Risk of Ischaemic Heart Disease in Patients with Inflammatory Bowel Disease: Cohort Study Using the General Practice Research Database.
Patients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association. This retrospective cohort study examined records from patients aged ≥ 15 years with IBD from 1987-2009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD. A higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority (4494, 51.5%) developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls (64.5y vs. 67.0y, p = 0.008) and coronary heart disease (65.7y vs.67.9y, p = 0.015). Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1-1.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1-1.6), p = 0.004). Although IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered.


Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility.
The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (-844G > A [rs2227631], -675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 -675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012-2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413-0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469-0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.


A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.


How much REST is enough?
Recent papers published in Nature by Guardavaccaro et al. and Westbrook et al. describe a nexus of two masters of negative regulation of protein levels. Both of these studies establish that the transcriptional repressor REST/NRSF is regulated by the highly versatile ubiquitin protein ligase (E3) SCF(beta-TrCP), adding a new dimension to the relationship between the ubiquitin-proteasome system and epigenetic regulation of transcription. These studies elucidate a critical means of regulation for REST, with implications for neuronal stem cell differentiation and the dual roles of this protein as a tumor suppressor and oncogene. These findings and their significance are discussed herein.


US Physical Activity Guidelines: Current state, impact and future directions.
Regular physical activity is one of the most powerful methods to lower the risk of all-cause mortality, help control multiple medical co-morbidities and improve overall quality of life. For optimal health it is recommended that adults obtain at least 150 min per week of moderate-intensity or 75 min per week of vigorous-intensity aerobic exercise per week along with at least 2 days of muscle-strengthening activity. Despite the known health benefits of exercise and long-standing recommendations from major health, medical and fitness societies, only half of Americans meet these guidelines. The Physical Activity Guidelines for Americans, 2nd edition from the U.S. Department of Health and Human Services provides an update from the 2008 guidelines adding specific recommendations for pre-school children while emphasizing the need to reduce sedentarism across the age spectrum ("move more and sit less"). This document provides a summary of the 2018 Physical Activity Guidelines for Americans as well as the impact of inactivity on health and future directions to improve utilization.


Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers.
Neuropsychiatric disorders are present in up to 90% of patients with Tuberous Sclerosis Complex (TSC), and represent an important issue for families. Autism Spectrum Disorder (ASD) is the most common neurobehavioral disease, affecting up to 61% of patients. The aims of this study were: 1) to assess the prevalence of ASD in a TSC population; 2) to describe the severity of ASD; 3) to identify potential risk factors associated with the development of ASD in TSC patients. We selected 42 individuals over age 4 years with a definite diagnosis of TSC and followed at a TSC clinic in Northern Italy. We collected and reported clinical and genetic data, as well as cognitive level, for each of them. We administered the Social Communication Questionnaire (SCQ) as a reliable screening tool for ASD, and performed comparisons between the average scores and each clinical and genetic feature. Seventeen out of 42 patients (40.5%) had a score at the SCQ suggestive of ASD (≥15 points). When calculated for each cognitive level category, the average SCQ score tended to be progressively higher in patients with a worse cognitive level, and the number of pathological SCQ scores increased with worsening of intellectual disability. With respect to ASD severity, the scores were equally distributed, indicating that the degree of ASD in TSC patients may have a large variability. By comparing the average SCQ scores with the clinical features, we found statistically significant correlations with epilepsy, seizure onset before age one year, spasms, mutations in TSC2, cognitive level, sleep disorders, and other psychiatric problems, but not with seizure frequency, tubers localization and gender. Our study showed a prevalence of ASD of 40.5%, confirming the higher risk for this disorder in patients with TSC. However, the severity seems to have a notable variability in TSC patients. Risk factors for ASD are epilepsy, infantile spams, and mutations in TSC2.


Synthesising research findings and practical experience to formulate principles in cervical screening.
Compared particularly with Scandinavian countries, the effects of cervical screening in the United Kingdom have been disappointing, both in terms of women screened and in relation to incidence and mortality. The underlying problem is the under-representation of women most at risk of cervical cancer in the screened population. In this paper we examine two possible hypotheses for such under-representation: one concerns the behavioural aspects of women's failure to attend and the second the effect of the organisation of current screening services on their attendance. We outline the features that an effective service would need to incorporate and propose principles for the development of a screening system designed to maximise the potential of the cervical smear test.


Novel boronated derivatives of 5,10,15,20-tetraphenylporphyrin: synthesis and toxicity for drug-resistant tumor cells.
We have developed the synthesis of boronated porphyrins for potential application in cancer treatment, based on the functional derivatives of 5,10,15,20-tetraphenylporphyrin. Boronated amide derivatives starting from 5,10,15,20-tetra(p-aminophenyl)porphyrin and 9-o- and 9-m-carborane carboxylic acid chlorides were prepared. Also, the reaction of 2-formyl-5,10,15,20-tetraphenylporphyrin with closo-C-lithium-o- and m-carboranes, as well as with closo-C-lithium monocarbon carborane, yielded neutral and anionic boronated hydroxy derivatives of 5,10,15,20-tetraphenylporphyrin, respectively. Water-soluble forms of neutral compounds were prepared by deboronation of closo-polyhedra with Bu4NF into nido-7,8- and nido-7,9-dicarbaundecaborate anions. Monocarbon carborane conjugated with copper (II) complex of 5,10,15,20-tetraphenylporphyrin was active for a variety of tumor cell lines (IC50 approximately 5 microM after 48-72 h of exposure) but was inert for non-malignant fibroblasts at up to 100 microM. At low micromolar concentrations, this compound caused the death of cells that express P-glycoprotein and other mechanisms of resistance to conventional anticancer drugs.


Quinidine-induced open channel block of K+ current in rat ventricle.
1. The effects of quinidine on calcium-independent outward K+ currents in rat ventricular myocytes were studied using whole-cell patch clamp techniques. 2. Quinidine sulphate (6 microM) significantly prolonged repolarization of the ventricular action potential. This effect was larger during early repolarization (25% level) than at later times (90% level). 3. Quinidine reduced the amplitude of a transient outward current, and accelerated its rate of decay by approximately 4 fold at membrane potentials between 0 to +50 mV. Quinidine also reduced the amplitude of a slowly inactivating, tetraethylammonium-sensitive 'pedestal' component of the outward current. 4. The quinidine-induced block of the transient outward current was dependent on time and membrane potential. Maximal block occurred with depolarizations of about 100 ms duration, and longer depolarizations (up to 1.5 s) produced little additional block. The membrane potential dependence of quinidine-induced block was very similar to the membrane potential dependence of activation of the transient outward current. The membrane potential dependence of steady-state inactivation of the transient outward current was not significantly affected by quinidine. 5. These results show that quinidine blocks outward K+ currents in rat ventricular cells. The time and potential dependence of this block suggests that quinidine blocks the transient outward K+ current by acting primarily on the open state of these channels.


How can policy protect public health and still foster innovation?
Tevi Troy brings experience from HHS, Capitol Hill, and the White House to bear on how the results of comparative effectiveness research will be communicated and by whom.


Automated image quality evaluation of structural brain MRI using an ensemble of deep learning networks.
Deep learning (DL) is a promising methodology for automatic detection of abnormalities in brain MRI. To automatically evaluate the quality of multicenter structural brain MRI images using an ensemble DL model based on deep convolutional neural networks (DCNNs). Retrospective. The study included 1064 brain images of autism patients and healthy controls from the Autism Brain Imaging Data Exchange (ABIDE) database. MRI data from 110 multiple sclerosis patients from the CombiRx study were included for independent testing. T1 -weighted MR brain images acquired at 3T. The ABIDE data were separated into training (60%), validation (20%), and testing (20%) sets. The ensemble DL model combined the results from three cascaded networks trained separately on the three MRI image planes (axial, coronal, and sagittal). Each cascaded network consists of a DCNN followed by a fully connected network. The quality of image slices from each plane was evaluated by the DCNN and the resultant image scores were combined into a volumewise quality rating using the fully connected network. The DL predicted ratings were compared with manual quality evaluation by two experts. Receiver operating characteristic (ROC) curve, area under ROC curve (AUC), sensitivity, specificity, accuracy, and positive (PPV) and negative (NPV) predictive values. The AUC, sensitivity, specificity, accuracy, PPV, and NPV for image quality evaluation of the ABIDE test set using the ensemble model were 0.90, 0.77, 0.85, 0.84, 0.42, and 0.96, respectively. On the CombiRx set the same model achieved performance of 0.71, 0.41, 0.84, 0.73, 0.48, and 0.80. This study demonstrated the high accuracy of DL in evaluating image quality of structural brain MRI in multicenter studies. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1260-1267.


Single-molecule fluorescence detection in microfluidic channels--the Holy Grail in muTAS?
Both single-molecule detection (SMD) methods and miniaturization technologies have developed very rapidly over the last ten years. By merging these two techniques, it may be possible to achieve the optimal requirements for the analysis and manipulation of samples on a single molecule scale. While miniaturized structures and channels provide the interface required to handle small particles and molecules, SMD permits the discovery, localization, counting and identification of compounds. Widespread applications, across various bioscience/analytical science fields, such as DNA-analysis, cytometry and drug screening, are envisaged. In this review, the unique benefits of single fluorescent molecule detection in microfluidic channels are presented. Recent and possible future applications are discussed.


