Switchable Diastereoselectivity in the Fluoride-Promoted Vinylogous Mukaiyama-Michael Reaction of 2-[(Trimethylsilyl)oxy]furan Catalyzed by Crown Ethers.
The fluoride-promoted vinylogous Mukaiyama-Michael reaction of 2-[(trimethylsilyl)oxy]furan with diverse α,β-unsaturated ketones is described. The TBAF-catalyzed VMMR afforded high anti-diastereoselectivity irrespective of the solvents used. The KF/crown ethers catalytic systems proved to be highly efficient in terms of yields and resulted in a highly diastereoselective unprecedented solvent/catalyst switchable reaction. Anti-adducts were obtained as single diastereomers or with excellent diastereoselectivities when benzo-15-crown-5 in CH2Cl2 was employed. On the other hand, high syn-diastereoselectivities (from 73:27 to 96:4) were achieved by employing dicyclohexane-18-crown-6 in toluene. On the basis of DFT calculations, the catalysts/solvent-dependent switchable diastereoselectivities are proposed to be the result of loose or tight cation-dienolate ion pairs.


Anchoring Ultrafine ZnFe2O4/C Nanoparticles on 3D ZnFe2O4 Nanoflakes for Boosting Cycle Stability and Energy Density of Flexible Asymmetric Supercapacitor.
Heterostructure-based metal oxide thin films are recognized as the leading material for new generation, high-performance, stable, and flexible supercapacitors. However, morphologies, like nanoflakes, nanotubes, nanorods, and so forth, have been found to suffer from issues related to poor cycle stability and energy density. Thus, to circumvent these problems, herein, we have developed a low-cost, high surface area, and environmentally benign self-assembled ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructure electrode via anchoring ZnFe2O4 and carbon nanoparticles using an in situ biomediated green rotational chemical bath deposition approach for the first time. The synthesized ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructure thin films demonstrate an excellent specific capacitance of 1884 F g-1 at a current density of 5 mA cm-2. Additionally, all solid-state flexible asymmetric supercapacitor devices were designed on the basis of ZnFe2O4 nanoflake@ZnFe2O4/C nanoparticle heterostructures as the negative electrode and reduced graphene oxide and energy density of 81 Wh kg-1 at a power density of 3.9 kW kg-1. Similarly, the asymmetric device exhibits ultralong cycle stability of 35 000 cycles by losing only 2% capacitance. The excellent performance of the device is attributed to the self-assembled organization of the heterostructures. Moreover, the in situ biomediated green strategy is also applicable for the synthesis of other metal oxide and carbon-based heterostructure electrodes.


Efficacy of fenbendazole against migrating Ascaris suum larvae in pigs.
Twenty-four weanling crossbred pigs were inoculated with 10,000 embryonated Ascaris suum eggs. The infection was aborted in 1 group (n = 8 pigs) with fenbendazole (3 mg/kg of body weight) given on postinfection days 2, 3, and 4 and in a 2nd group (n = 8 pigs) given fenbendazole at the same rate on postinfection days 6, 7, and 8; a 3rd group (n = 8 pigs) was not treated with fenbendazole. All pigs were necropsied at 24 days after they were inoculated. Fenbendazole was 99% effective against A suum larvae in the 2 treated groups. Early treated pigs had significantly higher daily weight gains (P less than 0.05) and were 22% more efficient in feed conversion than were nontreated pigs. Lung weights increased linearly with length of exposure to migrating A suum larvae (P less than 0.10). Liver weights were greater in treated pigs than in non-treated pigs (P less than 0.01). A negative correlation existed between number of liver lesions and liver weights of all pigs (P less than 0.05).


Solitary fibrous tumor of the orbit presenting 20 years after Hodgkin's disease.
A 54-year-old white male patient presented with a painless, slowly progressive proptosis and downward displacement of his right eye. He had been treated for Hodgkin's disease 20 years earlier. MRI revealed a well-circumscribed retro- and suprabulbar mass measuring 24 mm in its maximal diameter. The mass was isointense with brain on T1-weighted images, displayed a low signal on T2-weighted images and showed postcontrast enhancement. The tumor was removed in its entirety via an anterior orbitotomy. Histopathologic, immunohistochemical and ultrastructural studies revealed a solitary fibrous tumor. Both immunohistochemical and electron microscopic findings were essential in differentiating this entity from other similar soft-tissue lesions. Only 11 other cases of orbital solitary fibrous tumor have been reported in the literature. To our knowledge, this is the first one presenting after Hodgkin's disease.


