute) symptom onset. Data of five cohorts revealed that with older age of onset ACPA-negative RA is more frequent than ACPA-positive RA, while characteristics of ACPA-positive RA as judged by the composition of the ACPA response appeared not age dependent. Further biologic studies are needed to characterize the pathogenesis of ACPA-negative polyarthritis at older age and to promote personalized treatment decisions in ACPA-negative patients in daily practice.


Dipyrone versus paracetamol: a double-blind study in typhoid fever.
In a double-blind study in patients with typhoid fever 25 patients received 500 mg dipyrone and 28 received 500 mg paracetamol. Rectal temperature and pulse records were monitored every 30 min. The onset of anti-pyresis in patients given dipyrone (30 min) was significantly different from those given paracetamol (1 h). The area under the time-temperature curves was significantly greater for patients given dipyrone. The sum of the reduction in temperature at all times significantly favoured patients who had been given dipyrone. Both treatments were well tolerated.


Coherent anti-Stokes Raman metrology of phonons powered by photonic-crystal fibers.
Coherent anti-Stokes Raman scattering (CARS) is used to measure the amplitude, the dephasing lifetime, and parameters of optical nonlinearities of optical phonons in a synthetic diamond film. A compact CARS apparatus demonstrated in this work relies on the use of an unamplified 70 fs 340 mW Cr:forsterite laser output and photonic-crystal fibers optimized for the generation of wavelength-tunable Stokes field and the spectral compression of the probe pulse.


Interlocking Nailing Versus Plating in Tibial Shaft Fractures in Adults: A Comparative Study.
Tibial diaphyseal fractures are the commonest long bone fractures in adults, most commonly managed by intramedullary interlocking nailing. However, several meta-analysis show that locking plate osteosynthesis is equally effective in managing tibial diaphyseal fractures and are associated with less number of complications. To compare the results of fixation of tibial fractures following plating and nailing in terms of union, patient satisfaction and complications. A hospital based non randomized clinical trial was performed from September 2013 to August 2016 where closed or open diaphyseal or metaphyseo- diaphyseal fractures of the tibia (closed or open Gustilo Anderson type 1 through 3B) were included. Simple sequential allocation was used for allotting the patients to two groups, one for interlocking nailing and other for plating. The patients were followed up for clinical, radiographic and functional results. Forty patients with 41 involved limbs completed follow up for one year. The duration of surgery and average blood loss during surgery was 75.45±3.03 minutes and 165.00±5.31 ml respectively in case of nailing and 85.05±2.54 minutes and184.29±5.33 ml respectively in case of plating and their difference was statistically significant. In our study union was achieved in less than 20 weeks in 29 (70.8%) of the patients and 25-30 weeks in nine (22%) cases. The average time of union in our study was 19.55±0.69 weeks in case of interlocking nailing and 20.38±1.39 weeks in case of plating and there was no statistically significant difference between the two. However, there is statistically significant difference in the functional score in between the two groups in terms of Lower Extremity Functional Score (LEFS). Delayed union in one case of nailing and two cases of plating, valgus malunion in one case of nailing and joint stiffness in two cases each of nailing and plating were the major complications observed. There was no difference between the two modalities in terms of fracture union. Complications were lesser but more serious in case of plating. Patient satisfaction was more with plating.


Don't ask, sometimes tell. A survey of men who have sex with men sexual orientation disclosure in general practice.
Despite advances in lesbian, gay, bisexual and transgender equality in recent years, some men who have sex with men remain at increased risk of ill-health. Positive interventions in primary care include psychological support and strategies for risk reduction. It is important that men who have sex with men can disclose sexual orientation in primary care. To quantify disclosure of sexual orientation by men who have sex with men attending general practice and identify barriers to disclosure we surveyed a group of Scottish men. A questionnaire was distributed by voluntary organisations and the National Health Service in the West of Scotland, to rural and urban populations. Two hundred and four gave evaluable responses, with all ages represented. A total of 199 (98%) were registered with a General Practitioner and 167 (83%) attended in the previous year. A total of 81 (40%) stated staff were aware of their sexual orientation. A total of 93/121 (75%) men who have sex with men whose GP was unaware stated this was because they had never been asked. A total of 36/81(44%) men who have sex with men rated support from practices since disclosure as 'excellent' and qualitative responses were positive. It is reassuring that almost all respondents were registered with GPs and attending primary care services. However, only 40% had disclosed sexual orientation. This was not because of fear of negative impact on care but because men who have sex with men felt it was irrelevant to their attendance. GPs appear to be reluctant to raise the issue of sexual orientation without prompting.


Identification of uhp polypeptides and evidence for their role in exogenous induction of the sugar phosphate transport system of Escherichia coli K-12.
Cells of Escherichia coli possess a transport system that catalyzes the accumulation, in unaltered form, of a variety of sugar phosphates. Induction of the transport activity occurs in response to external glucose 6-phosphate and does not require detectable entry of this inducer. To define the genes that encode the Uhp transport system and those that mediate its exogenous induction, transposon insertions were isolated and mapped within a 6.5-kilobase HindIII-BamHI fragment that carries the entire uhp region. The transposon insertions were transferred by homologous recombination onto the chromosome to test their effect on Uhp expression when all genes were present in single copy number. The complementation behavior of plasmids carrying the insertions or subcloned fragments of the region was compared with their polypeptide coding capacity in maxicells. These studies defined three uhp regulatory genes (uhpABC), all of which are necessary for expression of the uhpT gene, which encodes the transporter. The products of uhpB and uhpC are not required when uhpA is present on a multicopy plasmid. The four genes, uhpA, uhpB, uhpC, and uhpT, are transcribed in the same direction, and their products have apparent molecular weights of 25,000, 48,000, 20,000, and 38,000, respectively. The UhpB and UhpT polypeptides are associated with the membrane fraction. These results led to a model of regulation in which the UhpB and UhpC regulatory proteins prevent the ability of UhpA to activate transcription of the uhpT gene under noninducing conditions.


A Partial Sulfuration Strategy Derived Multi-Yolk-Shell Structure for Ultra-Stable K/Na/Li-ion Storage.
Metal sulfides are attractive anodes for alkali metal ion batteries due to the high theoretical capacity, while their practical implementation is hampered by the inherent poor conductivity and vast volume variation during cycles. Approaching rational designed microstructures with good stability and fast charge transfer is of great importance in response to these issues. Herein, a partial sulfuration strategy for the rational construction of multi-yolk-shell (m-Y-S) structures, from which multiple Fe1- x S nanoparticles are confined within hollow carbon nanosheet with tunable interior void space is reported. As anode materials, the m-Y-S Fe1- x S@C composite can display high capacity and excellent rate capability (134, 365, and 447 mA h g-1 for K+ , Na+ , and Li+ storage at 20 A g-1 ). Remarkably, it exhibits ultra-stable potassium storage up to 1200, 6000, and 20 000 cycles under current densities of 0.1, 0.5, and 1 A g-1 , which is much superior to previous yolk-shell structures and metal-sulfide anodes. Based on comprehensive experimental analysis and theoretical calculations, the exceptional performance of m-Y-S structure can be ascribed to the optimized interior void space for good structure stability, as well as the multiple connection points and conductive carbon layer for superior electron/ion transportation.


[A diagnostic approach to relatively common mild bleeding symptoms: screening of congenital mild bleeding disorders].
Although mild skin and mucosal bleeding symptoms are common in patients with inherited bleeding disorders, both can also be observed in healthy individuals. These bleeding symptoms may be caused by disorders of primary hemostasis (i.e., von Willebrand disease and platelet function disorders), mild deficiencies of clotting factors and some rare hyper fibrinolytic disorders are also included. To date, mild bleeding symptoms pose a frequent and substantial diagnostic challenge, and the definitive diagnosis of inherited bleeding disorders is not feasible in a vast majority of individuals despite an extensive laboratory workup. However, it must be diagnosed precisely to avoid severe complications and decrease bleeding risks before invasive procedures. Thus, a comprehensive diagnostic approach, from structured patient history to highly specialized laboratory diagnosis, is warranted to establish diagnosis of inherited bleeding disorders. Furthermore, the prophylaxis should be offered to prevent excessive bleeding in these patients with bleeding symptoms, even if they remain undiagnose of bleeding disorders.