Biochemical and molecular insights of PGPR application for the augmentation of carotenoids, tocopherols, and folate in the foliage of Moringa oleifera.
Plant Growth Promoting Rhizobacteria (PGPR) were utilized to contemplate their impact on the foliage of Moringa oleifera and examined for changes in tocopherols, chlorophyll, carotenoids, and folate in the sixth week. Among the eight treatments, Bacillus subtilis GB03, B. pumilus SE34, B. pumilus T4, and Pseudomonas fluorescens UOM14 improved α-tocopherol (10-14 fold) and β-carotene (1-1.40 fold) altogether significantly (P ≤ 0.05). The most significant improvement in folate content was apparent for B. subtilis IN937B (5.47 fold) trailed by B. pumilus SE34 (5.05 fold) and B. pumilus T4 (5.12 fold) treatments. P. fluorescens UOM14 indicated remarkable improvement in Chl a (0.39 fold) and Chl b (0.44 fold) content. Organisms showing a significant increase for the analyzed molecules in individual treatment were blended in different combinations and were used for the next set of treatments. Of all the three combinations, Combination 2 (COM2-B. pumilus SE34 + B. pumilus T4 + B. pumilus INR7) showed the maximum increase in α-tocopherol (8.46 fold) and γ-tocopherol (8.45 fold), followed by Combination 3 (COM3-B. pumilus SE34 + B. pumilus T4 + P. fluorescens UOM14) (5.93 and 3.65 fold). On the whole COM2 containing different strains of B. pumilus was found to enhance the targeted metabolites in foliage significantly. Real-time PCR studies were conducted for the biochemical pathway genes of the targeted molecules, including, γ-tocopherol methyltransferase (γ-TMT), phytoene synthase (PSY), phytoene desaturase (PDS), lycopene β cyclase (LBC) and dihydrofolate reductase thymidylate synthase (DHFR-TS). All the selected genes exhibited an up-regulation compared to control, similar to the biochemical output. Our investigation provides the strong evidence that PGPR can be viably utilized in combination to enhance the quality of the food crops.


Automating academic literature searches with RSS Feeds and Google Reader(™).
Behavior analytic practitioners have an ethical obligation to stay abreast of the most recent research developments in their areas of expertise. Although conducting frequent and comprehensive literature searches is one way to meet this mandate, doing so can be a time intensive process. One way to reduce the effort involved in this process is setting up automated literature and news searches using RSS feeds via programs like Google Reader(™). This paper outlines the steps necessary for setting up a Google Reader(™) account and creating customized RSS feeds based on searches of the National Center for Biotechnology Information (NCBI) PubMed database and the World Wide Web.


A high-flux and anti-interference dual-functional membrane for effective removal of Pb(II) from natural water.
The development of high efficiency filter membranes, particularly those capable of removing trace heavy metals from drinking water sources, is a global challenge. In this study, a dual-functional membrane (PmGn@PVDF) was successfully developed by doping graphene oxide (GO) and then depositing polydopamine (PDA). The pure water flux (Jw) was 188 LMH/bar and Pb(II) could be effectively removed in the water volume of 2106.36 L m-2. Both PDA and GO performed positive functions. PDA layer exhibited a high affinity toward Pb(II) by chelating with amino groups. And doping GO maintained a high pure water flux, which had been decreased by the extra PDA layer. In addition, the effective treatment volume of Pb(II) was elevated to 5029.06 L/m2 by the co-existence of citric acid, since neutral PbHL coordinated with neutral NH2 and cationic PbL- interacted with NH3+ through electrostatic attraction. Furthermore, PmGn@PVDF showed the excellent anti-interference performance in high salt and nature organic matters solutions. Thus, this novel dual-functional membrane could be considered as a competitive alternative of NF/RO for the efficient and advanced removal towards heavy metals from natural water.


Penetration of cisplatin into mouse brain by lipopolysaccharide.
We investigated the penetration of cisplatin into the mouse cerebral cortex-rich region (CCR) induced by lipopolysaccharide (LPS). With the injection of cisplatin into mice 3 h after the LPS treatment, platinum was detected in the CCR during the 7 days after the injection, while platinum was not detected in the CCR of cisplatin-injected mice without LPS pretreatment and of mice simultaneous treated with cisplatin and LPS. The N(G)-nitro-L-arginine methyl ester dose-dependently lowered the platinum level. A dose of 5 mg/kg of aminoguanidine reduced the increase in the platinum level of the LPS-treated mouse, and platinum was no longer detected at doses of 20 mg/kg in the aminoguanidine-injected group. At doses of 500 mg/kg aminoguanidine, however, no effect was seen on the platinum level of the CCR induced by LPS. Regarding indomethacin, the injection of 5 mg/kg resulted in a decrease in the platinum content of the CCR, but not undetectable level. These results suggest that LPS increases the penetration of cisplatin into the mouse brain, and platinum may be accumulated in the CCR. Nitric oxide and prostaglandins contribute to the penetration of platinum into the cerebral cortex.


Comparing the surgical timelines of military and civilians traumatic lower limb amputations.
The care and challenges of injured service have been well documented in the literature from a variety of specialities. The aim of this study was to analyse the surgical timelines of military and civilian traumatic amputees and compare the surgical and resuscitative interventions. A retrospective review of patient notes was undertaken. Military patients were identified from the Joint Theatre Trauma Registry (JTTR) in 2009. Civilian patients were identified using the hospital informatics database. Patient demographics, treatment timelines as well as surgical and critical care interventions were reviewed. In total 71 military patients sustained traumatic amputations within this time period. This represented 11% of the total injury demographic in 2009. Excluding upper limb amputees 46 patients sustained lower extremity amputations. These were investigated further. In total 21 civilian patients were identified in a 7-year period. Analysis revealed there was a statistically significant difference between patient age, ITU length of stay, blood products used and number of surgical procedures between military and civilian traumatic amputees. This study identified that military patients were treated for longer in critical care and required more surgical interventions for their amputations. Despite this, their time to stump closure and length of stay were not statistically different compared to civilian patients. Such observations reflect the importance of an Orthoplastic approach, as well as daily surgical theatre co-ordination and weekly multi-disciplinary meetings in providing optimal care for these complex patients. This study reports the epidemiological observed differences between two lower limb trauma groups.


Plant oil bodies: novel carriers to deliver lipophilic molecules.
Oil bodies (OBs) are specialised organelles ubiquitously detected in plant oil seeds, which serve as lipid storage compartments. OBs consist of a hydrophobic core of triacylglycerol (TAGs), surrounded by a monolayer of phospholipids (PLs) embedded with some specific proteins with a size ranging from 0.5 to 2 μm. In this work, we report an easy method to reconstitute OBs starting from their constituents and to encapsulate lipophilic molecules, i.e. the fluorescent fluorescein isothiocyanate (FITC) and carboxyfluorescein (CF), into reconstituted OBs. This methods allowed us to produce OBs 4- to 10-fold smaller (50-200 nm) than the native one and to obtain a good recovery (about 40%) of both the fluorescent compounds used in the present work. The properties of reconstituted OBs were investigated by a combination of Brewster angle microscopy, scanning force microscopy, ζ-potential techniques. OBs were stable and formed ordered monolayers when patterned on hydrophobic substrates whereas they showed a higher tendency to aggregate into larger, coalescing OBs when were deposited onto hydrophilic substrates or at the air/water interface. Furthermore, we verified the uptake of FITC-loaded OBs by the MCF-7 breast cancer cell line. Our results indicated that OBs could be envisaged as novel carriers to deliver hydrophobic bioactive compounds.


Comparison of amniotic fluid optical density and foam stability test in predicting fetal lung maturity.
The ability of optical density measurements and the foam stability test to predict the L/S ratio of amniotic fluid (AF) was examined. Optical density measurements and the foam test predicted the L/S ratio with a similar degree of accuracy; neither was able to replace biochemical measurement of the L/S ratio because both gave false negative and false positive predictions. Optical density measurements and the foam test did not combine to increase the accuracy of prediction.


Prevalence of comorbidities, and affective disorders in epilepsy: A latent class analysis approach.
Epilepsies are severe chronic neurological diseases that impair several domains in life and are often accompanied by various somatic and psychiatric comorbidities. Associations between epilepsy and its comorbidities remain poorly understood. As epidemiological research mainly relies on cross-sectional designs and descriptive results, homogeneities regarding comorbidities in individuals suffering from epilepsy remain uncovered. Therefore, we aimed to identify clusters of individuals based on selected seizure-related variables and somatic comorbidities, and their respective risk of experiencing affective disorders, using a Latent Class Analysis (LCA). Latent class analysis, is a model-driven statistical approach, which aims at latent, unobservable clusters on selected disease features. LCA has therefore the potential for uncovering previously unobservable groups or classes with similar comorbidity patterns. It allows for comparisons between those classes regarding risk or promotive factors - such as affective disorders. Our data derives from the Austrian cohort of the European Study on Burden and Care of Epilepsy (ESBACE; http://www.esbace.eu/). In ESBACE, multiple factors were collected to get a detailed picture on prevalence, epilepsy-related variables and comorbidities in a population-based cohort from the region of Salzburg, Austria. We used LCA to identify epilepsy-somatic-comorbidity-clusters and further, compared them to the observed the risk of suffering from affective disorders. The prevalence of epilepsy in the study region was 9.14/1000 inhabitants. LCA unveiled a three-cluster solution, of which one cluster, mainly consisting of individuals with mixed seizure types, higher age, and discrete somatic comorbidities (stroke, cardiovascular - and respiratory/pulmonary diseases) had a higher risk of experiencing affective disorders. To our knowledge, this is the first large scale study that uses LCA to identify epilepsy-related comorbidity phenotypes, and therefore it might open a new way for epidemiological research.


Ionization of pesticides using a far-ultraviolet femtosecond laser in gas chromatography/time-of-flight mass spectrometry.
The fourth harmonic emission (200 nm) of a femtosecond Ti:sapphire laser (35 fs) was generated and used in the multiphoton ionization of 49 pesticides in gas chromatography/time-of-flight mass spectrometry. The limit of detection was improved when the ionization source from the third harmonic emission (267 nm) was replaced with the fourth harmonic emission for several pesticide molecules that contained no conjugated double bonds since their absorption bands are located in the far-ultraviolet region. This analytical instrument was used in the analysis of a series of real samples including potatoes, carrots, and cabbage, and a signal suspected to arise from di-allate was observed for the potato sample.