Evaluating the malignant potential of intraductal papillary mucinous neoplasms of the pancreas: added value of non-enhanced endoscopic ultrasound to supplement non-enhanced magnetic resonance imaging.
To evaluate the diagnostic performance of combining non-enhanced magnetic resonance imaging (MRI) and non-enhanced endoscopic ultrasonography (EUS) for assessing the malignant potential of lesions in patients with intraductal papillary mucinous neoplasms of the pancreas (IPMNs). Data from 38 patients histopathologically diagnosed with IPMN adenomas or IPMN adenocarcinomas were retrospectively analysed. Preliminary univariate and multivariate analyses were conducted to identify statistically significant associations. Three blinded radiologists evaluated the image sets to assess the diagnostic performance of combined use of non-enhanced MRI and EUS as opposed to non-enhanced MRI alone in distinguishing malignant from benign lesions. Observer performance and interobserver variability were determined using receiver-operating-characteristic curve analysis and weighted κ statistics. Multivariate analyses identified a significant difference between the abrupt change in the main pancreatic duct (MPD) calibre with distal pancreatic atrophy and the signal intensity of lesion-to-spinal cord ratio on MRI; a significant difference was observed in MPD size on EUS. Diagnostic performance assessments of the image sets did not differ significantly between the blinded radiologists. The clinical utility of non-enhanced EUS may be attributive in evaluating IPMN that has already been evaluated by non-enhanced MRI.


Giving schools a nudge: can behavioural insights improve recruitment of schools to randomised controlled trials?
It is widely acknowledged that recruitment to randomised controlled trials (RCTs) is challenging, particularly trials that operate across multiple sites. A research area in need of further high-quality evaluation, including RCTs, is school-based mental health interventions for refugee children and adolescents. However, engaging schools with interventions and associated evaluations can be challenging. This paper explores the application of behavioural insights, i.e. evidence-based understanding of how people behave and make decisions, to RCT recruitment at the school level via email communications. A pilot study of applying behavioural insights to mail outs attempting to recruit schools to a RCT of a trauma-focused group intervention for refugee children and adolescents experiencing symptoms of post-traumatic stress is reported. Rates of school involvement between the behavioural insights approach (n = 31) and a standard outreach approach (n = 65) are compared. Schools were more likely to give a positive response to the mail out designed using the behavioural insights framework than standard outreach. Accounts of recruitment strategies such as this are valuable additions to the literature on RCT methodology given the potential for recruitment issues to affect trial operations.


Activation of the planar cell polarity formin DAAM1 leads to inhibition of endothelial cell proliferation, migration, and angiogenesis.
The Wnt/planar cell polarity (PCP) pathway regulates directed cell movement during development and was recently found to play a critical role in endothelial cell proliferation and angiogenesis [Zhang Y, et al. (2006) Chem Biol 13:1001-1009; Masckauchan TN, et al. (2006) Mol Biol Cell 17:5163-5172]. However, the mechanisms by which PCP signaling components regulate angiogenesis remain unknown. We report that expression of a constitutively active C-terminal domain of Dishevelled-associated activator of morphogenesis 1 (DAAM1) selectively inhibited endothelial cell proliferation. Moreover, this activated construct suppressed endothelial cell migration and the ability to form coordinated networks in vivo and in vitro. Although constitutively active DAAM1 (CDAAM1) induced both actin polymerization and microtubule (MT) stabilization, the stabilization of MTs alone was sufficient to inhibit endothelial cell growth selectively. Inhibition of actin polymerization alone by jasplakinolide treatment failed to reproduce the inhibitory effects of CDAAM1. These results indicate that DAAM1 regulates endothelial cell growth through MT stabilization in a cell type-selective manner and suggest that PCP signaling plays a pivotal role in angiogenesis by regulating MT stabilization.