Functional analysis of differentially expressed genes associated with glaucoma from DNA microarray data.
Microarray data of astrocytes extracted from the optic nerves of donors with and without glaucoma were analyzed to screen for differentially expressed genes (DEGs). Functional exploration with bioinformatic tools was then used to understand the roles of the identified DEGs in glaucoma. Microarray data were downloaded from the Gene Expression Omnibus (GEO) database, which contains 13 astrocyte samples, 6 from healthy subjects and 7 from patients suffering from glaucoma. Data were pre-processed, and DEGs were screened out using R software packages. Interactions between DEGs were identified, and networks were built using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). GENECODIS was utilized for the functional analysis of the DEGs, and GOTM was used for module division, for which functional annotation was conducted with the Database for Annotation, Visualization, and Integrated Discovery (DAVID). A total of 371 DEGs were identified between glaucoma-associated samples and normal samples. Three modules included in the PPID database were generated with 11, 12, and 2 significant functional annotations, including immune system processes, inflammatory responses, and synaptic vesicle endocytosis, respectively. We found that the most significantly enriched functions for each module were associated with immune function. Several genes that play interesting roles in the development of glaucoma are described; these genes may be potential biomarkers for glaucoma diagnosis or treatment.


Comparison of DNA decatenation by Escherichia coli topoisomerase IV and topoisomerase III: implications for non-equilibrium topology simplification.
Type II topoisomerases are essential enzymes that regulate DNA topology through a strand-passage mechanism. Some type II topoisomerases relax supercoils, unknot and decatenate DNA to below thermodynamic equilibrium. Several models of this non-equilibrium topology simplification phenomenon have been proposed. The kinetic proofreading (KPR) model postulates that strand passage requires a DNA-bound topoisomerase to collide twice in rapid succession with a second DNA segment, implying a quadratic relationship between DNA collision frequency and relaxation rate. To test this model, we used a single-molecule assay to measure the unlinking rate as a function of DNA collision frequency for Escherichia coli topoisomerase IV (topo IV) that displays efficient non-equilibrium topology simplification activity, and for E. coli topoisomerase III (topo III), a type IA topoisomerase that unlinks and unknots DNA to equilibrium levels. Contrary to the predictions of the KPR model, topo IV and topo III unlinking rates were linearly related to the DNA collision frequency. Furthermore, topo III exhibited decatenation activity comparable with that of topo IV, supporting proposed roles for topo III in DNA segregation. This study enables us to rule out the KPR model for non-equilibrium topology simplification. More generally, we establish an experimental approach to systematically control DNA collision frequency.


Association between critical limb ischemia and arterial stiffness measured by brachial artery oscillometry.
Elevated arterial stiffness is associated with increased cardiovascular mortality. The relationship between arterial stiffness and critical limb ischemia (CLI) is not well established. The objective of this study is to analyze the relationship between arterial stiffness indices and the degree of limb ischemia measured by the ankle-brachial index (ABI). A cross-sectional study comparing patients with CLI and controls. Arterial stiffness was measured using brachial artery oscillometry. The arterial stiffness indices pulse wave velocity (PWV) and augmentation index normalized to 75 beats/min (AIx@75) were determined. Multiple linear regression was applied to identify predictors of arterial stiffness indices. Patients in the CLI group had higher PWV (12.1±1.9 m/s vs. 10.1±1.9 m/s, p < 0.01) and AIx@75 (31.8±7.8% vs. 17.5±10.8%, p < 0.01) than controls. Central systolic pressure was higher in the CLI group (129.2±18.4 mmHg vs. 115.2±13.1 mmHg, p < 0.01). There was an inverse relationship between AIx@75 and ABI (Pearson coefficient = 0.24, p = 0.048), but there was no relationship between ABI and PWV (Pearson coefficient = 0.19, p = 0.12). In multiple regression analysis, reduced ABI was a predictor of elevated levels of AIx@75 (β = -25.02, p < 0.01). Patients with CLI have high arterial stiffness measured by brachial artery oscillometry. The degree of limb ischemia, as measured by the ABI, is a predictor of increased AIx@75. The increased AIx@75 observed in CLI may have implications for the prognosis of this group of patients with advanced atherosclerosis.


Heart rate variability may index emotion dysregulation in alcohol-related intimate partner violence.
Intimate partner violence is a serious public health problem that costs the United States more than $4.1 billion in direct medical and mental health costs alone. Furthermore, alcohol use contributes to more frequent and more severe intimate partner violence incidents. Compounding this problem is treatments for intimate partner violence have largely been socially informed and demonstrate poor efficacy. We argue that improvements in intimate partner treatment will be gained through systematic scientific study of mechanisms through which alcohol is related to intimate partner violence. We hypothesize that poor emotional and behavioral regulation as indexed by the respiratory sinus arrythymia measure of heart rate variability is a key mechanism between alcohol use and intimate partner violence. The present study is a placebo-controlled alcohol administration study with an emotion-regulation task that investigated heart rate variability in distressed violent and distressed nonviolent partners. We found a main effect for alcohol on heart rate variability. We also found a four-way interaction whereby distressed violent partners exhibited significant reductions in heart rate variability when acutely intoxicated and attempting to not respond to their partners evocative stimuli. These findings suggest that distressed violent partners may adopt maladaptive emotion regulation strategies such as rumination and suppression when intoxicated and attempting to not respond to partner conflict. Such strategies of emotion regulation have been shown to have many deleterious emotional, cognitive and social consequences for individuals who adopt them, possibly including intimate partner violence. These findings also highlight an important novel treatment target for intimate partner violence and suggest that novel treatments should focus on teaching effective conflict resolution and emotion-regulation strategies that may be augmented by biobehavioral treatments such as heart rate variability biofeedback.


Immediate and delayed hyperbaric oxygen therapy as a neuroprotective treatment for traumatic brain injury in mice.
Traumatic brain injury is the most common cause of death or chronic disability among people under-35-years-old. There is no effective pharmacological treatment currently existing for TBI. Hyperbaric oxygen therapy (HBOT) is defined as the inhalation of pure oxygen in a hyperbaric chamber that is pressurized higher than 1atm. HBOT offers physiological and mechanical effects by inducing a state of increased pressure and hyperoxia. HBOT has been proposed as an effective treatment for moderate traumatic brain injury (mTBI), yet the exact therapeutic window and mechanism that underlies this effect is not completely understood. HBOT was administrated for 4 consecutive days, post a mouse closed head weight drop moderate TBI (mTBI) in 2 different time lines: immediate treatment - initiated 3h post-injury and delayed treatment - initiated 7days post-injury. Behavioral cognitive tests and biochemical changes were assessed. The results were similar for both the immediate and the delayed treatments. mTBI mice exhibited impairment in learning abilities, whereas mTBI mice treated with HBO displayed significant improvement compared with the mTBI group, performing similar to the sham groups. mTBI mice had a decline in myelin basic protein, an increase in neuronal loss (NeuN staining), and an increase in the number of reactive astrocytes (GFAP). The HBO treated mice in both groups did not exhibit these changes and remained similar to the sham group. The delayed HBOT has a potential to serve as a neuroprotective treatment for mTBI with a long therapeutic window. Further research is needed for fully understanding the cellular changes.


Fluoxetine overdose in an adolescent.
The response to and management of an acute ingestion of a large quantity of fluoxetine hydrochloride in a 13-year-old boy with Tourette's syndrome and obsessive compulsive disorder is described. The patient's symptomatic course following the ingestion included a grand mal seizure, depressed ST segments on EKG, nausea, dizziness, and headache. In general, the fluoxetine was well tolerated: all of the symptoms and signs remitted spontaneously.