Aberrant expression of the apoptosis-related proteins BAK and MCL1 in T cells in multiple sclerosis.
Pathogenic T cells of multiple sclerosis (MS) patients have been suggested to be endowed with an increased resistance to apoptosis, contributing to their increased survival. We report herein increased levels of the anti-apoptotic MCL1 protein and its half-life in activated lymphocytes of MS patients, which were not associated with differences in MCL1 RNA levels or with alterations in the expression levels of the known E3 ligases of MCL1-β-TrCP and HUWE1. Concomitantly, the expression levels of the pro-apoptotic protein BAK were decreased in MS patients at relapse. These findings suggest the dysregulation of the apoptosis-related proteins MCL1 and BAK in MS.


Effects of chronic bretylium treatment on the sympathetic neuron and the smooth musculature of the rat.
The effects of chronic i.p. injection of high doses of bretylium on sympathetic nerves on the smooth musculature of the vas deferens of adult and newborn rats were examined using fluorescence histochemistry, light and electron microscopy and organ bath physiological techniques. Bretylium treatment caused mitochondrial swelling, loss of cristae and the formation of electron-dense inclusions in the mitochondria of sympathetic neurons. However, neuron degeneration was not observed and fluorescent histochemical appearance of adrenergic neurons was normal. A small transient supersensitivity of the isolated vas deferens of bretylium-treated rats to noradrenaline, but not to acetylcholine, occurred. There was, however, considerable increase in the maximal contractile response to both noradrenaline and acetylcholine. In high calcium concentrations acetylcholine-induced contractions of vasa deferentia from bretylium-treated rats were significantly greater than control; there was no difference in magnitude of noradrenaline-induced contractions.


Experimentally verified model of mechanomyograms recorded during single motor unit contractions.
The aim of the paper is to create a model which enables to observe the mechanomyographic (MMG) wave generated during single motor unit contractions in a muscle, while the muscle is immersed in paraffin oil. The muscle model is described as a rheological membrane. Both the muscle and the medium models have been built by using Stiff-Finite-Element-Method (SFEM), which allows one to simulate the muscle surface displacement and the acoustic propagation of this effect in the oil. Such a modelling enables one to determine the impact of the rheological properties of the liquid environment on the shape of the MMG wave. In order to verify the model, the MMG signals and the contraction forces have been recorded in vivo from the medial gastrocnemius muscle of a rat. In these experiments single motor units were stimulated with various stimulation frequencies. A piezotransducer, immersed in paraffin oil, has been used to record the MMG signal recording. The signals recorded during individual twitches of the motor units have been used to estimate the parameters of the model. Subsequently, the model has been experimentally verified. The signals recorded in experiments during unfused and fused tetani have been compared with the simulated model responses in the analogous stimulation program. It has been observed that the MMG signals obtained with the proposed linear model have been consistent with the results of in vivo experiments.


The comparison of adductor canal block with femoral nerve block following total knee arthroplasty: a systematic review with meta-analysis.
Although several studies have compared the clinical efficacy of an adductor canal block (ACB) to that of a femoral nerve block (FNB) for analgesia after total knee arthroplasty (TKA), disputes mainly exist in the recovery of quadriceps strength and mobilization ability between the two methods. The aim of the present study was to compare, in a systematic review and meta-analysis, the clinical efficacy of ACB with that of FNB. We systematically searched randomized controlled trials comparing FNB with ACB for analgesia after TKA in Pubmed and the Cochrane Library from inception to April 30th 2015. There was no limitation of publication language. Trial quality was assessed using the modified Jadad scale, and eligible data were pooled for meta-analysis. Five studies of 348 patients were included. Outcomes showed that patients who received ACB had similar or better recovery of quadriceps strength and mobilization ability than those that underwent FNB. Similar efficacy was found between the two strategies regarding adductor strength, pain scores [at rest (p = 0.86), at or after knee flexion (p = 0.31)], opioid consumption (p = 0.99), opioid-associated adverse effects (p = 0.60), length of hospital stay (p = 0.42), patient satisfaction (p = 0.57), and success rate of blockade (p = 0.20). The present study suggests that TKA patients who receive ACB can achieve similar or even better recovery of quadriceps strength and mobilization ability than those treated with FNB. Taken as a whole, ACB may be a better analgesia strategy after TKA at present.


Effects of patient age on patency of chronic hemodialysis vascular access.
In this single-center, retrospective observational study, we assessed the long-term patency of vascular access (VA) after first VA placement to uncover independent risk factors associated with VA patency in Asian hemodialysis (HD) patients stratified by age. We also investigated factors associated with VA patency among older HD patients according to the type of VA in the overall study population. The study period was from January 2011 to December 2013. A total of 651 chronic HD patients with confirmed first upper-extremity VA placement were enrolled, and their records were analyzed retrospectively. A total of 445 patients (68.4%) made up the nonelderly group (< 65 years), and 206 patients (31.6%) were in the elderly group (≥ 65 years). Study outcomes were defined as primary or secondary VA patency. Autologous arteriovenous fistula (AVF) was more common in the nonelderly group (P < 0.01). Kaplan-Meier curve survival analysis indicated that primary patency was longer in the nonelderly group (P < 0.01); secondary patency, however, was similar between groups (P = 0.37). The multivariate analysis of factors associated with primary VA patency revealed that increased age (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.01-1.03; P < 0.01) was associated with shorter primary patency, and AVF (HR, 0.38; 95% CI, 0.28-0.51; P < 0.01) was associated with longer primary patency. AVF (HR, 0.57; 95% CI, 0.37-0.87; P = 0.010) and diabetes mellitus (HR, 1.56; 95% CI, 1.07-2.29; P = 0.02) were independently associated with longer and shorter secondary patency periods, respectively; however, increased age was not a risk factor for decreased secondary patency. Increased age was associated with shorter primary patency but not secondary patency, whereas AVF placement was associated with longer primary and secondary patency. Considering the similar rates of secondary patency between groups and the superior patency of AVF compared to arteriovenous graft, a fistula-first strategy should be applied to appropriate older patients.


Sickle cell disease mice have cerebral oxidative stress and vascular and white matter abnormalities.
Strokes are feared complications of sickle cell disease (SCD) and yield significant neurologic and neurocognitive deficits. However, even without detectable strokes, SCD patients have significant neurocognitive deficits in domains of learning and memory, processing speed and executive function. In these cases, mechanisms unrelated to major cerebrovascular abnormalities likely underlie these deficits. While oxidative stress and stress-related signaling pathways play a role in SCD pathophysiology, their role in cerebral injury remains unknown. We have shown that Townes and BERK SCD mice, while not having strokes, recapitulate neurocognitive deficits reported in humans. We hypothesized that cognitive deficits in SCD mice are associated with cerebral oxidative stress. We showed that SCD mice have increased levels of reactive oxygen species, protein carbonylation, and lipid peroxidation in hippocampus and cortex, thus suggesting increased cerebral oxidative stress. Further, cerebral oxidative stress was associated with caspase-3 activity alterations and vascular endothelial abnormalities, white matter changes, and disruption of the blood brain barrier, similar to those reported after ischemic/oxidative injury. Additionally, after repeated hypoxia/reoxygenation exposure, homozygous Townes had enhanced microglia activation. Our findings indicate that oxidative stress and stress-induced tissue damage is increased in susceptible brain regions, which may, in turn, contribute to neurocognitive deficits in SCD mice.


Interfacial control of oxygen vacancy doping and electrical conduction in thin film oxide heterostructures.
Oxygen vacancies in proximity to surfaces and heterointerfaces in oxide thin film heterostructures have major effects on properties, resulting, for example, in emergent conduction behaviour, large changes in metal-insulator transition temperatures or enhanced catalytic activity. Here we report the discovery of a means of reversibly controlling the oxygen vacancy concentration and distribution in oxide heterostructures consisting of electronically conducting In2O3 films grown on ionically conducting Y2O3-stabilized ZrO2 substrates. Oxygen ion redistribution across the heterointerface is induced using an applied electric field oriented in the plane of the interface, resulting in controlled oxygen vacancy (and hence electron) doping of the film and possible orders-of-magnitude enhancement of the film's electrical conduction. The reversible modified behaviour is dependent on interface properties and is attained without cation doping or changes in the gas environment.


The effect of completeness of revascularization during CABG with single versus multiple arterial grafts.
Incomplete coronary revascularization is associated with suboptimal outcomes. We investigated the long-term effects of Incomplete, Complete, and Supra-complete revascularization and whether these effects differed in the setting of single-arterial and multi-arterial coronary artery bypass graft (CABG). We analyzed 15-year mortality in 7157 CABG patients (64.1 ± 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (single-arterial) or with at least one additional arterial graft (multi-arterial) and were grouped based on a completeness of revascularization index (CRI = number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRI ≤ -1 [N = 320;4.5%]); Complete (CRI = 0 [N = 2882;40.3%]; reference group); and two Supra-complete categories (CRI = +1[N = 3050; 42.6%]; CRI ≥ + 2 [N = 905; 12.6%]). Risk-adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression. Incomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval] = 1.53 [1.29-1.80]), those undergoing single-arterial CABG (AHR = 1.27 [1.04-1.54]) and multi-arterial CABG (AHR = 2.18 [1.60-2.99]), as well as in patients with 3-Vessel (AHR = 1.37 [1.16-1.62]) and, to a lesser degree, with 2-Vessel (AHR = 1.67 [0.53-5.23]) coronary disease. Supra-complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRI = +1] = 0.94 [0.87-1.03]); AHR [CRI ≥ +2] = 0.74 [0.64-0.85]), and was driven by a significantly decreased mortality risk in single-arterial CABG (AHR [CRI = +1] = 0.90 [0.81-0.99]; AHR [CRI ≥ +2] = 0.64 [0.53-0.78]); and 3-Vessel disease patients (AHR [CRI = +1] = 0.94 [0.86-1.04]; and AHR [CRI ≥ +2] = 0.75 [0.63-0.88]) with no impact in multi-arterial CABG (AHR [CRI = +1] = 1.07 [0.91-1.26]; AHR [CRI ≥ +2] = 0.93 [0.73-1.17]). Incomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supra-complete revascularization is associated with improved survival in patients with 3-Vessel CAD, and in single-arterial but not multi-arterial CABG.