Brighter Time: A Smartphone App Recording Cognitive Task Performance and Illuminance in Everyday Life.
Light is an influential regulator of behavioural and physiological state in mammals. Features of cognitive performance such as memory, vigilance and alertness can be altered by bright light exposure under laboratory and field conditions. However, the importance of light as a regulator of performance in everyday life is hard to assess and has so far remained largely unclear. We set out to address this uncertainty by developing a tool to capture measures of cognitive performance and light exposure, at scale, and during everyday life. To this end, we generated an app (Brighter Time) which incorporated a psychomotor vigilance (PVT), an N-back and a visual search task with questionnaire-based assessments of demographic characteristics, general health, chronotype and sleep. The app also measured illuminance during task completion using the smartphone's intrinsic light meter. We undertook a pilot feasibility study of Brighter Time based on 91-week-long acquisition phases within a convenience sample (recruited by local advertisements and word of mouth) running Brighter Time on their own smartphones over two study phases in winter and summer. Study compliance was suitable (median = 20/21 requested task completions per subject). Statistically significant associations were observed between subjective sleepiness and performance in all tasks. Significant daily variations in PVT and visual search performance were also observed. Higher illuminance was associated with reduced reaction time and lower inverse efficiency score in the visual search. Brighter Time thus represents a viable option for large-scale collection of cognitive task data in everyday life, and is able to reveal associations between task performance and sleepiness, time of day and current illuminance. Brighter Time's utility could be extended to exploring associations with longer-term patterns of light exposure and/or other light metrics by integrating with wearable light meters.


Effects of Lemon Beverage Containing Citric Acid with Calcium Supplementation on Bone Metabolism and Mineral Density in Postmenopausal Women: Double-Blind 11-Month Intervention Study.
A critical factor for preventing osteoporosis after menopause is attenuation of the accelerated turnover rate of bone metabolism. The present randomized controlled study was conducted to clarify the effects of a lemon beverage with calcium (Ca) supplementation that makes use of the chelating action of citric acid. Comprehensive evaluations of bone were performed by assessments of bone mineral density (BMD) and biomarkers related to bone turnover. Seventy-nine postmenopausal women were enrolled and asked to participate in an 11-month continuous intake of the test beverages. The subjects were divided into three groups: those who consumed a lemon beverage containing citric acid with Ca supplementation (LECA group), those who consumed a lemon beverage containing citric acid without Ca supplementation (LE group), and those who consumed no test beverage (control group). Using a double-blind protocol, subjects in the LECA and LE groups consumed one bottle containing 290 mL of the test beverage each day. The ratio of change in BMD after 11 months was significantly higher in the LECA group as compared to the control and LE groups. The LECA group also showed significant decreases in concentrations of tartrate-resistant acid phosphatase 5b (TRACP-5b), a bone resorption marker, and bone alkaline phosphatase (BAP) as compared to the other groups, as well as a significant decrease in concentration of osteocalcin (OC), a bone formation marker, as compared to the LE group. Based on our findings, we speculated that bone resorption and bone formation in postmenopausal women might be suppressed along with an increase in Ca resorption caused by chelation of citric acid in association with continuous ingestion of a Ca-supplemented lemon beverage containing citric acid, resulting in suppression of high bone metabolic turnover. In addition, the results provide information regarding BMD maintenance in the bones of the trunk, including the lumbar spine and proximal femur.


Role of anions on the crystal structures of copper(II) and zinc(II) complexes of a tunable butterfly cyclophane macrocycle.
Three crystal structures of a ditopic cyclophane ligand (L) in which two 1,5,8,12-tetraamine molecules have been attached through methylene spacers to the ortho positions of a benzene ring are reported. The first one (1) corresponds to the tetraprotonated free macrocycle (H4L4+) having two tetrachlorozincate(II) counteranions (C24H54O2N8Cl8Zn2, a = 9.1890(2) A, b = 14.0120(3) A, c = 15.3180(3) A, alpha = 89.2320(7) degrees , beta = 82.0740(6) degrees , gamma = 83.017(1) degrees , Z = 2.00, triclinic, P); the second one (2) is of a binuclear Cu2+ complex having coordinated chloride anions and perchlorate counteranions (C24H58O14N8Cl4Cu2 a = 9.9380(2) A, b = 30.2470(6) A, c = 53.143(1) A, orthorhombic, F2dd, Z = 18), and the third one (3) corresponds to an analogous Zn2+ complex that has been crystallized using triflate as counteranion (C26H(51.2)O(6.6)N8Cl2F6S2Zn2 a = 8.472(5) A, b = 9.310(5), c = 13.745(5) A, alpha = 84.262(5) degrees , beta = 77.490(5) degrees , gamma = 73.557(5) degrees , triclinic, P, Z = 2). The analysis of the crystallographic data clearly shows that the conformation of the macrocycle and, in consequence, the overall architecture of the crystals are controlled by the anions present in the moiety, pi-pi-stacking associations, and hydrogen bonding interactions. The protonation and stability constants for the formation of the Cu2+ and Zn2+ complexes in aqueous solution have been determined potentiometrically in 0.15 mol dm(-3) NaClO4 at 298.1 K. Intramolecular hydrogen bonding defines the protonation behavior of the compound. Positive cooperativity is observed in the formation of the Cu2+ complexes.