Numerical simulation of a continuum model of growth of thin composite films.
We present the results of extensive numerical integration in ( 1+1 ) dimensions of a set of equations that couple the Kardar-Parisi-Zhang (KPZ) equation to the time-dependent Ginzburg-Landau (TDGL) equation, recently proposed for modeling the growth of thin composite solid films. We find that for times t shorter than a crossover time t(c) the mean domain size L(t) grows logarithmically with the time, whereas for t>> t(c) L(t) grows as t(1/ z(m) ), with z(m) being nonuniversal and depending on the parameters of the model. The roughness exponent is also found to be nonuniversal. Thus, neither the dynamics of the domains' growth is governed by the TDGL equation, nor is the scaling of the surface roughness described by the KPZ equation.


Platelet-associated IgG and IgM in myelofibrosis.
Elevated levels of platelet-associated IgG and/or IgM were found in 15 of 18 patients with myelofibrosis (83%). All but 5 patients with elevated PAIg had active disease. The amounts of PAIg were not correlated to either S-Ig, platelet count or spleen size. Levels of PAIgG well above the normal range were especially found in patients with short duration of disease and/or a transitional myeloproliferative state. It is debated whether immune-mediated platelet dysfunction may be of importance for the development of bone marrow fibrosis, mediated by the release of platelet-derived growth factors in the bone marrow. Elevated PAIg may also contribute to abnormal haemostasis and thrombocytopenia in myelofibrosis.


Personal protection measures to prevent tick bites in the United States: Knowledge gaps, challenges, and opportunities.
Personal protection measures to prevent human tick encounters from resulting in bites are widely recommended as the first line of defense against health impacts associated with ticks. This includes using repellents, wearing untreated or permethrin-treated protective clothing, and conducting tick checks after coming inside, aided by removing outdoor clothing articles and running them in a dryer on high heat (to kill undetected ticks) and taking a shower/bath (to aid in detecting ticks on the skin). These measures have the benefit of incurring no or low cost, but they need to be used consistently to be most effective. In this paper, I review the level of use (acceptability combined with behavior) of the above-mentioned personal protection measures and their effectiveness to prevent tick bites and tick-borne disease. Studies on the level of use of personal protection measures to prevent tick bites have used different recruitment strategies, focused on different types of respondent populations, employed variable phrasings of survey questions relating to a given personal protection measure, and presented results based on variable frequencies of taking action. This complicates the synthesis of the findings, but the studies collectively indicate that members of the public commonly take action to prevent tick bites, most frequently by wearing untreated protective clothing or conducting tick checks (done routinely by 30 to 70% of respondents in most studies of the public), followed by showering/bathing after being outdoors or using repellents on skin/clothing (15 to 40% range), and with permethrin-treated clothing being the least frequently used tick bite prevention method (<5 to 20% range). A suite of experimental studies have shown that applying repellents or permethrin to coveralls or uniform-style clothing can result in decreased numbers of tick bites, but similar studies are lacking for members of the public wearing summer-weight clothing during normal daily activities. Moreover, a set of case-control and cross-sectional studies have explored associations between use of different personal protection measures to prevent tick bites and Lyme disease or other tick-borne infections. The results are mixed for each personal protection measure, with some studies indicating that regular use of the measure is associated with a reduction in tick-borne disease while other studies found no similar protective effect. One possible interpretation is that these personal protection measures can protect against tick-borne infection but the information gathered to date has not been sufficiently detailed to clarify the circumstances under which protection is achieved, especially with regards to frequency of use, parts of the body being protected, and use of combinations of two or more potentially protective measures. In conclusion, personal protection measures to prevent tick bites are used by the public and merit further study to better understand how they need to be used to have the greatest public health impact.


Mercury's magnetosphere after MESSENGER's first flyby.
Observations by MESSENGER show that Mercury's magnetosphere is immersed in a comet-like cloud of planetary ions. The most abundant, Na+, is broadly distributed but exhibits flux maxima in the magnetosheath, where the local plasma flow speed is high, and near the spacecraft's closest approach, where atmospheric density should peak. The magnetic field showed reconnection signatures in the form of flux transfer events, azimuthal rotations consistent with Kelvin-Helmholtz waves along the magnetopause, and extensive ultralow-frequency wave activity. Two outbound current sheet boundaries were observed, across which the magnetic field decreased in a manner suggestive of a double magnetopause. The separation of these current layers, comparable to the gyro-radius of a Na+ pickup ion entering the magnetosphere after being accelerated in the magnetosheath, may indicate a planetary ion boundary layer.


Novel technique to prevent lymphocele recurrence after laparoscopic lymphocele fenestration in renal transplant patients.
To describe the use of nonabsorbable polymer ligating (NPL) clips to prevent recurrence after laparoscopic lymphocele fenestration and to determine the efficacy and safety of this treatment in renal-transplant patients at our center. From December 2000 to October 2005, nine patients with a mean age of 38.5 years (range 26-54 years) and symptomatic lymphoceles were treated laparoscopically among 144 renal-transplant patients. The overall incidence of symptomatic lymphocele was 6.2% (9/144). The mean time from transplantation to diagnosis was 55.5 days (range 20-98 days). Patient and lymphocele characteristics, complications, recurrence rate, and outcomes of this procedure were analyzed retrospectively. Laparoscopic treatment was successful in eight patients; the other was converted to open surgery. One patient sustained an allograft-ureteral injury. The mean operative time was 90.7 minutes (range 75-120 minutes), and the mean postoperative stay was 4.1 days (range 1-7 days). Lymphocele recurrence was found in the first two patients after laparoscopic surgery without NPL clips. With a mean follow-up of 42.3 months (range 31-51 months), no recurrence was observed in patients in whom NPL clips were used to maintain the patency of the peritoneal window. No late laparoscopy-related complications occurred. Laparoscopic lymphocele fenestration with NPL clips is a safe, technically easy, and efficacious procedure for the treatment of symptomatic lymphoceles after renal transplantion.


Engaging disparities in prostate cancer: Piloting an interactive, virtual workshop to educate providers on shared decision-making for underserved populations.
Shared decision-making (SDM) is an approach to patient-centered care that is strongly recommended when counseling patients for screening and treatment of prostate cancer. However, providers report lack of comfort with SDM and particularly in disparate populations. We report our experience designing and piloting an online workshop to educate practicing urologists on SDM in diverse populations. Our objective was to create a valued interactive SDM workshop to help urologists learn to lead SDM discussions with men form underserved populations. Therefore, we tested the hypothesis that urologists would agree or strongly agree that we met our learning objectives on postcourse survey. With the support of the American Urologic Association, we developed a case-based workshop with interactive role-playing to demonstrate and teach integration of SDM into clinical care. Cases were centered around screening and treatment decisions for localized prostate cancer in diverse patients. Brief surveys were used to track success with learning objectives and urologists' satisfaction with the workshop. The session included 14 participants from 6 countries. A postworkshop survey indicated that 100% of respondents (8 of 8) "strongly agreed" that the activity met learning objectives, and 100% rated the session as "good" (1), "very good" (1), or "excellent" (6). Participants' knowledge also improved on shared decision-making concepts and the knowledge was maintained one month after the workshop. We successfully created and piloted an interactive online workshop to improve urologists' comfort using shared decision-making in caring for diverse patient populations. The course met its objectives and participant feedback for the course was positive. Sharing this process and framework for development of this intervention may inform future workshops that can be applied to medical students, residents, and providers.


Histopathological, immunohistochemical and molecular analyses of foetuses from a female dog naturally infected by Leishmania (Leishmania) infantum - Case report.
This report presents anatomo-histopathological, immunohistochemical and molecular analyses of an asymptomatic female dog naturally infected with Leishmania (Leishmania) infantum and her four pups. In addition to routine serological tests, the mother's positivity was confirmed by real-time PCR of a bone marrow sample; the placenta and ovaries, however, were negative with the same analysis. The pups presented no positivity in any of the techniques used. It is suggested that the gestational period and factors related to the female's immunological condition cause greater variability in the occurrence of vertical infection.


Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds.
Epolactaene (compound 1), a neuritogenic compound found in human neuroblastoma cells, was found to show anti-inflammatory activity in vivo in this study. DNA polymerases and DNA topoisomerase II (topo II) were some of the major molecular targets of compound 1. Since the agent seems to be a potential pharmaceutical medicine, we synthesized derivatives chemically and obtained seven compounds, 1 to 7 to screen clinically more efficient epolactaene derivatives. A comparison of its structural derivatives revealed that the long alkyl side chain seemed to have an important role in the inhibitory effect. Notably, C18-alkyl chain conjugated epolactaene (compound 5) was the strongest inhibitor of DNA polymerase alpha, beta, lambda (pol alpha, beta, lambda) and topo II, with IC50 values of 13, 135, 4.4 and 5 microM, respectively, and 500 microg of compound 5 caused a marked reduction in TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation (inhibitory effect, 65.0%). Compound 5 did not influence the activities of plant or prokaryotic DNA polymerases, or of other DNA metabolic enzymes such as telomerase, RNA polymerase and deoxyribonuclease I. Based on these results, the relationship among the three-dimensional structure of epolactaene derivatives and the inhibition of polymerases and topo II, and anti-inflammation is discussed.


Grayanane Diterpenoids from the Leaves of Rhododendron auriculatum and Their Analgesic Activities.
Twenty-four grayanane diterpenoids (1-24) including 12 new ones (1-12) were isolated from Rhododendron auriculatum. The structures of the new grayanane diterpenoids (1-12) were defined via extensive spectroscopic data analysis. The absolute configurations of compounds 2-4, 10-12, 14, and 16 were established by single-crystal X-ray diffraction analysis, and electronic circular dichroism data were used to define the absolute configurations of auriculatols D (8) and E (9). Auriculatol A (1) is the first example of a 5,20-epoxygrayanane diterpenoid bearing a 7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system. Auriculatol B (2) is the first example of a 3α,5α-dihydroxy-1-βH-grayanane diterpenoid. 19-Hydroxy-3-epi-auriculatol B (6) and auriculatol C (7) represent the first examples of 19-hydroxygrayanane and grayan-5(6)-ene diterpenoids, respectively. Diterpenoids 1-24 showed analgesic activities in the writhing test induced by HOAc, and 2, 6, 10, 13, 19, and 24 at a dose of 5.0 mg/kg exhibited significant analgesic effects (inhibition rates >50%). Grayanane diterpenoids grayanotoxins I (19) and IV (24) at doses of 0.2 and 0.04 mg/kg showed more potent analgesic activities than morphine.


Leukemia cutis with lymphoglandular bodies: a clue to acute lymphoblastic leukemia cutis.
Leukemia cutis describes cutaneous lesions produced by infiltrates of leukemic cells. It usually manifests contemporaneously with the initial diagnosis of systemic leukemia, but may also precede or follow systemic leukemia. Most cases are associated with acute myeloid leukemia. Adult B-cell lymphoblastic leukemia cutis is very rare. We report a 59-year-old woman with a history of B-cell acute lymphoblastic leukemia who relapsed with aleukemic lymphoblastic leukemia cutis. Lymphoglandular bodies were conspicuous on biopsy and may serve as a morphologic clue to lymphocytic differentiation while molecular and immunophenotypic studies are pending. The patient was successfully treated with local radiation therapy and oral ponatinib.


Impact of eugenol and isoeugenol on AhR translocation, target gene expression, and proliferation in human HaCaT keratinocytes.
The phenolic derivatives eugenol and isoeugenol, which are naturally found in essential oils of different spices, are commonly used as fragrances. Recently data demonstrated that growth suppression produced by these substances occurs in keratinocytes and that the effects may be mediated via aryl hydrocarbon receptor (AhR) interactions. In this study the effects of eugenol and isoeugenol were determined on intracellular localization of AhR, AhR target gene expression, AhR-dependent cell cycle regulation, and proliferation in HaCaT cells. Both compounds produced a rapid and marked translocation of AhR into the nucleus, induced the expression of the AhR target genes cytochrome P-450 1A1 (CYP1A1) and AhR repressor (AhRR), and inhibited proliferation of HaCaT cells. Among the G(1) phase cell cycle-related proteins, levels of the retinoblastoma protein (RB), which is known to interact with AhR, and levels of the cyclin dependent kinase (CDK) 6 were reduced by eugenol and isoeugenol, whereas steady-state levels of CDK2 and CDK4 remained unaffected. Protein levels of CDK inhibitor (CKI) p27(KIP1), known to be modulated in an AhR-dependent manner, were increased after treatment with both substances. In conclusion, data show that the antiproliferative properties of eugenol and isoeugenol in HaCaT cells are mediated through AhR, and thereby the molecular mechanisms of action in these cells were identified for the first time in this study.


Hole formation in thin polymer films: a two-stage process.
Thin, supported liquid films are known to rupture, creating holes throughout the film, due to defects or to van der Waals interactions. We show that the hole formation process before rupturing occurs in two stages, each characterized by distinct dynamical and morphological features. The time scale for the formation process is orders of magnitude slower than the translational (reptation) relaxation time of the individual chains. This has implications regarding the transition from the formation regime to subsequent hole growth regime on the underlying substrate.


Clinical significance of locoregional and systemic treatment in operable high-risk breast cancer patients with more than four positive axillary lymph nodes.
Breast cancer cases with four or more involved axillary lymph nodes (ALNs) feature an aggressive clinical history despite intensive treatment. However, therapies for improving the prognosis for these high-risk patients and the prognostic role of clinical characteristics have been little investigated. Therefore, we sought to assess potential prognostic factors for these patients in female Chinese patients and identify the treatment modalities they might benefit from, which offers implications for clinical practice. A total of 518 patients with four or more involved ALNs were retrospectively analyzed. Survival-curve analysis was performed with the Kaplan-Meier method, and Cox proportional hazard regression was applied to identify independent variables for disease-free survival (DFS) and overall survival (OS). The patients were divided into groups depending on the number of ALNs, with 38.22% having four to six positive ALNs and 61.78% having seven or more ALNs. Compared with the seven or more-positive ALN subgroup, patients with four to six positive ALNs tended to have smaller tumors and were more likely to undergo modified radical mastectomy rather than radical mastectomy (both P<0.001). Univariate analysis revealed that a fluorouracil/doxorubicin (epirubicin)/cyclophosphamide (CA[E]F) regimen or a CA(E)F followed by docetaxel (CA[E] F > T) regimen conferred significantly better DFS (P=0.0075) and OS (P<0.0001) than those achieved from a cyclophosphamide/methotrexate/fluorouracil regimen, which was almost completely generated by the seven or more ALN subgroup (P=0.0088 and P=0.0001, respectively). Postoperative radiotherapy was associated with better DFS (P=0.0360), which was also generated by the seven or more ALN subgroup (P=0.0107). Subgroup analysis also clarified that the type of surgery conferred a modest effect on DFS in the seven or more ALN subgroup (P=0.0305). Multivariate survival analysis revealed that ALN status (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.31-3.05; P=0.001), tumor size (HR 1.48, 95% CI 1.06-2.08; P=0.022), and type of surgery (HR 0.47, 95% CI 0.30-0.74; P=0.001) were independent prognostic factors for DFS. Meanwhile, ALN status (HR 2.96, 95% CI 1.51-5.77; P=0.002), tumor size (HR 2.32, 95% CI 1.38-3.89; P=0.001), type of surgery (HR=0.39, 95% CI 0.20-0.76; P=0.006), and regimen of chemotherapy (HR=0.64, 95% CI 0.50-0.85; P=0.002) were identified as independent prognostic factors for OS. Besides the classical prognostic factors and the improvement of prognosis achieved from the anthracycline-based or anthracycline-taxane combination chemotherapy compared to cyclophosphamide/methotrexate/fluorouracil chemotherapy, our findings showed benefits on DFS and OS for appropriate local treatments, including radiotherapy and sufficient ALN dissection for high-risk breast cancer patients with four or more ALNs involved, which suggests that much importance should also be attached to local treatment besides adjuvant systemic therapy.