Use of ballasted flocculation (BF) sludge for the manufacturing of lightweight aggregates.
Ballasted flocculation (BF) is an efficient way to remove the turbidity from surface water. The objective of the present study is to optimize the ballast (magnetite), coagulant (poly aluminum chloride) concentration and pH for efficient turbidity removal from surface water. To do this, the sludge produced from an optimized dose of a BF treatment was utilized for the production of lightweight (LW) aggregates by combining it with hard clay and sewage sludge. The LW aggregates were formed by means of rapid sintering in the temperature range of 1000-1200 °C with an exposure time of 10 min. The physical properties of the LW aggregates, in this case the leaching of heavy metals, the bulk density and the microstructure, were investigated. The results indicated that corresponding ballast and coagulant concentrations of 0.75 g/L and 30 mg/L (poly aluminum chloride (PAC)) resulted in the maximum removal efficiency of ≈95%. Using a mixture of BF sludge (30 wt%), dry sewage sludge (20 wt%), and hard clay (50 wt%), aggregates with a density of around 1.0 g/cm3 could be produced. In addition, it was confirmed that the manufactured aggregate was environmentally stable as the elution of heavy metals was suppressed.


Novel indol-3-yl-thiosemicarbazone derivatives: Obtaining, evaluation of in vitro leishmanicidal activity and ultrastructural studies.
Parasitic diseases still represent serious public health problems, since the high and steady emergence of resistant strains is evident. Because parasitic infections are distributed predominantly in developing countries, less toxic, more efficient, safer and more accessible drugs have become desirable in the treatment of the infected population. This is the case of leishmaniasis, an infectious disease caused by a protozoan of the genus Leishmania sp., responsible for triggering pathological processes from the simplest to the most severe forms leading to high rates of morbidity and mortality throughout the world. In the search for new leishmanicidal drugs, the thiosemicarbazones and the indole fragments have been identified as promising structures for leishmanicidal activity. The present study proposes the synthesis and structural characterization of new indole-thiosemicarbazone derivatives (2a-j), in addition to performing in vitro evaluations through cytotoxicity assays using macrophages (J774) activity against forms of Leishmania infantum and Leishmania amazonensis promastigote as well as ultrastructural analyzes in promastigotes of L. infantum. Results show that the indole-thiosemicarbazone derivatives were obtained with yield values varying from 32.09 to 94.64%. In the evaluation of cytotoxicity, the indole-thiosemicarbazone compounds presented CC50 values between 53.23 and 357.97 μM. Concerning the evaluation against L. amazonensis promastigote forms, IC50 values ranged between 12.31 and > 481.52 μM, while the activity against L. infantum promastigotes obtained IC50 values between 4.36 and 23.35 μM. The compounds 2d and 2i tested against L. infantum were the most promising in the series, as they showed the lowest IC50 values: 5.60 and 4.36 respectively. The parasites treated with the compounds 2d and 2i showed several structural alterations, such as shrinkage of the cell body, shortening and loss of the flagellum, intense mitochondrial swelling and vacuolization of the cytoplasm leading the parasite to cellular unviability. Therefore, the indole-thiosemicarbazone compounds are promising because they yield considerable synthesis, have low cytotoxicity to mammalian cells and act as leishmanicidal agents.


Who was William Ray Rumel?
This report details the life and contributions of William Ray Rumel, an early cardiovascular surgeon known for his innovations, particularly the "Rumel tourniquet," and the ability to repair the diseased mitral valve without replacing it.


Atypical modulation of cognitive control by arousal in autism.
We examined the effects of viewing high-arousal pictures on regional brain activations elicited by a cognitive control task in participants with high-functioning autism and neurotypical controls. Specifically, using event-related functional magnetic resonance imaging, we assessed the effects of brief presentations of highly arousing pictures (i.e., both very pleasant and very unpleasant) on the processing of stimuli requiring cognitive control. Similar to previous findings, when stimuli with high cognitive control demands were preceded by low-arousal pictures, individuals with autism demonstrated regional brain activations that were comparable to neurotypical control individuals. When the presentation of the cognitive control stimuli was preceded by high-arousal pictures, however, the control group was characterized by relatively greater activation in the right lateral midfrontal cortex in response to cognitive control stimuli. In contrast, preceding high-arousal stimuli did not modulate activity elicited in this region by cognitive control stimuli in the autism group. Differential modulation of right lateral midfrontal activation by high-arousal stimuli in autism is consistent with the "inefficiency model" of brain functioning in autism spectrum disorders, and contributes to a growing body of evidence that autism may be characterized by anomalous sensitivity of cognitive control brain regions to social-emotional context.


Sulfatase activity assay using an activity-based probe by generation of N-methyl isoindole under reducing conditions.
Sulfatases catalyze the hydrolysis of sulfate esters that are present in a range of biomolecules. This is an important step in several biological processes such as cellular degradation, hormone regulation, and cell signaling. We have developed a new activity-based sulfatase probe (probe 1) that generates a fluorescent N-methylisoindole upon hydrolysis by sulfatase. Because of the autoxidation of N-methylisoindole, the sulfatase activity was also tested under reducing conditions, containing either glutathione (GSH) or tris(2-carboxyethyl)phosphine (TCEP), exhibiting little change in kinetic parameters compared to non-reducing conditions. Probe 1 displayed reasonable kinetic parameters under both non-reducing and reducing conditions, among which the use of Tris buffer and Tris buffer containing GSH appeared to be appropriate conditions for inhibitor screening. Probe 1 showed stronger intensity upon treatment with sulfatase under neutral conditions than under acidic conditions, but it still has limitations in the selectivity for a specific sulfatase. Nevertheless, the fluorescent signal generated as a result of the release of N-methylisoindole after treatment of probe 1 with sulfatase provides a new assay for measuring sulfatase activity that could be adapted for high throughput screening.


Comparison of adult food protein-induced enterocolitis syndrome to crustaceans and immediate-type food allergy.
Food protein-induced enterocolitis syndrome (FPIES) is increasingly found in adults. FPIES requires different treatment from immediate-type food allergy (FA) in emergency medicine. However, no comparison of the clinical presentations of these diseases has been reported. To compare the clinical presentations and causative crustaceans of adult FPIES and FA using a standardized questionnaire and to thereby lay the groundwork for establishing an algorithm that distinguishes those diseases. We conducted a retrospective cohort study of crustacean-avoidant adults by telephone interview based on the previously reported diagnostic criteria for adult FPIES to compare the clinical features and crustacean intake status between FPIES and FA. Of 73 adult patients with crustacean allergy, 8 (11%) were diagnosed with having FPIES and 53 (73%) FA. Compared with the patients with FA, those with FPIES had a longer latency period (P < .01), more episodes (P = .02), longer duration of symptoms (P = .04), more frequent abdominal distention (P = .02), and severe colic pain (P = .02). Half of the patients with FPIES experienced fear of death during an episode. Panulirus japonicus (Japanese spiny lobster) and Homarus weber (lobster) were significantly common FPIES-causing foods. A statistically significant 62.5% of patients with FPIES were able to ingest some type of crustacean. FPIES and FA can be clearly differentiated by the abdominal symptoms, latency period, and duration of episodes. Furthermore, some patients with FPIES do not necessarily need to avoid all crustaceans. Our findings lay the groundwork for establishing an algorithm that distinguishes FPIES from FA in adults.


Protein consumption in Canadian habitual diets: usual intake, inadequacy, and the contribution of animal- and plant-based foods to nutrient intakes.
The 2019 Canada's Food Guide (CFG) emphasizes consumption of plant protein with implications for protein adequacy and nutrient intakes, yet a baseline with which to compare future dietary trends that may result from its adoption is not available. The objectives were to assess usual protein intake, inadequacy, and the contribution of animal- and plant-based foods to intake of protein, nutrients, and energy in Canada. Twenty-four-hour dietary recalls from the 2015 Canadian Community Health Survey - Nutrition were used to assess dietary intake among adults (n = 13 616). The National Cancer Institute method was used to estimate usual protein intake and inadequacy. Population ratios were used to determine the contribution of animal- and plant-based foods to intake of protein, nutrients, and energy. Usual protein intake averaged 79.47 ± 0.70 g/d; inadequacy was highest for females ≥71 y (9.76 ± 2.04%). Top protein contributors were red and processed meat (21.6 ± 0.55%), poultry and eggs (20.1 ± 0.81%), cereals, grains, and breads (19.5 ± 0.31%), and dairy (16.7 ± 0.38%). Dairy contributed most to calcium (53.4 ± 0.61%), vitamin D (38.7 ± 1.01%), but also saturated fat (40.6 ± 0.69%), whereas cereals, grains, and breads contributed most to iron (46.5 ± 0.57%) and vegetables and fruit to potassium (32 ± 0.45%). Given that animal sources contributed overwhelmingly to protein intake in 2015, dietary shifts towards plant protein needed to meet the 2019 CFG recommendations may pose a challenge, particularly for populations most at risk of inadequacy. Novelty: Older adults and females are most at risk of not meeting protein recommendations. Animal sources contribute two-thirds of the protein consumed by Canadian adults.


Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors.
Heart failure is a common complication among patients with type 2 diabetes mellitus and is associated with significantly increased risks of subsequent morbidity and mortality. Until recently, therapies and strategies were lacking to attenuate this excess risk of heart failure in this population. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a unique class of glucose-lowering therapies that have multisystem health benefits. Three large cardiovascular outcomes trials have demonstrated consistent reductions in heart failure events among patients with type 2 diabetes mellitus with, or at risk for, atherosclerotic cardiovascular disease. Another trial recently showed that an SGLT2 inhibitor, canagliflozin, also significantly reduced heart failure events among patients with type 2 diabetes mellitus and albuminuric chronic kidney disease. The SGLT2 inhibitor class represents an important new therapeutic approach for the prevention of heart failure in at-risk patients with type 2 diabetes mellitus, and is actively being studied for use in treating patients with heart failure (with or without type 2 diabetes mellitus). (Supplementary video "Preventing and Treating Heart Failure with Sodium-Glucose Co-Transporter 2 Inhibitors" is available online.).


Cyanogen induced phosphorylation of D-fructose.
Cyanogen-induced phosphorylation of D-fructose at pH 8.8 led to the formation of a phosphorylated sugar identified as alpha-D-furcto-pyranose 2-phosphate on the basis of its chromatographic and electrophoretic properties, its lability to hydrolysis by alkaline phosphatase, the rate of its acid-catalysed hydrolysis, the results of periodate oxidation and optical rotatory measurements.


Constructing a novel zwitterionic surface of PVDF membrane through the assembled chitosan and sodium alginate.
A novel zwitterionic surface of PVDF membrane with significantly improved antifouling properties was prepared though pressure-assisted layer by layer self-assembly method based on the electrostatic interactions of chitosan (CS), sodium alginate (SA) and polyfunctional lysine. For the modified C-S-C-S-L membrane, the contact angle decreased to 35°, the bovine serum albumin (BSA) adsorption mass of static fouling on the membrane surface decreased to 10μg/cm(2), and the secondary water flux recovery rate (FRR) of dynamic fouling of BSA and humic acid (HA) pollutants increased to 98% and 99%, respectively, exhibiting excellent antifouling performance. The results demonstrated that using charged bio-macromolecules and amino acids to build zwitterionic surface was effective and convenient to change the interface properties of the separation membrane through the pressure-assisted self-assembly modification method, and provided a new way for the industrial scale hydrophilic modification of hydrophobic porous membrane materials.


[Healthcare and Christianity, the human person at the heart of God's concerns].
French society is still influenced by its Christian traditions and many patients are attached to this aspect. It is therefore important to clarify the reference framework put forward by the Christian religion when dealing with the notions of health, illness and care in this context. The human person, with his/her strengths and weaknesses, is at the heart of Christian reflections.


Inhaled β-agonist does not modify sympathetic activity in patients with COPD.
Neurohumoral activation is present in COPD and might provide a link between pulmonary and systemic effects, especially cardiovascular disease. Because long acting inhaled β-agonists reduce hyperinflation, they could reduce sympathoexcitation by improving the inflation reflex. We aimed to evaluate if inhaled therapy with salmeterol reduces muscle sympathetic nerve activity (MSNA) evaluated by microneurography. MSNA, heart rate, blood pressure, and respiration were continually measured. After baseline recording of 20 minutes, placebo was administered; after further 45 minutes salmeterol (50 μg) was administered which was followed by a further 45 minutes of data recording. Additionally, lung function, plasma catecholamine levels, arterial pulse wave velocity, heart rate variability, and baroreflex sensitivity were evaluated. Following 4 weeks of treatment with salmeterol 50 μg twice daily, measurements were repeated without placebo administration. A total of 32 COPD patients were included. Valid MSNA signals were obtained from 18 patients. Change in MSNA (bursts/100 heart beats) following acute administration of salmeterol did not differ significantly from the change following placebo (-1.96 ± 9.81 vs. -0.65 ± 9.07; p = 0.51) although hyperinflation was significantly reduced. Likewise, no changes in MSNA or catecholamines were observed after 4 weeks. Heart rate increased significantly by 3.8 ± 4.2 (p < 0.01) acutely and 3.9 ± 4.3 bpm (p < 0.01) after 4 weeks. Salmeterol treatment was safe and well tolerated. By using microneurography as a gold standard to evaluate sympathetic activity we found no change in MSNA following salmeterol inhalation. Thus, despite an attenuation of hyperinflation, the long acting β-agonist salmeterol does not appear to reduce nor incite sympathoexcitation. This study was registered with the European Clinical Trials Database (EudraCT No. 2011-001581-18) and ClinicalTrials.gov ( NCT01536587 ).


Offspring fitness in relation to population size and genetic variation in the rare perennial plant species Gentiana pneumonanthe (Gentianaceae).
Seeds were sampled from 19 populations of the rare Gentiana pneumonanthe, ranging in size from 5 to more than 50,000 flowering plants. An analysis was made of variation in a number of life-history characters in relation to population size and offspring heterozygosity (based on seven polymorphic isozyme loci). Life-his-tory characters included seed weight, germination rate, proportion of seeds germinating, seedling mortality, seedling weight, adult weight, flower production per plant and proportion of plants flowering per family. Principal component analysis (PCA) reduced the dataset to three main fitness components. The first component was highly correlated with adult weight and flowering performance, the second with germination performance and the third component with seed and seedling weight and seedling mortality. The latter two components were considered as being maternally influenced, since these comprised life-history traits that were significantly correlated with seed weight. Multiple regression analysis showed that variation in the first fitness component was mainly associated with heterozygosity and not with population size, while the third fitness component was only correlated with population size and not with heterozygosity. The latter relationship appeared to be non-linear, which suggests a stronger loss of fitness in the smallest populations. The second (germination) component was neither correlated with population size nor with genetic variation. There was only a weak association between population size, heterozygosity and the population coefficients of variation for each life history character. Most correlation coefficients were negative, however, which suggests that there is more variation among progeny from smaller populations. We conclude that progeny from small populations of Gentiana pneumonanthe show reduced fitness and may be phenotypically more variable. One of the possible causes of the loss of fitness is a combination of unfavourable environmental circumstances for maternal plants in small populations and increased inbreeding. The higher phenotypic variation in small populations may also be a result of inbreeding, which can lead to deviation of individuals from the average phenotype through a loss of developmental stability.


Flow synthesis, characterization, anticoagulant activity of xylan sulfate from sugarcane bagasse.
High-value utilization of hemicellulose is critical to improve the append value of integrated biorefineries. In this research, the alkali-soluble sugarcane bagasse hemicellulose was sulfated using chlorosulfonic acid and N,N-dimethylformamide/LiCl under homogeneous conditions. With the aid of flow technique, a rapid, mild, and efficient method for the synthesis of xylan sulfate with high molecular weight and controllable degree of substitution was achieved. The results showed that the reaction time and the degradation of xylan chain were drastically reduced compared to the "in flask" batch conditions. High molecular weight of the product (Mw = 148,217) with a reasonable degree of substitution (DS = 1.49) could be obtained even at room temperature in 10 min under the present flow system. Anticoagulant experiments showed good anticoagulant activity of the resultant xylan sulfate, which could significantly prolong the activated partial thromboplastin time and thrombin time. This work not only provides a novel method for the synthesis of xylan sulfate, but also offers new opportunities for the production of other functional polysaccharide derivatives under the flow reaction conditions.


"In-between orthorexia" profile: the co-occurrence of pathological and healthy orthorexia among male and female non-clinical adolescents.
The profile of adolescents with orthorexic eating behaviors remains to be explored. This study is the first to explore the typology of Lebanese adolescents from a large non-clinical sample based on orthorexia nervosa (ON) and healthy orthorexia (HO). A total of 555 adolescents (aged between 15 and 18 years) completed a set of questionnaires assessing orthorexic behaviors, self-esteem, stress, depressive and anxiety symptoms. Cluster analysis based on ON and HO scores was used to identify the typology of the sample. More precisely, this analysis was used to reveal and distinguish between naturally occurring subgroups of individuals with different orthorexic eating profiles, within the studied sample. Further, a series of one-way ANOVA was used to compare observed clusters based on their scores on used questionnaires. This analysis was used to capture the behavioral and psychological differences between previously yielded subgroups of individuals. Cluster analysis based on ON and HO scores yielded 3 distinct groups: "Low orthorexia", "Moderate in-between orthorexia" and "High in-between orthorexia". While the first group represented individuals with no particular (healthy or pathological) interest in healthy eating, the two latter groups represented those with respectively moderate and high degrees of an interest in healthy eating that has both pathological and healthy aspects. Significant differences between clusters regarding their levels of stress, depression, anxiety and self-esteem was observed, yet they were found to be negligible due to poor effect sizes. Findings from this study suggest that ON and HO can indeed co-occur among adolescents, that this co-occurrence can be experienced at different severity levels. Low effect sizes for ANOVA comparisons may suggest the possibility of the co-occurrence of ON and HO reducing the negative effects of ON behavior to some degree. The potential role of confusion around what constitutes "healthy eating" in the emergence of these "in-between orthorexia" profiles is put forward.