Molecular evolution using intramolecular acyl migration on myo-inositol benzoates with thermodynamic and kinetic selectors.
A molecular evolution model was successfully demonstrated by combining the intramolecular acyl migration on inositol tribenzoates and boron selectors. The addition of boric acid to 12 members of DCL (dynamic combinatorial library) induced the dramatic amplification of myo-I(2,4,6)Bz(3) (1) with up to 94 % under thermodynamic (see Figure 1 c) control while a portion of phenyl boronic acid caused two significant different distributions: under kinetic control, the pre-equilibrium of DCL shifted to induce the exclusive amplification of 1,4,6-tribenzoyl myo-inositol (7) with decrease of other members up to 82 % from the mixture (see Figure 2 b), and changed gradually to form 2,4,6-tribenzoyl myo-inositol (1) with up to 96 % under thermodynamic control (Figure 2 c).


Age and sex bias in the reconstruction of past population structures.
Palaeodemographical studies are founded on the assumption that the sex and age distribution of the skeletal sample reflects the constitution of the original population. It is becoming increasingly clear, however, that the type and amount of information that may be derived from osteoarchaeological collections are related to the state of preservation of remains. This work proposes a new method to evaluate bone preservation, to identify age and sex biases in the preservation of human skeletal remains, and to assess whether differences in preservation patterns are more dependent on factors intrinsic or extrinsic to anatomical features of human bones. Three osteological collections and over 600 skeletons were observed. The state of preservation of human bones was assessed using three preservation indexes: the anatomical preservation index (API), the bone representation index (BRI), and the qualitative bone index (QBI). The results suggest that subadult skeletons are generally more poorly preserved and with bones less well-represented than adult skeletons. Among subadults, female and male skeletons have different patterns of preservation according to their age. This pattern of preservation depends on intrinsic anatomical properties of bones themselves, while external factors can only increase these differences in the state of preservation and representation of osseous remains. It is concluded from this that failure to recognize these differences may lead to misleading interpretations of paleodemography of past human populations.


Clinical effects of Lewy body pathology in cognitively impaired individuals.
There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting with Alzheimer's disease (AD) pathology (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein in 883 memory clinic patients with mild cognitive impairment or dementia from the BioFINDER study. Twenty-three percent had LB pathology, of which only 21% fulfilled clinical criteria of Parkinson's disease or dementia with Lewy bodies at baseline. Among these LB-positive patients, 48% had AD pathology. Fifty-four percent had AD pathology in the whole sample (17% of mild cognitive impairment and 24% of patients with dementia were also LB-positive). When examining independent cross-sectional effects, LB pathology but not amyloid-β or tau, was associated with hallucinations and worse attention/executive, visuospatial and motor function. LB pathology was also associated with faster longitudinal decline in all examined cognitive functions, independent of amyloid-β, tau, cognitive stage and a baseline diagnosis of dementia with Lewy bodies/Parkinson's disease. LB status provides a better precision-medicine approach to predict clinical trajectories independent of AD biomarkers and a clinical diagnosis, which could have implications for the clinical management of cognitive impairment and the design of AD and LB drug trials.