How does the outcome of research training fellowships funded via the NHS compare with that from competitively funded fellowships from the MRC and other charities: a cross-sectional retrospective survey of trainees undertaking research training in the West Midlands.
This study aimed to investigate the impact of research training funded via the National Health Service (NHS) on medical trainees compared with traditional clinical research training fellowships (CRTFs). Online survey of 221 clinical trainees who had completed a period of research during their clinical training between 2009 and 2015 in the West Midlands. Research outcomes. Overall response rate was 59%, of whom 72 participants were funded by CRTFs and 51 funded by the NHS. Although participants with CRTFs were more likely to be awarded a higher degree compared with those on NHS-administered funding (66/72 CRTFs and 37/51 NHS, P=0.005), similar proportions of NHS-funded and CRTF-funded participants entered clinical lecturer posts on completing initial research training (8/51 NHS and 16/72 CRTF, P=0.37). 77% of participants had three or more publications (CRTF 57 and NHS 39, P=0.72). 57 participants had completed clinical training; similar proportions of CRTF-funded and NHS-funded trainees had research included in their consultant contract (12/22 NHS and 14/26 CRTF, P=0.96) or were appointed to academic posts (3 of 25 NHS funded and 6 of 32 CRTF, P>0.05). 95% of participants would recommend to colleagues and 82% of participants felt the research experience improved their provision of clinical care with no difference between CRTF-funded and NHS-funded participants (P=0.49). Continuing to participate in clinical work during the research reduced reports of trainee difficulty on returning to clinical work (23/108 continued clinical work vs 12/22 no clinical work, P=0.001). Research training funded by the NHS provides a quality experience and contributes to the clinical academic capacity within the UK. More needs to be done to support NHS participants to successfully achieve a higher degree.


Proteomics unravel the regulating role of salicylic acid in soybean under yield limiting drought stress.
Drought is a major concern for sustainable yield under changing environment. Soybean, an economically important oil and protein crop, is prone to drought resulting in yield instability. Salicylic acid (SA), a multifaceted growth hormone, modulates a series of parallel processes to confer drought tolerance thereby relieving yield limitations. The present study was performed in soybean plants treated with SA (0.5 mM) through seed pretreatment under drought regimes: severe stress (50% RWC) and moderate stress (75% RWC), and rehydration. Differential leaf proteome profiling with morphological, physiological and antioxidative metabolism studies were performed at two developmental stages (vegetative and flowering). This explained the tolerance attribution to soybean throughout the development attaining yield stability. Abundance of proteins involved in photosynthesis and ATP synthesis generated energy driving metabolic processes towards plant growth, development and stress acclimation. Carbon (C) metabolism proteins involved in growth, osmoregulation and C partition relieved drought-induced C impairment under SA. Defensive mechanisms against redox imbalance and protein misfolding and degradation under stress were enhanced as depicted by the abundance of proteins involved in redox balance and protein synthesis, assembly and degradation at vegetative stage. Redox signaling in chloroplast and its interplay with SA signaling triggered different defense responses as shown through thioredoxin protein abundance. Amino acid metabolism proteins abundance resulted in increased osmoprotectants accumulation like proline at initial stage which contributed later towards N (nitrogen) remobilization to developing sink. At later stage, abundance of these proteins maintained redox homeostasis and N remobilization for improved sink strength. The redox homeostasis was supported by the increased antioxidative metabolism in SA treated plants. The downregulation of proteins at flowering also contributed towards N remobilization. Yield potential was improved by SA under drought through acclimation with enhanced N and C remobilization to sink as demonstrated by increased yield parameters like seed number and weight per plant, thousand seed weight and harvest index. The potential of SA in conferring drought tolerance to plants to maintain sustainable yield possess future research interests.


Forward modeling of Doppler velocity interferometer system for improved shockwave measurements.
When near-instantaneous shocks are recorded by using a Doppler velocity interferometer velocity interferometer system for any reflector (VISAR), they typically exceed the detector's ability to react and "skipped fringes" result, where its visibility briefly reduces. Traditionally, replacing skipped fringes required guesswork in analysis, which increased arrival time errors. Second, the use of long but velocity-sensitive interferometer delays with fast detectors which can resolve the delay has traditionally been avoided because of the fear of confusing the arrival time signal. However, shorter delays produce smaller fringe phase shifts per velocity and, thus, can decrease velocity precision. We realize that while some loss of fringe information occurs at shock events, this is often just a partial loss and the residual fringe information can still hold valuable information. We describe a forward model (FM) of the interferometer action and detector blurring that assists with VISAR fringe analysis at skipping events: (1) more precise shock arrival times, (2) arrival time precision not limited by long delays, and (3) improved ghost subtraction, which improves accuracy over a broad time region. We demonstrate the utility of a FM on National Ignition Facility and Laboratory for Laser Energetics Omega shots and discuss data process methods to increase the high time resolution of VISAR systems despite their limitations and complexities.


The response to Trendelenburg position is minimally affected by underlying hemodynamic conditions in patients with aortic stenosis.
Trendelenburg positioning is commonly used to temporarily treat intraoperative hypotension. The Trendelenburg position improves cardiac output in normovolemic or anesthetized patients, but not hypovolemic or non-anesthetized patients. Therefore, the response to Trendelenburg positioning may vary depending on patient population or hemodynamic conditions. We thus tested the hypothesis that the effectiveness of the Trendelenburg position, as indicated by an increase in cardiac output, improves after replacement of a stenotic aortic valve. Secondarily, we evaluated whether measurements of left ventricular preload, systolic function, or afterload were associated with the response to Trendelenburg positioning. This study is a secondary analysis of a clinical trial which included patients having aortic valve replacement (AVR) who were monitored with pulmonary artery catheters (NCT01187329). We examined changes in thermodilution cardiac output with Trendelenburg positioning before and after AVR. We also examined whether echocardiographic and hemodynamic measurements of preload, afterload, and systolic function were associated with changes in cardiac output during Trendelenburg positioning. Thirty-seven patients were included. The median [IQR] cardiac output change with Trendelenburg positioning was -3% [-10%, 5%] before AVR versus +4% [-4%, 15%] after AVR. Estimated median difference in cardiac output with Trendelenburg was 5% (95% CI 1, 15%, P = 0.04) greater after AVR. The response to Trendelenburg positioning was largely independent of hemodynamic conditions. The response to Trendelenburg positioning improved following AVR, but by a clinically unimportant amount. The response to Trendelenburg positioning was independent of hemodynamic conditions.


Continuous cytotoxic T cell lines reactive against murine plasmacytoma tumor-associated antigens.
Continuous cytotoxic T cell lines against murine tumor-associated antigens (TAA) were generated from normal BALB/c and (C57BL/6 X BALB/c)F1 spleen lymphocytes by sensitizing these cells in vitro to the BALB/c plasmacytoma (PCT) MPC-11. These cytotoxic T cell lines (CTLL) were maintained for periods of over 1 yr in T cell growth factor from cultures of mitogen-stimulated rat spleen cells. The lines were highly cytotoxic against the immunizing tumor, as well as against a select number of other tumor cell lines, and the patterns of reactivity of 3 of these lines against the various tumor cell targets indicated that these lines each recognized different PCT TAA. The antigens recognized included an MHC-restricted PCT antigen, an antigen shared by PCT and T lymphomas, and an MPC-11 unique PCT antigen. phenotypic characterization of the CTLL populations for cell surface marker expression indicated that they were largely homogeneous with respect to their differentiation state, and expressed Thy-1.2, Lyt-2, Lyt-3.2, and T30 antigens on their cell surface. In addition, 1 of the lines demonstrated variable low-level expression of Lyt-1. Thus, the populations were characteristics of mature T cells, and did not express cell surface markers characteristic of other lymphocyte subpopulations.