Can Triatoma virus inhibit infection of Trypanosoma cruzi (Chagas, 1909) in Triatoma infestans (Klug)? A cross infection and co-infection study.
Triatoma virus occurs infecting Triatominae in the wild (Argentina) and in insectaries (Brazil). Pathogenicity of Triatoma virus has been demonstrated in laboratory; accidental infections in insectaries produce high insect mortality. When more than one microorganism enters the same host, the biological interaction among them differs greatly depending on the nature and the infection order of the co-existing species of microorganisms. We studied the possible interactions between Triatoma virus (TrV) and Trypanosoma cruzi (the etiological agent of Chagas disease) in three different situations: (i) when Triatoma virus is inoculated into an insect host (Triatoma infestans) previously infected with T. cruzi, (ii) when T. cruzi is inoculated into T. infestans previously infected with TrV, and (iii) when TrV and T. cruzi are inoculated simultaneously into the same T. infestans individual. Trypanosoma cruzi infection was found in 57% of insects in the control group for T. cruzi, whereas 85% of insects with previous TrV infection were infected with T. cruzi. TrV infection was found in 78.7% of insects in the control group for TrV, whereas insects previously infected with T. cruzi showed 90% infection with TrV. A total of 67.9% of insects presented simultaneous infection with both types of microorganism. Our results suggest that TrV infection could increase adhesion of T. cruzi to the intestinal cells of triatomines, but presence of T. cruzi in intestinal cells would not increase the possibility of entry of TrV into cells. Although this study cannot explain the mechanism through which TrV facilitates the infection of triatomines with T. cruzi, we conclude that after TrV replication, changes at cellular level should occur that increase the adhesion of T. cruzi.


MHC class II-independent CD25+ CD4+ CD8alpha beta+ alpha beta T cells attenuate CD4+ T cell-induced transfer colitis.
CD4+ alpha beta T cell populations that develop in mice deficient in MHC class II (through 'knockout' of either the Aalpha, or the Abeta chain of the I-A(b) molecule) comprise a major 'single-positive' (SP) CD4+ CD8- subset (60-90%) and a minor 'double-positive' (DP) CD4+ CD8alpha beta+ subset (10-40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from Aalpha(-/-) or Abeta(-/-) B6 mice into congenic RAG(-/-) hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25+ T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25- CD4+ T cells.


Suture erosion rates and long-term surgical outcomes in patients undergoing sacrospinous ligament suspension with braided polyester suture.
The objective of the study was to describe suture erosion rates and long-term surgical outcomes in patients undergoing sacrospinous ligament suspension (SSLS) using braided polyester suture. This was a retrospective cohort study of patients undergoing SSLS for vaginal prolapse between 1999 and 2005. Outcomes included rate and timing of suture erosion and related symptoms, additional treatment, and long-term success rates. Sixty-four of 92 subjects had SSLS with braided polyester suture and had an average follow-up of 26.5 months. Suture-related complications occurred in 36% of patients. Mean time to presentation was 18.9 months. Vaginal bleeding occurred in 74%, and suture removal was required in 70% of patients with symptoms. Recurrent prolapse developed in 27% of patients, but additional therapy was required in only 6%. Permanent braided polyester sutures are associated with a high rate of suture-related complications over the long term and frequently require additional intervention to resolve associated symptoms.


Literature review to integrate information to assist workers to select masks even at workplaces without occupational health personnel.
With the COVID-19 pandemic, the idea of universal mask wearing to prevent infecting others when one becomes infected has prevailed among people. In general, any workplace is not exempt and workers are required to wear a mask while working at the sites. This study aims to integrate information to assist workers to select effective protectors for the prevention of droplet infection even at workplaces without occupational health personnel. A total of 94 studies were included in this study: 91 studies were identified in MEDLINE, which was used for the literature search, and an additional three studies were identified from other information sources. The studies were checked to eliminate duplication and narrowed down to 31 based on the titles and abstracts. The contents of the 31 studies were read through and then 19 studies were extracted for careful reading. Regarding the protectors used at workplaces, it was suggested that (1) workers continue to use respiratory protectors as needed at sites where respiratory protectors such as an N95 respirator had to be used even before the spread of COVID-19 and (2) wear surgical masks, multi-layer cloth masks, or hybrid fabric masks made of several types of fabrics that are recommended in terms of preventing dissemination of droplets and protecting against inhalation of droplets, selected according to the working conditions, taking account of air permeability, breathability, and durability.


Doppler ultrasound scoring to predict chemotherapeutic response in advanced breast cancer.
Doppler ultrasonography (US) is increasingly being utilized as an imaging modality in breast cancer. It is used to study the vascular characteristics of the tumor. Neoadjuvant chemotherapy is the standard modality of treatment in locally advanced breast cancer. Histological examination remains the gold standard to assess the chemotherapy response. However, based on the color Doppler findings, a new scoring system that could predict histological response following chemotherapy is proposed. Fifty cases of locally advanced infiltrating duct carcinoma of the breast were studied. The mean age of the patients was 44.5 years. All patients underwent clinical, Doppler and histopathological assessment followed by three cycles of CAF (Cyclophosphamide, Adriamycin and 5-Fluorouracil) chemotherapy, repeat clinical and Doppler examination and surgery. The resected specimens were examined histopathologically and histological response was correlated with Doppler findings. The Doppler characteristics of the tumor were graded as 1-4 for <25%, 25-50%, >50% and complete disappearance of flow signals respectively. A cumulative score was calculated and compared with histopathological response. Results were analyzed using Chi square test, sensitivity, specificity, positive and negative predictive values. The maximum Doppler score according to the proposed scoring system was twelve and minimum three. Higher scores corresponded with a more favorable histopathological response. Twenty four patients had complete response to chemotherapy. Sixteen of these 24 patients (66.7%) had a cumulative Doppler score more than nine. The sensitivity of cumulative score >5 was 91.7% and specificity was 38.5%. The area under the ROC curve of the cumulative score >9 was 0.72. Doppler scoring can be accurately used to objectively predict the response to chemotherapy in patients with locally advanced breast cancer and it correlates well with histopathological response.


Reliability of the Achilles tendon tap reflex evoked during stance using a pendulum hammer.
The tendon tap reflex (T-reflex) is often evoked in relaxed muscles to assess spinal reflex circuitry. Factors contributing to reflex excitability are modulated to accommodate specific postural demands. Thus, there is a need to be able to assess this reflex in a state where spinal reflex circuitry is engaged in maintaining posture. The aim of this study was to determine whether a pendulum hammer could provide controlled stimuli to the Achilles tendon and evoke reliable muscle responses during normal stance. A second aim was to establish appropriate stimulus parameters for experimental use. Fifteen healthy young adults stood on a forceplate while taps were applied to the Achilles tendon under conditions in which postural sway was constrained (by providing centre of pressure feedback) or unconstrained (no feedback) from an invariant release angle (50°). Twelve participants repeated this testing approximately six months later. Within one experimental session, tap force and T-reflex amplitude were found to be reliable regardless of whether postural sway was constrained (tap force ICC=0.982; T-reflex ICC=0.979) or unconstrained (tap force ICC=0.968; T-reflex ICC=0.964). T-reflex amplitude was also reliable between experimental sessions (constrained ICC=0.894; unconstrained ICC=0.890). When a T-reflex recruitment curve was constructed, optimal mid-range responses were observed using a 50° release angle. These results demonstrate that reliable Achilles T-reflexes can be evoked in standing participants without the need to constrain posture. The pendulum hammer provides a simple method to allow researchers and clinicians to gather information about reflex circuitry in a state where it is involved in postural control.


Direct cloning and heterologous expression of the salinomycin biosynthetic gene cluster from Streptomyces albus DSM41398 in Streptomyces coelicolor A3(2).
Linear plus linear homologous recombination-mediated recombineering (LLHR) is ideal for obtaining natural product biosynthetic gene clusters from pre-digested bacterial genomic DNA in one or two steps of recombineering. The natural product salinomycin has a potent and selective activity against cancer stem cells and is therefore a potential anti-cancer drug. Herein, we separately isolated three fragments of the salinomycin gene cluster (salO-orf18) from Streptomyces albus (S. albus) DSM41398 using LLHR and assembled them into intact gene cluster (106 kb) by Red/ET and expressed it in the heterologous host Streptomyces coelicolor (S. coelicolor) A3(2). We are the first to report a large genomic region from a Gram-positive strain has been cloned using LLHR. The successful reconstitution and heterologous expression of the salinomycin gene cluster offer an attractive system for studying the function of the individual genes and identifying novel and potential analogues of complex natural products in the recipient strain.


Energy levels of Moiré patterns: relation to human perception.
Quantitative analyses were undertaken to obtain a priori information regarding the energy levels of the random-dot display or Moiré patterns as a function of the angle of rotation theta by employing classical Newtonian mechanics. The energy profiles for these patterns were found to be similar for 10 degrees <t heta < 350 degrees in which the energies exhibited a maxima. For 10 degrees > or = theta > or = 350 degrees , the profiles were found to be dramatically different, especially for the focus pattern where the profile exhibited a downward spike. Specifically, it was found that the minimum energy levels correspond to the angles of rotation where the profiles are perceived by humans. These results may provide insights into the underlying mechanism responsible for the perception of these patterns and information processing in the brain, specifically in the cerebral cortex.


Epidemiology of cytomegalovirus infection in end stage renal disease.
Since primary cytomegalovirus (CMV) infection is a cause of morbidity among renal transplant recipients, we undertook a prospective study of our maintenance hemodialysis patients and personnel to determine whether these sources posed a risk for transmission of CMV. Our study of 85 patients and 49 personnel showed that CMV was detected in eight nontransplanted, older dialysis patients and 13 patients who had lost their allograft. In spite of the presence of CMV on the unit, no patient or staff member developed primary infection from interpersonal transmission or from transfused frozen red blood cells. All primary infections in renal transplant patients could be accounted for by acquisition from the transplanted kidney, thus eliminating the dialysis unit or frozen blood as a risk to either patients or personnel.