The optimal number of surveys when detectability varies.
The survey of plant and animal populations is central to undertaking field ecology. However, detection is imperfect, so the absence of a species cannot be determined with certainty. Methods developed to account for imperfect detectability during surveys do not yet account for stochastic variation in detectability over time or space. When each survey entails a fixed cost that is not spent searching (e.g., time required to travel to the site), stochastic detection rates result in a trade-off between the number of surveys and the length of each survey when surveying a single site. We present a model that addresses this trade-off and use it to determine the number of surveys that: 1) maximizes the expected probability of detection over the entire survey period; and 2) is most likely to achieve a minimally-acceptable probability of detection. We illustrate the applicability of our approach using three practical examples (minimum survey effort protocols, number of frog surveys per season, and number of quadrats per site to detect a plant species) and test our model's predictions using data from experimental plant surveys. We find that when maximizing the expected probability of detection, the optimal survey design is most sensitive to the coefficient of variation in the rate of detection and the ratio of the search budget to the travel cost. When maximizing the likelihood of achieving a particular probability of detection, the optimal survey design is most sensitive to the required probability of detection, the expected number of detections if the budget were spent only on searching, and the expected number of detections that are missed due to travel costs. We find that accounting for stochasticity in detection rates is likely to be particularly important for designing surveys when detection rates are low. Our model provides a framework to do this.


Prospective randomized controlled trial: early weight bearing after conservative treatment of Weber B ankle fractures (pancake trial).
Different studies have shown that weightbearing is safe in stable transsyndesmotic, isolated lateral simple ankle fractures. Despite this evidence, AO guidelines still recommend immobilization with above-the-knee cast for 4-6 weeks for these fractures. The objective of this study was to compare the outcomes of mobilization and weightbearing to those of immobilization and non-weightbearing in patients with stable transsyndesmotic, lateral isolated simple ankle fractures. Fifty patients were randomly assigned to permissive weightbearing in a walking boot or non-weightbearing immobilization using a below-the-knee cast. Primary outcome was ankle functionality as scored by the Olerud-Molander Ankle Score (OMAS). Secondary outcomes were radiological displacement of fracture, range of motion (ROM), calf circumference, and RAND 36-item health survey. Patients were in follow-up for 24 months. Ankle functionality after six and twelve weeks was significantly higher for the intervention group, with respectively 30 points (p = 0.001) and 10 points (p = 0.015) of difference. ROM improved significantly in the intervention group after six weeks. All fractures showed radiological progression of fracture healing. RAND 36-item showed differences in both physical (60.3 vs. 46.3, p = 0.017) and mental (78.5 vs. 58.2, p = 0.034) components in favor of the intervention group. In 16% of patients who initially showed stable fractures on radiographic imaging, joint dislocation was identified on weightbearing radiographs prior to randomization, leading to exclusion. Weightbearing and mobilization using a walking boot may be a safe treatment for patients with stable Weber B fractures.


Assessment of cognitive screening tests as predictors of driving cessation: A prospective cohort study of a median 4-year follow-up.
Assessing fitness to drive and predicting driving cessation remains a challenge for primary care physicians using standard screening procedures. The objective of this study was to prospectively evaluate the properties of neuropsychological screening tests, including the Trail Making Test (TMT), Clock Drawing Test (CDT), Montreal Cognitive Assessment (MoCA), Useful Field of View (UFOV), and Timed Up and Go (TUG) test, in predicting driving cessation for health reasons in drivers older than 70 years of age. This prospective cohort study, with a median follow-up of 4 years for drivers of 70 years old or older with an active driving license in Switzerland, included 441 participants from a driving refresher course dedicated to volunteer senior drivers. Cases were drivers reported in the national driving registry who lost their license following a health-related accident, who were reported as unfit to drive by their physician or voluntarily ceased driving for health reasons. Survival analysis was used to measure the hazard ratio of driving cessation by adjusting for age and sex and to evaluate the predictive value of combining 3 or more positive tests in predicting driving cessation during a 4-year follow-up. A total of 1738 person-years were followed-up in the cohort, with 19 (4.3%) having ceased driving for health reasons. We found that participants with a TMT-A < 54 sec and TMT-B < 150 sec at baseline had a significantly lower cumulative hazard of driving cessation in 4 years than those with slower performance (adjusted HR 3, 95% CI: 1.16-7.78, p = 0.023). Participants who performed a CDT ≥ 5 had a significantly lower cumulative hazard of driving cessation (adjusted HR 2.89, 95% CI: 1.01-7.71, p = 0.033). Similarly, an MoCA score ≥ 26, TUG test <12 sec or a UFOV of low risk showed a lower but not significant cumulative risk at a median follow-up of 4 years. When using tests as a battery, those with three or more positive tests out of five were 3.46 times more likely to cease driving (95% CI: 1.31-9.13, p = 0.012). The CDT and the TMT may predict driving cessation in a statistically significant way, with a better performance than the UFOV and MoCA tests during a median 4-year follow-up. Combining tests may increase the predictability of driving cessation. Although our results are consistent with current evidence, they should be interpreted with precaution; more than 95% of the participants above the set threshold were able to continue driving for 4 years without any serious incident.