Age at menarche and adult body mass index: a Mendelian randomization study.
Pubertal timing has psychological and physical sequelae. While observational studies have demonstrated an association between age at menarche and adult body mass index (BMI), confounding makes it difficult to infer causality. The Mendelian randomization (MR) technique is not limited by traditional confounding and was used to investigate the presence of a causal effect of age at menarche on adult BMI. MR uses genetic variants as instruments under the assumption that they act on BMI only through age at menarche (no pleiotropy). Using a two-sample MR approach, heterogeneity between the MR estimates from individual instruments was used as a proxy for pleiotropy, with sensitivity analyses performed if detected. Genetic instruments and estimates of their association with age at menarche were obtained from a genome-wide association meta-analysis on 182,416 women. The genetic effects on adult BMI were estimated using data on 80,465 women from the UK Biobank. The presence of a causal effect of age at menarche on adult BMI was further investigated using data on 70,692 women from the GIANT Consortium. There was evidence of pleiotropy among instruments. Using the UK Biobank data, after removing instruments associated with childhood BMI that were likely exerting pleiotropy, fixed-effect meta-analysis across instruments demonstrated that a 1 year increase in age at menarche reduces adult BMI by 0.38 kg/m2 (95% CI 0.25-0.51 kg/m2). However, evidence of pleiotropy remained. MR-Egger regression did not suggest directional bias, and similar estimates to the fixed-effect meta-analysis were obtained in sensitivity analyses when using a random-effect model, multivariable MR, MR-Egger regression, a weighted median estimator and a weighted mode-based estimator. The direction and significance of the causal effect were replicated using GIANT Consortium data. MR provides evidence to support the hypothesis that earlier age at menarche causes higher adult BMI. Complex hormonal and psychological factors may be responsible.


Self-healing properties of symmetrical power-exponent-phase vortices.
The self-healing properties of symmetrical power-exponent-phase vortices (SPEPVs) are analyzed in this paper. By placing an obstacle in the optical path of SPEPVs, we simulated the propagation of the obstructed SPEPVs and verified the self-healing of the beam theoretically. We also explored the influence of external factors (e.g., obstacle size and position) and internal parameters (topological charge l and power exponent n) on the self-healing effect of obstructed SPEPVs. Furthermore, the energy flow density, similarity coefficient, effective self-healing distance, and diffraction efficiency of the obstructed SPEPVs were also discussed. The results demonstrated that the transverse energy flows around the obstructed region of SPEPVs will recover with the propagation distance increased, and the effective self-healing distance gradually increases linearly with the obstacle size r x increased. The self-healing characteristic gives the petal-like SPEPVs the ability to trap microparticles three-dimensionally.


Colocalization of P2Y2 and P2Y6 receptor genes at human chromosome 11q13.3-14.1.
Extracellular nucleotides mediate a number of physiological responses through either ligand gated P2X or G protein-coupled P2Y receptors. To date, six P2Y receptor subtypes, P2Y1-P2Y6, have been cloned. We mapped the human P2Y6 receptor gene to chromosome 11q13.3-13.5. Oligonucleotide primers complementary to a part of the human P2Y6 receptor cDNA were used to amplify a region from genomic DNA from a panel of mouse/human somatic cell hybrid cell lines, each containing a single human chromosome. A PCR product of the expected size (714 bp) resulted from a single hybrid cell line containing human chromosome 11. The gene was further localized to a region of chromosome 11 using a subchromosomal hybrid panel containing different segments of chromosome 11. Based on the specific PCR product obtained and its Southern hybridization to the P2Y6 receptor cDNA, the human P2Y6 receptor gene was localized to chromosome 11q13.3-13.5. Previously, we have localized the P2Y2 receptor gene to human chromosome 11q13.5-14.1. This is the first report of the clustering of the P2 receptor genes. The clustering of these two P2Y receptor subtypes suggests a relatively recent expansion of the gene family by gene duplication.


Feasibility and Proof-of-Concept of Delivering an Autonomous Music-Based Digital Walking Intervention to Persons with Parkinson's Disease in a Naturalistic Setting.
Reduced motor automaticity in Parkinson's disease (PD) negatively impacts the quality, intensity, and amount of daily walking. Rhythmic auditory stimulation (RAS), a clinical intervention shown to improve walking outcomes, has been limited by barriers associated with the need for ongoing clinician input. To assess the feasibility, proof-of-concept, and preliminary clinical outcomes associated with delivering an autonomous music-based digital walking intervention based on RAS principles to persons with PD in a naturalistic setting. Twenty-three persons with PD used the digital intervention independently for four weeks to complete five weekly 30-minute sessions of unsupervised, overground walking with music-based cues. The intervention progressed autonomously according to real-time gait sensing. Feasibility of independent use was assessed by examining participant adherence, safety, and experience. Intervention proof-of-concept was assessed by examining spatiotemporal metrics of gait quality, daily minutes of moderate intensity walking, and daily steps. Preliminary clinical outcomes were assessed following intervention completion. Participants completed 86.4% of sessions and 131.1% of the prescribed session duration. No adverse events were reported. Gait speed, stride length, and cadence increased within sessions, and gait variability decreased (p < 0.05). Compared to baseline, increased daily moderate intensity walking (mean Δ= +21.44 minutes) and steps (mean Δ= +3,484 steps) occurred on designated intervention days (p < 0.05). Quality of life, disease severity, walking endurance, and functional mobility were improved after four weeks (p < 0.05). Study findings supported the feasibility and potential clinical utility of delivering an autonomous digital walking intervention to persons with PD in a naturalistic setting.


Characterization by gas chromatography-olfactometry of the most odour-active compounds in Italian balsamic vinegars with geographical indication.
Odour-active compounds in three traditional balsamic vinegars from Modena (TB) and seven balsamic vinegars from Modena (PGI) were determined by gas chromatography-olfactometry (GC-O) using frequency of detection methodology (modified frequency, MF, %). The main odour compounds (mean MF > 60%) were 2,3-butanedione (75%), acetic acid (70%), furan-2-carbaldehyde (62%), 1-(furan-2-yl)ethanone (62%), 2-methylpropanoic acid (66%), butanoic acid (78%), 3-methylbutanoic acid (83%), 2-phenylethyl acetate (65%), 2-hydroxy-3-methylcyclopent-2-en-1-one (61%), 2-phenylethan-1-ol (84%), 3-hydroxy-2-methylpyran-4-one (60%), (5-formylfuran-2-yl)methyl acetate (68%), 2-phenylacetic acid (69%) and 4-hydroxy-3-methoxybenzaldehyde (86%). All odour impact compounds were grouped into 7 categories according to their aromatic character: cheesy-butter-lactic, sweet, flower, empyreumatic, fruity, chemical and miscellaneous. Balsamic vinegars from Modena showed lower values for the sweet category whereas for the miscellaneous and chemical categories they exhibited higher values than those found in traditional balsamic vinegars from Modena. A principal component analysis showed that both types of vinegars from Modena could be clearly differentiated based on olfactometric data.


Proline availability regulates proline-4-hydroxylase synthesis and substrate uptake in proline-hydroxylating recombinant Escherichia coli.
Microbial physiology plays a crucial role in whole-cell biotransformation, especially for redox reactions that depend on carbon and energy metabolism. In this study, regio- and enantio-selective proline hydroxylation with recombinant Escherichia coli expressing proline-4-hydroxylase (P4H) was investigated with respect to its interconnectivity to microbial physiology and metabolism. P4H production was found to depend on extracellular proline availability and on codon usage. Medium supplementation with proline did not alter p4h mRNA levels, indicating that P4H production depends on the availability of charged prolyl-tRNAs. Increasing the intracellular levels of soluble P4H did not result in an increase in resting cell activities above a certain threshold (depending on growth and assay temperature). Activities up to 5-fold higher were reached with permeabilized cells, confirming that host physiology and not the intracellular level of active P4H determines the achievable whole-cell proline hydroxylation activity. Metabolic flux analysis revealed that tricarboxylic acid cycle fluxes in growing biocatalytically active cells were significantly higher than proline hydroxylation rates. Remarkably, a catalysis-induced reduction of substrate uptake was observed, which correlated with reduced transcription of putA and putP, encoding proline dehydrogenase and the major proline transporter, respectively. These results provide evidence for a strong interference of catalytic activity with the regulation of proline uptake and metabolism. In terms of whole-cell biocatalyst efficiency, proline uptake and competition of P4H with proline catabolism are considered the most critical factors.