Application of colloidal photonic crystals in study of organoids.
As alternative disease models, other than 2D cell lines and patient-derived xenografts, organoids have preferable in vivo physiological relevance. However, both endogenous and exogenous limitations impede the development and clinical translation of these organoids. Fortunately, colloidal photonic crystals (PCs), which benefit from favorable biocompatibility, brilliant optical manipulation, and facile chemical decoration, have been applied to the engineering of organoids and have achieved the desirable recapitulation of the ECM niche, well-defined geometrical onsets for initial culture, in situ multiphysiological parameter monitoring, single-cell biomechanical sensing, and high-throughput drug screening with versatile functional readouts. Herein, we review the latest progress in engineering organoids fabricated from colloidal PCs and provide inputs for future research.


Comparative characterization of cytokine production by concanavalin A-activated splenocytes from BALB/c and C57BL/6 mice after cold exposure.
The level of cytokines produced by ConA activated splenocytes was studied in male BALB/c and C57Bl/6 mice after single and repeated cold exposure (-20 degrees C, 3 min). Single cold exposure significantly decreased IL-2, -3, -4, -5, -10, -12, IFN-gamma production in BALB/c mice and decreased IL-2 content and increased TNF-alpha level in C57Bl/6 mice. Repeated cold exposure normalized the content of IL-2, -4, -10, -12, and IFN-gamma in BALB/c mice, which reflects the development of adaptive immune reactions. In C57Bl/6 mice IL-2, -3, -5, -10, -12, and IFN-gamma production remained significantly decreased, which attested to dysadaptive processes.


Immersive virtual reality simulated learning environment versus role-play for empathic clinical communication training.
The use of immersive virtual reality simulated learning environments (VR SLEs) for improving clinical communication can offer desirable qualities including repetition and determinism in a safe environment. The aim of this study was to establish whether the mode of delivery, VR SLE versus clinical role-play, could have a measurable effect on clinical empathic communication skills for MRI scenarios. A split-cohort study was performed with trainee practitioners (n = 70) and qualified practitioners (n = 9). Participants were randomly assigned to four groups: clinician VR (CVR), clinician role-play (CRP), trainee VR (TVR), and trainee RP (TRP). Clinical communication skills were assessed using two methods: firstly, a self-reported measure - the SE-12 communication questionnaire and, secondly, a training and assessment tool developed by a panel of experts. Participants in the VR trainee (TVR) and clinician (CVR) groups reported 11% (P < 0.05) and 7.2% (P < 0.05) improvements in communication confidence post training, whereas trainees assigned to the role-play (TRP) intervention reported a 4.3% (P < 0.05) improvement. Empirical assessment of communication training scores assessing a participant's ability to select empathic statements showed the TVR group performed 5% better on average than their role-play counterparts (P < 0.05). The accuracy of participant's selection of appropriate empathic responses was shown to differ significantly following the training intervention designed to improve interactions with patients that present for an MRI scan. The results may demonstrate the capacity for immersion into an emotional narrative in a VR environment to increase the user's susceptibility for recalling and selecting empathic terminology.


Induction of mRNA specific for cytochrome P1-450 in wild type and variant mouse hepatoma cells.
We have used a cDNA probe specific for an aromatic hydrocarbon-inducible form of cytochrome P-450 to analyze the accumulation of enzyme-specific mRNA in wild type Hepa 1c1c7 cells and in variant cells defective in aryl hydrocarbon hydroxylase induction. In wild type cells, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces a 25-50-fold increase in the steady state concentration of cytochrome P1-450-specific RNA. This RNA binds to oligo(dT)-cellulose and migrates in agarose gels as a single species of about 2900 nucleotides. Dot hybridization analyses of total RNA indicate that half-maximal induction of P1-450 mRNA occurs at about 10 pM TCDD; maximal induction occurs at about 100 pM TCDD. Parallel increases occur in aryl hydrocarbon hydroxylase activity. RNA induction precedes aryl hydrocarbon hydroxylase induction by 2-4 h. Kinetic analyses of mRNA induction in response to submaximal concentrations of TCDD reveal no change in the degradation of P1-450 mRNA during induction. We detect an increase in P1-450 mRNA 30 min after TCDD administration. Full accumulation of mRNA occurs in cells in which protein synthesis is inhibited by 95-97%. Variant cells with decreased TCDD receptors exhibit decreased basal and inducible levels of P1-450 mRNA. Variant cells with a defect in nuclear localization of the inducer-receptor complex exhibit virtually no basal or inducible levels of P1-450 mRNA. Hybrid cells formed by fusing these different variants contain wild type basal and inducible levels of P1-450 mRNA. We conclude that expression of the cytochrome P1-450 gene is under transcriptional control and requires nuclear localization of the TCDD receptor.


Proton NMR study of the cyanide metmyoglobin reconstituted with meso-tetraalkylhemins. Dynamic free rotation of the synthetic hemins in the heme pocket.
Incorporation of the three synthetic hemins, Fe(III) meso-tetraalkylporphyrins with the methyl, ethyl, or n-propyl groups, into apomyoglobin was followed by spectrophotometry, and the stoichiometric complex formation was confirmed. The reconstituted myoglobins bind with an equimolar amount of cyanide to exhibit visible absorption peaks at 419, 570, and 608 nm. The spectral feature was independent of the cyanide concentrations. Proton NMR spectra of the cyanide complexes resolved the pyrrole-proton signals of the hemins in a -5 to -15-ppm region, which is comparable with that of the corresponding signals of deuterohemin-containing low-spin methemoproteins. These spectral observations indicate the presence of the NC-Fe-N(His-F8) structure in the presently reconstituted cyanide metmyoglobins. The pyrrole-proton NMR signals of the hemins in cyanide metmyoglobins appeared as a singlet, doublet, or quartet for the methyl, ethyl, or n-propyl hemin complexes, respectively. The systematic NMR spectral changes suggest the dynamic free rotation of the alkylhemins about the Fe-N(His-F8) bond. Temperature-dependent NMR spectral transition of the meso-tetraethylhemin-reconstituted myoglobin was consistent with thermally regulated dynamic free rotation of the hemin in the myoglobin heme pocket.


Antibiotic synergist OM19r reverses aminoglycoside resistance in multidrug-resistant Escherichia coli.
The continued emergence and spread of multidrug-resistant (MDR) bacterial pathogens require a new strategy to improve the efficacy of existing antibiotics. Proline-rich antimicrobial peptides (PrAMPs) could also be used as antibacterial synergists due to their unique mechanism of action. Utilizing a series of experiments on membrane permeability, In vitro protein synthesis, In vitro transcription and mRNA translation, to further elucidate the synergistic mechanism of OM19r combined with gentamicin. A proline-rich antimicrobial peptide OM19r was identified in this study and its efficacy against Escherichia coli B2 (E. coli B2) was evaluated on multiple aspects. OM19r increased antibacterial activity of gentamicin against multidrug-resistance E. coli B2 by 64 folds, when used in combination with aminoglycoside antibiotics. Mechanistically, OM19r induced change of inner membrane permeability and inhibited translational elongation of protein synthesis by entering to E. coli B2 via intimal transporter SbmA. OM19r also facilitated the accumulation of intracellular reactive oxygen species (ROS). In animal models, OM19r significantly improved the efficacy of gentamicin against E. coli B2. Our study reveals that OM19r combined with GEN had a strong synergistic inhibitory effect against multi-drug resistant E. coli B2. OM19r and GEN inhibited translation elongation and initiation, respectively, and ultimately affected the normal protein synthesis of bacteria. These findings provide a potential therapeutic option against multidrug-resistant E. coli.


Draft Genome Sequences of Seven Strains of Paenibacillus spp. (Phylum Firmicutes) Inhabiting the Seeds of Cucumis melo L. (Cantaloupe) and Exhibiting Plant Probiotic Traits.
Here, we report the draft genome sequences of seven Paenibacillus sp. strains (EKM202P, EKM205P, EKM206P, EKM207P, EKM208P, EKM211P, and EKM212P) that were previously isolated from cultivated surface-sterilized seeds of Cucumis melo L. (cantaloupe). These candidate Paenibacillus plant probiotics displayed in vitro growth-promoting traits and suppressive activity against root-associated fungal/oomycete pathogens.


Electrochemical DNA detection of hepatitis E virus genotype 3 using PbS quantum dot labelling.
The aim of this study was to develop a highly specific electrochemical DNA sensor using functionalized lead sulphide (PbS) quantum dots for hepatitis E virus genotype 3 (HEV3) DNA target detection. Functionalized-PbS quantum dots (QDs) were used as an electrochemical label for the detection of HEV3-DNA target by the technique of square wave anodic stripping voltammetry (SWASV). The functionalized-PbS quantum dots were characterized by UV-vis, FTIR, XRD, TEM and zeta potential techniques. As-prepared, functionalized-PbS quantum dots have an average size of 4.15 ± 1.35 nm. The detection platform exhibited LOD and LOQ values of 1.23 fM and 2.11 fM, respectively. HEV3-DNA target spiked serum is also reported.Graphical abstract.


Effect of disorder outside the CuO2 planes on Tc of copper oxide superconductors.
The effect of disorder on the superconducting transition temperature T(c) of cuprate superconductors is examined. Disorder is introduced into the cation sites in the plane adjacent to the CuO2 planes of two single-layer systems, Bi(2.0)Sr(1.6)Ln(0.4)CuO(6+delta) and La(1.85-y)Nd(y)Sr0.15CuO4. Disorder is controlled by changing rare earth (Ln) ions with a different ionic radius in the former, and by varying the Nd content in the latter with the doped carrier density kept constant. We show that this type of disorder works as weak scatterers in contrast to the in-plane disorder produced by Zn, but remarkably reduces T(c), suggesting novel effects of disorder on high-T(c) superconductivity.


Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes.
Antioxidant response element (ARE)-mediated expression and coordinated induction of genes encoding detoxifying enzymes is one mechanism of critical importance to cellular protection against oxidative stress. In the present report, we demonstrate that nuclear transcription factors Nrf2 and Nrf1 associate with Jun (c-Jun, Jun-B and Jun-D) proteins to upregulate ARE-mediated expression and coordinated induction of detoxifying enzymes in response to antioxidants and xenobiotics. Nrf-Jun association/heterodimerization and binding to the ARE required unknown cytosolic factor(s). Nrf2 containing one mutated leucine in its leucine zipper region was more efficient in upregulation of ARE-mediated gene expression, as compared to Nrf1 with two mutated leucines.


Associations of Chinese visceral adiposity index and new-onset stroke in middle-aged and older Chinese adults: an observational study.
Stroke represents the second most prevalent contributor to global mortality. The Chinese Visceral Adiposity Index (CVAI) serves as an established metric for assessing visceral adiposity in the Chinese population, exhibiting prognostic capabilities. This investigation aimed to explore the association of CVAI and new-onset stroke among middle-aged and older Chinese populations. The study employed data from the 2011 and 2018 China Health and Retirement Longitudinal Study (CHARLS) to assess the association of CVAI and the incidence of new-onset stroke. Utilizing a directed acyclic graph (DAG), 10 potential confounders were identified. Moreover, to explore the association between CVAI and new-onset stroke, three multifactor logistic regression models were constructed, accounting for the identified confounders and mitigating their influence on the findings. The study comprised 7070 participants, among whom 417 (5.9%) experienced new-onset strokes. After controlling for confounding variables, regression analysis suggested that the new-onset stroke's highest risk was linked to the fourth quartile (Q4) of the CVAI, with an odds ratio (OR) of 2.33 and a 95% confidence interval (CI) of 1.67-3.28. The decision tree analysis demonstrated a heightened probability of new-onset stroke among hypertensive individuals with a CVAI equal to or greater than 83, coupled with a C-reactive protein level no less than 1.1 mg/l. Age seemed to have a moderating influence on the CVAI and new-onset stroke association, exhibiting a more prominent interaction effect in participants under 60 years. In middle-aged and older Chinese populations, a linear relationship was discerned between CVAI and the probability of new-onset stroke. CVAI provides a predictive framework for stroke incidence in this demographic, laying the groundwork for more sophisticated risk prediction models that improve the precision and specificity of stroke risk evaluations.


Identification of 33 novel HLA alleles in Arab potential bone marrow donors.
Between 2008 and April 2018, we recruited more than 37 000 potential Arab donors to the Hadassah Bone Marrow Donor Registry, all of whom were typed for high resolution HLA-A, -B, and -DRB1. In addition, more than 22% of them were also typed for their HLA-C and -DQB1 alleles. A comparison of the sequences obtained from these donors with the IPD-IMGT/HLA Database showed 33 novel alleles from five loci (HLA-A, -B, -C, -DR, -DQ). All of these novel HLA alleles were detected in the local Arab communities; 79% of these alleles have not been described in other groups yet and remain unique to the local Arab communities.


Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction.
Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target.


Inhibition of proteolytic activation of influenza virus hemagglutinin by specific peptidyl chloroalkyl ketones.
Lysates of cultured cells have been analyzed for arginine-specific endoproteases using peptidyl-p-nitroanilides as chromogenic substrates. The enzymes present in MDBK, MDCK, VERO, BHK, and chick embryo cells required lysine-arginine or arginine-arginine pairs as cleavage sites, whereas chorioallantoic membrane cells contained, in addition, an activity that could cleave at a single arginine. The effect of peptidyl chloroalkyl ketones on the activation of the fowl plague virus hemagglutinin by the proteases specific for paired basic residues has been investigated. When virions containing uncleaved hemagglutinin were incubated with lysates of uninfected cells, cleavage was completely inhibited by peptidyl chloroalkyl ketones containing paired basic residues at a concentration of 1 mM. In contrast a compound containing a single arginine had no inhibitory activity. When dibasic peptidyl chloroalkyl ketones were added to infected cell cultures, cleavage of hemagglutinin and multiple cycles of virus replication were inhibited at 10 mM. However, a 100- to 200-fold increase of the inhibitory activity in intact cells could be achieved by N-terminal acylation. These studies suggest a potential role of peptidyl chloroalkyl ketones as antiviral agents.


Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells.
Dendritic cells (DCs) are characterized by their extraordinary capacity to induce T-cell responses, providing the opportunity of DC-based cancer vaccination protocols. In the present study, we conducted a phase I/II clinical trial to determine the capability of DCs differentiated from immunomagnetically isolated CD14+ monocytes and pulsed with a carcinoembryonic antigen-derived altered peptide (CEAalt) to induce specific CD8+ T cells in cancer patients. Nine patients with CEA-positive colorectal cancer (n=7) or lung cancer (n=2) were enrolled in this study. Autologous CD14+ monocytes were isolated by large-scale immunomagnetic separation and differentiated to mature DCs in sufficient numbers and at high purity. After incubation with the CEAalt peptide and keyhole limpet hemocyanin, DCs were administered to patients intravenously at dose levels of 1 x 10(7) and 5 x 10(7) cells. Patients received four immunizations every second week. ELISPOT analysis revealed a vaccine-induced increase in the number of CEAalt peptide-specific Interferon (IFN)-gamma producing CD8+ T cells in five of nine patients and of CD8+ T lymphocytes recognizing the native CEA peptide in three of nine patients. In addition, CD8+ T lymphocytes derived from one patient exhibiting an immunological response after vaccination efficiently lysed peptide-loaded T2 cells and tumor cells. Immunization was well tolerated by all patients without severe signs of toxicity. Vaccination with CEAalt-pulsed DCs derived from immunomagnetically isolated CD14+ monocytes efficiently expand peptide-specific CD8+ T lymphocytes in vivo and may be a promising alternative for cancer immunotherapy.


Controlled local delivery of tetracycline with polymer strips in the treatment of periodontitis.
Several antibacterial agents have been studied as a means to produce bactericidal or bacteriostatic activity as an adjunct to mechanical treatment of periodontal disease. The primary purpose of this study was to evaluate the efficacy of tetracycline strips administered singly or in multiples in conjunction with root planing, versus root planing alone, or to an untreated control. Secondary purposes were to compare gingival crevicular fluid (GCF) volume and GCF concentrations of tetracycline in pockets treated with strips; to evaluate strip insertion time; and to compare ease of placement for single or multiple strips. Using a 4-quadrant design, 4 test teeth in 24 patients were treated with either root planing and single strip application; root planing and multiple strip application; root planing alone; or an untreated control. Single and multiple strip placement resulted in a significant reduction in probing depth (P = 0.033) compared to root planing and untreated groups. The multiple strip group significantly decreased bleeding on probing (P = 0.05) compared to all other treatment groups. There was no treatment effect on GCF; however, there was a significant reduction in the GCF volume over time (P = 0.001). The time required for placement was, on average, 1.9 minutes for single strips and 3.25 minutes for multiple strips. Our data suggest that multiple strips are superior to a single strip in reducing bleeding on probing, and that local delivery of tetracycline is superior to root planing alone in reducing probing depth.


[A comparative ontogenetic study of respiration and oxidative phosphorylation of chicken myocardium mitochondria].
When adding alpha-ketoglutarate and glutamate the intensity of respiration by the myocardium mitochondria increases gradually from the 15th day of embryonic development till the chicken hatching out. In the presence of succinate respiration of mitochondria of 15- and 20-day embryos and 5-day chickens is almost the same and decreases noticeably in adult chickens. When the above-mentioned substrates are added the value of P/O gradually decreases during the chicken development.


SPECT imaging of peripheral amyloid in mice by targeting hyper-sulfated heparan sulfate proteoglycans with specific scFv antibodies.
Amyloid deposits are associated with a broad spectrum of disorders including monoclonal gammopathies, chronic inflammation, and Alzheimer's disease. In all cases, the amyloid pathology contains, in addition to protein fibrils, a plethora of associated molecules, including high concentrations of heparan sulfate proteoglycans (HSPGs). We have evaluated radioiodinated scFvs that bind HS for their ability to image amyloid deposits in vivo. scFv's with different binding characteristics were isolated by phage display using HS extracted from bovine kidney or mouse and human skeletal muscle glycosaminoglycans (GAGs). Following purification and radioiodination, the biodistribution of (125)I-scFv's was assessed in mice with inflammation-associated AA amyloidosis or in amyloid-free mice by using SPECT imaging, biodistribution measurements and tissue autoradiography. Four different scFv's all showed binding in vivo to amyloid in the spleen, liver and kidney of diseased mice; however, three of the scFv's also bound to sites within these organs in disease free mice. One scFv specific for hypersulfated HSPGs preferentially bound amyloid and did not accumulate in healthy tissues. These data indicate that HS expressed in amyloid deposits has unique qualities that can be distinguished from HS in normal tissues. A scFv specific for rare hypersulfated HS was used to selectively image AA amyloid in mice with minimal retention in normal tissue.


Identification of Fusion Transcripts from Unaligned RNA-Seq Reads Using ChimeRScope.
Fusion transcripts that are frequent in cancer can be exploited to understand the mechanisms of malignancy and can serve as diagnostic or prognostic markers. Several algorithms have been developed to predict fusion transcripts from DNA or RNA data. The majority of these algorithms align sequencing reads to the reference transcriptome for predicting fusions; however, this results in several undetected fusions due to the highly perturbed nature of cancer genomes. Here, we describe a novel method that uses a k-mer based algorithm to predict fusion transcripts accurately using the unaligned reads from the regular RNA-seq data analysis pipelines.