Predatory journals: The rise of worthless biomedical science.
In today's world when biomedical science is experiencing continuous threats from various sources, publication of research articles in predatory journals has created a major havoc. These predatory journals are publishing worthless biomedical science which will haunt genuine researchers and keen readers of authentic biomedical journals for several decades. Hence, researchers of various disciplines and academic experience should be continuously made aware of these predatory publishers and potential ways to recognize them. The main aim of this article is to discuss the issues related to predatory publishing, techniques and strategies used by these publishers to prey young inexperienced researchers, and disadvantages of publishing in predatory journals.


Biomechanical functional and sensory modelling of the gastrointestinal tract.
The aim of this review is to describe the biomechanical, functional and sensory modelling work that can be used to integrate the physiological, anatomical and medical knowledge of the gastrointestinal (GI) system. The computational modelling in the GI tract was designed, implemented and evaluated using a series of information and communication technologies-based tools. These tools modelled the morphometry, biomechanics, functions and sensory aspects of the human GI tract. The research presented in this review is based on the virtual physiological human concept that pursues a holistic approach to representation of the human body. Such computational modelling combines imaging data, GI physiology, the gut-brain axis, geometrical and biomechanical reconstruction, and computer graphics for mechanical, electronic and pain analysis. The developed modelling will aid research and ensure that medical professionals benefit through the provision of relevant and precise information about a patient's condition. It will also improve the accuracy and efficiency of the medical procedures that could result in reduced cost for diagnosis and treatment.


[Histone H4 lysine 16 acetylation: from genome regulation to tumoral progression].
The histones, that wrap the DNA to form the nucleosome core, are targeted by diverse post-translational modifications. How those modifications affect DNA accessibility and chromatin folding is a fundamental biological issue. Furthermore, tremendous amounts of data suggest that the loss of specific modifications as well as an inappropriate ectopic pattern of modifications at given loci contributes to the development of several human syndromes as well as cancers. In this review, we focus on the current knowledge of the regulation and impact of histone H4 lysine 16 acetylation on the genome. Recent discoveries highlight its crucial involvement in events such as transcription regulation, chromatin specialization, chromosome compaction and tumoral progression.


Analysis of the resistome of a multidrug-resistant NDM-1-producing Escherichia coli strain by high-throughput genome sequencing.
The resistome of the multidrug-resistant Escherichia coli strain 271 carrying the plasmid-mediated bla(NDM-1) carbapenemase gene was analyzed by high-throughput genome sequencing. The p271A plasmid carrying the bla(NDM-1) gene was 35.9 kb in size and possessed an IncN-type backbone that harbored a novel replicase gene. Acquisition of the bla(NDM-1) gene on plasmid p271A had been likely the result of a cointegration event involving the transposase of Tn5403. The expression of bla(NDM-1) was associated with the insertion sequence ISAba125 likely originating from Acinetobacter baumannii. E. coli 271 accumulated multiple resistance determinants, including five β-lactamase genes (comprising the extended-spectrum β-lactamase CTX-M-15), two 16S RNA methylase ArmA- and RmtB-encoding genes, and the qepA gene encoding an efflux pump involved in resistance to fluoroquinolones. These resistance genes were located on three additional plasmids, of 160 kb (IncA/C), 130 kb (IncF), and 110 kb (IncI1). In addition, several chromosomally encoded resistance determinants were identified, such as topoisomerase mutations, porin modifications and truncations, and the intrinsic ampC gene of E. coli that was weakly expressed. The multidrug resistance pattern observed for E. coli 271 was therefore the result of combined chromosome- and plasmid-encoded mechanisms.