Use of infrarenal conduits for arterial revascularization in orthotopic liver transplantation.
Arterial conduits that use donor iliac arteries represent a reliable technique for graft revascularization in orthotopic liver transplantation. We reviewed 757 consecutive liver transplantations performed between 1989 and 1995 for acute or chronic liver disease in adults and children. Of these, 218 patients received arterial conduits that used donor iliac arteries. The incidence of hepatic artery thrombosis (HAT) for conduits was 4.1% (9 of 218 patients) compared with 4% (22 of 539 patients) for direct arterial anastomosis. Patients in the arterial conduit group included 66% (99 of 159) of the children younger than 5 years of age, 75% (67 of 89) of all patients who underwent retransplantation, and, in particular, 25 patients regrafted for HAT. Arterial conduits provide an effective and reliable method of revascularization in patients at higher risk of arterial thrombosis. The actuarial 3-year patency rate for conduits is 95% and the incidence of HAT is similar to that in standard arterial anastomoses.


N-heterocyclic phosphenium cations: syntheses and cycloaddition reactions.
A series of trifluoromethanesulfonate (OTf) salts of N-heterocyclic phospheniums (NHP) bearing phenyl (1a), para-methoxyphenyl (1b), 2,6-diisopropylphenyl (1c) and mesityl (1d) substituents is reported. The compounds are made by a modification to a literature procedure that improves the overall yields for and by 15 and 23%, respectively. Two unwanted side-products in the synthesis of , the diammonium salt, [(2,6-iPr-C6H3)N(H)2CH2CH2N(H)2(2,6-iPr-C6H3)]Cl2 (4) and the bisphosphine (2,6-iPr-C6H3)N(PCl2)CH2CH2N(PCl2)(2,6-iPr-C6H3) (5), are crystallographically characterized, as is the intermediate cyclic chlorophosphine, C1PN(4-OMe-C6H4)CH2CH2N(4-OMe-C6H4) (3b). The phenyl-substituted NHP is fully characterized, including by X-ray crystallography, for the first time; this compound contains a short P-O contact of 2.1850(14) A. Cycloaddition reactions of with 2,3-dimethyl-1,3-butadiene give the expected spirocyclic phospholeniums, 7,8-dimethyl-1,4-diaryl-1,4-diaza-5-phopshoniaspiro[4.4]non-7-ene, as their OTf salts (6a-d), while reactions with N,N'-dimesityl-1,4-diaza-1,3-butadiene give, except in the case of , which is too bulky to react, the aza analogues, 1,4-dimesityl-6,9-diaryl-1,4,6,9-tetraaza-5-phosphoniaspiro[4.4]non-2-ene (7a, 7b and 7d). The sterically congested is in thermal equilibrium with and free diazadiene, and undergoes a substitution reaction with 2,3-dimethyl-1,3-butadiene to give .


Eagle's Syndrome: A Case Report of a Unilateral Elongated Styloid Process.
When styloid process elongation or stylohyoid ligament calcification can lead to various symptoms, such as dysphagia, facial pain, globus sensation, and headache, it is termed Eagle's syndrome. It may be unilateral or bilateral. Though the overall prevalence in adults is 4%, only 0.16% of patients are symptomatic. Since the symptoms mimic several other orofacial pains and neuralgia, the diagnosis must be made through a detailed history, clinical examination, and various imaging modalities. The case of facial pain in a 22-year-old female patient who was diagnosed to have a unilateral elongated styloid process is discussed in this paper.


Production of PtdInsP3 at endomembranes is triggered by receptor endocytosis.
Phosphatidylinositol-3,4,5-trisphosphate (PtdInsP(3)) regulates diverse cellular functions, including cell proliferation and apoptosis, and has roles in the progression of diabetes and cancer. However, little is known about its production. Here, we describe fluorescent indicators for PtdInsP(3) that allow a spatio-temporal examination of PtdInsP(3) production in single living cells. After ligand stimulation, PtdInsP(3) levels increased to a larger extent at the endomembranes (that is, the endoplasmic reticulum and the Golgi) than at the plasma membrane. This increase was found to originate from in situ production at the endomembranes, a process stimulated directly by receptor tyrosine kinases endocytosed from the plasma membrane to the endomembranes. The demonstration of PtdInsP(3) production through receptor endocytosis addresses a long-standing question about how signalling pathways downstream of PtdInsP(3) are activated at intracellular compartments remote from the plasma membrane.


Results of the First National Kaiser Permanente Continuing Medical Education Needs Assessment Survey.
Needs assessment is an important part of planning effective continuing medical education (CME) programs. The Kaiser Permanente National CME Committee (KPNCME) was formed in 1998 to accredit and provide oversight and assistance to Kaiser Permanente (KP) national CME programs and to provide expertise on an as-needed basis to regional and local KP CME efforts. To develop, distribute, and analyze a CME needs assessment survey of Permanente physicians. Cross-sectional survey completed by Permanente physicians on paper or online during September 2000 through December 2000. Physician motivations for, preferences about, and perceived barriers to participating in CME programs. Of 10,959 surveys distributed to KP physicians, 1976 (19.1%) were completed. Survey responses showed that Permanente physicians choose topics on the basis of self-perceived need and tend not to be influenced by objective performance data. Survey respondents preferred evidence-based, clinical CME topics that address a major aspect of their practice and that potentially provide an opportunity to learn new skills. Respondents preferred CME programs delivered in group format, although a subset of respondents found the computerized format valuable. In choosing a CME program, respondents were influenced more by program location than by time of day at which programs were scheduled. At all levels-from individual to national-CME planning should incorporate objectively determined quality, program utilization, and other objective data as well as more subjectively determined need as perceived by individual physicians and CME experts. Live programs delivered onsite should use interactive format. The need for clinicians to develop cultural competence and effective communication skills should be framed in clinical context. Locations of KP national CME programs should periodically be rotated to make these programs more accessible to prospective attendees from all KP Regions.


Validation of a GC-MS screening method for anabolizing agents in aqueous nutritional supplements.
A sensitive and selective method for the screening of anabolizing agents in aqueous nutritional supplements is described and validated. A total of 28 different anabolizing agents are screened for, including testosterone and prohormones, nandrolone and prohormones, stanozolol, and metandienone. The different analytes are extracted from the aqueous nutritional supplements by liquid-liquid extraction with a mixture of pentane and freshly distilled diethylether (1:1) after the supplements have been made alkaline with a NaHCO3-K2CO3 (2:1) buffer. The anabolizing agents are derivatized with a mixture of MSTFA-NH4I-ethanethiol (320:1:2) as routinely used for the screening of anabolic steroids extracted from urine. The derivatives are analyzed by gas chromatography (GC)-mass spectrometry (MS) in the selective ion monitoring mode. The limits of detection range from 1 to 10 ng/mL. One aqueous nutritional supplement (creatine serum) was analyzed with this screening method and was found to contain dehydroepiandrosterone (DHEA) at very low concentrations. The presence of DHEA could be confirmed with GC-MS-MS. Results of the application of this method and a similar method for solid nutritional supplements previously described are given.


Consequences of prolonged caffeine administration and its withdrawal on pilocarpine- and kainate-induced seizures in rats.
To investigate the consequences of caffeine consumption on epileptic seizures, we used the pilocarpine and the kainate models of epilepsy. We hypothesized that prolonged caffeine consumption or its withdrawal would alter adenosine levels and hence alter seizure susceptibility. We administered a 0.1% caffeine solution in the drinking water of adult male Wistar rats over a 2-week period. We challenged another group of animals with the same doses of pilocarpine or kainate 12 h after the withdrawal of the same caffeine-administration protocol. This did not alter the threshold for the induction of seizures by a subconvulsant dose of pilocarpine (200 mg/kg, i.p.) or kainic acid (8 mg/kg, i.p.). Similarly, challenging another group of animals with the same doses of pilocarpine or kainate 12 h after the withdrawal of the same caffeine-administration protocol did not lead to any significant changes in seizures. With the pilocarpine model of epilepsy, we were not able to find any significant difference in seizure profile that could stem from either caffeine administration or its withdrawal. Despite the extensive laboratory evidence on the convulsant properties of xanthine derivatives in animal models of epilepsy, such strong evidence is lacking in clinical settings. Our current findings with the administration of caffeine at doses similar to those of daily life both support and confirm the clinical experience.