Ifosfamide by bolus as treatment for advanced non-small cell lung cancer.
Ifosfamide at 5 g/m2 was given as a bolus to 48 patients with advanced progressing non-small cell lung cancer. Mesna (5 g/m2) was also given with the ifosfamide, both over 30 min. Further mesna was then given p.o. (3 g/m2) at 4, 8, and 12 h. If oral mesna was not acceptable then one or, if necessary, two 4-h to 6-h infusions (3 g/m2) were administered. A maximum of six courses at 3-weekly intervals was prescribed. A total of 174 courses was administered, and oral mesna was given during 64 courses: discharge was considered possible within 8-10 h after 55% of courses. Haematological toxicity was mild and no renal dysfunction was noted. Two patients became drowsy shortly after ifosfamide, but recovered 24-36 h later. The objective response rate was 29%, with one complete responder. A further 31% of patients (symptomatic responders) with stable disease symptomatically improved after the chemotherapy, by 20 or more points on the Karnofsky scale. The median survival was 5 months for the whole group, and 8 months each for the objective and symptomatic responder groups. Most patients' Karnofsky and respiratory scores improved with the chemotherapy. Ifosfamide with mesna can be given by short infusions, and the mesna given p.o. prevents any urothelial toxicity. Further exploration of short-infusion ifosfamide and mesna therapy would reduce hospitalization and allow for day-case regimens.


Substrate promiscuity in DNA methyltransferase M.PvuII. A mechanistic insight.
M.PvuII is a DNA methyltransferase from the bacterium Proteus vulgaris that catalyzes methylation of cytosine at the N4 position. This enzyme also displays promiscuous activity catalyzing methylation of adenine at the N6 position. In this work we use QM/MM methods to investigate the reaction mechanism of this promiscuous activity. We found that N6 methylation in M.PvuII takes place by means of a stepwise mechanism in which deprotonation of the exocyclic amino group is followed by the methyl transfer. Deprotonation involves two residues of the active site, Ser53 and Asp96, while methylation takes place directly from the AdoMet cofactor to the target nitrogen atom. The same reaction mechanism was described for cytosine methylation in the same enzyme, while the reversal timing, that is methylation followed by deprotonation, has been described in M.TaqI, an enzyme that catalyzes the N6-adenine DNA methylation from Thermus aquaticus. These mechanistic findings can be useful to understand the evolutionary paths followed by N-methyltransferases.


Cattle dung breeding Diptera in pastures in southeastern Brazil: diversity, abundance and seasonallity.
Diptera that breed in undisturbed cattle droppings in pastures present great diversity and abundance, and several species are of veterinary importance and may cause economic losses. To survey the diversity, abundance and seasonality of Diptera associated to this microhabitat, 83 samples of 10 dung pats each were taken from April 1992 to April 1994 in the vicinity of São Carlos, State of São Paulo, Southeastern Brazil. A total of 46,135 Diptera belonging to 20 families and at least 51 species were found to breed in the pats. The most abundant and diverse families were Sepsidae, Muscidae, Sarcophagidae and Sphaeroceridae. In general, the abundance was higher from October to March, the warm and wet months. The importance of some Diptera, both as horn fly enemies and as cattle dung decaying agents, is discussed.


Validation of the Portuguese version of the Psychotic Symptom Rating Scales (PSYRATS).
The Psychotic Symptom Rating Scales (PSYRATS) is a clinical assessment tool that focuses on the detailed measurement of delusions and hallucinations in patients with psychosis. The goal of this study was to examine the psychometric properties of the Portuguese version of the PSYRATS. A sample of 92 outpatients suffering from schizophrenia or schizoaffective disorders and presenting persistent psychotic symptoms was assessed using the PSYRATS and the Positive and Negative Syndrome Scale (PANSS). Good inter-rater reliability, test-retest reliability, concurrent validity and internal consistency were found. Factor analysis of the auditory hallucinations scale items disclosed a four-factor solution: emotion characteristics and disruption factor (factor 1), a physical characteristics factor (factor 2), a control characteristics factor (factor 3) and a cognitive attribution factor (factor 4). Regarding the delusions scale items, a two-factor solution was found: cognitive interpretation and disruption factor (factor 1) and an emotional characteristics (factor 2). The Portuguese version of the PSYRATS partially replicates previously published results in other countries.