Functional role and signal-induced modulation of proteins recognizing the conserved TCATTT-containing promoter elements in the murine IL-5 and GM-CSF genes in T lymphocytes.
The TCATTT-containing element extending from -61 to -41 of the mouse IL-5 gene is highly conserved in the corresponding region of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene and has been previously shown to be involved in regulating inducible GM-CSF gene expression. By using stable transfection assays in the mouse Th2 clone D10.G4.1, we show that the TCATTT-containing element is also involved in the regulation of inducible IL-5 gene expression. The mouse IL-5 and GM-CSF homologues of this element were found by gel shift analysis to form DNA-nuclear protein complexes of similar electrophoretic mobility under conditions in which expression of these genes is induced. However, comparative studies using extracts of D10.G4.1 cells treated with the cellular activators Con A and PMA and the inhibitors cycloheximide and cyclosporin A indicated that the binding activities to the conserved elements in the IL-5 and GM-CSF genes (designated NF-IL-5A and NF-GM-CSFA, respectively) are regulated by different signaling pathways. In addition, NF-IL-5A is not induced in the Th1 clone HDK-1 which does not express the IL-5 gene. The strong correlation between the signal-dependent and cell-specific modulation of IL-5 and GM-CSF gene expression patterns and the binding activities of NF-IL-5A and NF-GM-CSFA suggests that these nuclear proteins are involved in the transduction of T cell activation signals to the transcriptional machinery of these genes through their interactions with their respective TCATTT-containing elements.


Setting up a support network for specialist nurses.
This article describes the establishment of an All-Wales Network for Nurses and Midwives Working in Abortion Services. This network provides a professional arena and active support for practitioners to enable professional development.


An Isoxazole Derivative SHU00238 Suppresses Colorectal Cancer Growth through miRNAs Regulation.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Isoxazoline and isoxazole derivatives represent an important class of five-membered heterocycles, which play a pivotal role in drug discovery. In our previous study, we developed a series of isoxazole derivatives with an efficient method. In this study, we evaluated their effects on tumor cell growth. HCT116 cells were treated with isoxazole derivatives; an cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 (half maximal inhibitory concentration) of each derivative. Compound SHU00238, which was obtained by the copper nitrate-mediated [2+2+1] cycloaddition reaction of olefinic azlactone with naphthalene-1,4-dione, has a lower IC50; we analyzed its inhibitory activity in further assays. Cell apoptosis was estimated by flow cytometry analysis in vitro. SHU00238 injection was used to treat tumor-bearing mice. We found that SHU00238 suppressed cell viability and promoted cell apoptosis in vitro. SHU00238 treatment significantly inhibited colonic tumor growth in vivo. Furthermore, we compared the miRNAs expression changes in HCT116 cells before and after SHU00238 treatment. MiRNA profiling revealed that SHU00238 treatment affected cell fate by regulating a set of miRNAs. In conclusion, SHU00238 impedes CRC tumor cell proliferation and promotes cell apoptosis by miRNAs regulation.


[The relationship between smoking behavior and self-esteem among elementary and junior high school students].
This study examined the relationship between smoking behavior and self-esteem among Japanese early adolescents. The study sample comprised 1,486 fourth through ninth grade students from 10 elementary schools and six junior high schools throughout nine prefectures. Data were collected using an anonymous self-administered questionnaire which included items measuring smoking behavior, self-esteem, intention to smoke in the future, self-efficacy to refuse peer pressure to smoke, the smoking behaviors of their parents, siblings and friends. Self-esteem was measured using the Harter Perceived Competence Scale which includes four areas: cognitive, social, physical, and general. The main results were as follows: 1) Ever smokers had lower cognitive and general competence scores, but a higher physical competence score than never smokers, especially among males. 2) Ever smokers had more smoking parents, siblings and friends than never smokers. 3) Ever smokers had stronger intention to smoke in the future than never smokers. 4) Ever smokers had lower self-efficacy to refuse peer pressure to smoke than never smokers. The results of this study about the relationship between smoking behavior and self-esteem were consistent with those of some previous studies in the U.S. Therefore, it is suggested that effective smoking prevention programs for Japanese early adolescents should include strategies to enhance self-esteem.


Novel easy to fabricate liquid crystal composite with potential for electrically or thermally controlled transparency windows.
Switchable liquid crystal (LC) composites are a unique and attractive class of functional materials due to their extensive use in various applications including smart and privacy windows. Demand for developing smart windows with good switchable performance has steadily increasing in the past decades due to their importance in energy saving. Herein, we present the use of novel and highly active switchable LC composite material-octadecanol-doped LC-prepared via a facile, low-cost, and scalable process, for thermally or electrically controlled transparency windows. A systematic study of the switchable behavior reveals the formation of a reversible molecular arrangement between the LC and the octadecanol, which allows control of the transparency through scattering modulation of the device by voltage or temperature. The devices fabricated by sandwiching the LC composite material between two ITO-covered glass slides present switchable performance with high potential for cost-effective utilization in various applications, such as light shutters, smart or privacy windows.


Mixed lineage kinase 3 promotes breast tumorigenesis via phosphorylation and activation of p21-activated kinase 1.
Mixed lineage kinase 3 (MLK3), a MAP3K member has been envisioned as a viable drug target in cancer, yet its detailed function and signaling is not fully elucidated. We identified that MLK3 tightly associates with an oncogene, PAK1. Mammalian PAK1 being a Ste20 (MAP4K) member, we tested whether it is an upstream regulator of MLK3. In contrast to our hypothesis, MLK3 activated PAK1 kinase activity directly, as well as in the cells. Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3. Stable overexpression of PAK1S204A in breast cancer cells, impedes migration, invasion, and NFĸB activity. In vivo breast cancer cell tumorigenesis is significantly reduced in tumors expressing PAK1S204A mutant. These results suggest that mammalian PAK1 does not act as a MAP4K and MLK3-induced direct activation of PAK1 plays a key role in breast cancer tumorigenesis.


Generation of the arachidonic acid metabolite 8-HETE by extracts of mouse skin treated with phorbol ester in vivo; identification by 1H-n.m.r. and GC-MS spectroscopy.
After a single in vivo application of 20 nmol of the 'complete' tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or of the 'incomplete' promoter 12-O-retinoylphorbol-13-acetate (RPA) to the back skin of mice, a major arachidonic acid metabolite (AAMX) was found in cell-free epidermal preparations after addition of arachidonic acid (AA). Studies with cyclooxygenase and lipoxygenase inhibitors indicated that this metabolite is a lipoxygenase product. The metabolite has been purified by sequential use of t.l.c. and h.p.l.c. and identified as 8-hydroxy-5Z,9E,11Z,14Z-eicosatetraenoic acid (8-HETE) by means of GC-MS and 1H-n.m.r. spectroscopy. To assist in the characterization of AAMX, a reference mixture of 8-HETE and 9-HETE was used for which a complete structural analysis could be performed using one- and two-dimensional 1H-n.m.r. at 500 MHz. The production of 8-HETE has been shown to start with a lag phase of 3 h after TPA treatment and to reach a maximum after 24-48 h. Nonpromoting phorbol esters are 10-fold, the Ca2+-ionophore A 23187 100-fold, less efficient in inducing in vivo the lipoxygenase responsible for 8-HETE production. 3-Day-old neonatal mice cannot be induced to generate 8-HETE in response to TPA, whereas 8-day-old mice show an extremely strong response. Neither primary basal keratinocytes, isolated from TPA-treated mouse epidermis nor TPA-treated epidermal cell lines generate 8-HETE, indicating that the metabolite may not originate from these epithelial cells.