Loss of life expectancy derived from a standardized mortality ratio in Denmark, Finland, Norway and Sweden.
The standardized mortality ratio (SMR) is a widely used measure. A recent methodological study provided an accurate approximate relationship between an SMR and difference in lifetime expectancies. This study examines the usefulness of the theoretical relationship, when comparing historic mortality data in four Scandinavian populations. For Denmark, Finland, Norway and Sweden, data on mortality every fifth year in the period 1950 to 2010 were obtained. Using 1980 as the reference year, SMRs and difference in life expectancy were calculated. The assumptions behind the theoretical relationship were examined graphically. The theoretical relationship predicts a linear association with a slope, [Formula: see text], between log(SMR) and difference in life expectancies, and the theoretical prediction and calculated differences in lifetime expectancies were compared. We examined the linear association both for life expectancy at birth and at age 30. All analyses were done for females, males and the total population. The approximate relationship provided accurate predictions of actual differences in lifetime expectancies. The accuracy of the predictions was better when age was restricted to above 30, and improved if the changes in mortality rate were close to a proportional change. Slopes of the linear relationship were generally around 9 for females and 10 for males. The theoretically derived relationship between SMR and difference in life expectancies provides an accurate prediction for comparing populations with approximately proportional differences in mortality, and was relatively robust. The relationship may provide a useful prediction of differences in lifetime expectancies, which can be more readily communicated and understood.


[Tissue basophils in vascular plexuses of the lateral ventricles of the brain in humans and various mammals].
By means of histological and histochemical methods cell composition of vascular plexuses in the lateral ventricles of the rats, dogs and man has been investigated. Besides ependymocytes, endotheliocytes, pericytes, myocytes in the microcirculatory bed, described in literature, tissue basophils (TB) have been revealed and what is more--only in dog and man. The most variable forms and localizations of TB are observed in vascular plexuses of the lateral ventricles of the human brain. The following varieties of TB can be defined: small with ortochromic granularity and large ones with abundant metachromic granularity. Sometimes degranulating TB occur. According to their localization they are divided into stromal (+interstitial++), perivascular subepithelial and intraepithelial. The variable TB localization in the vascular plexuses of the brain can probably demonstrate their participation in performing functions of the hematoencephalic barrier.


The Potential Impact of Widespread Cessation Treatment for Smokers With Depression.
Experts recommend integrating smoking-cessation treatments within U.S. mental health settings, but the population health benefits of doing so have not been estimated. This study simulates the impact of widespread cessation treatment for patients with depression under best-case treatment and maximum potential cessation scenarios. Cessation interventions were simulated for U.S. adult smokers seeing a health professional for depression from 2020 to 2100. Interventions included (1) Any Treatment (behavioral counseling, pharmacological, combination) and (2) Pharmacological Treatment (including counseling), combined with increased mental health service utilization each. These were compared with a maximum potential cessation scenario where all patients with major depression quit smoking. Analyses were conducted in 2016-2020. Widespread uptake of Any Treatment among patients with depression would avert 32,000 deaths and result in 138,000 life-years gained by 2100; Any Treatment combined with 100% mental health service utilization would result in 53,000 and 231,000, respectively. Pharmacological Treatment would avert 125,000 deaths, with 540,000 life-years gained. Pharmacological Treatment combined with 100% mental health service utilization would result in 203,000 deaths averted and 887,000 life-years gained. Health gains under best-case treatment scenarios represent modest fractions of those projected under maximum potential cessation scenarios at current mental health service utilization levels (835,000 deaths averted, 3.73 million life-years gained) and at 100% utilization (1.11 million deaths averted, 5.07 million life years gained). Providing smoking-cessation treatment to patients with depression and increasing mental health service utilization would reduce the toll of tobacco on this population. These gains would be considerably larger if cessation treatments were more effective.


Resistive switching memory based on bioinspired natural solid polymer electrolytes.
A solution-processed, chitosan-based resistive-switching memory device is demonstrated with Pt/Ag-doped chitosan/Ag structure. The memory device shows reproducible and reliable bipolar resistive switching characteristics. A memory device based on natural organic material is a promising device toward the next generation of nonvolatile nanoelectronics. The memory device based on chitosan as a natural solid polymer electrolyte can be switched reproducibly between high and low resistance states. In addition, the data retention measurement confirmed the reliability of the chitosan-based nonvolatile memory device. The transparent Ag-embedded chitosan film showed an acceptable and comparable resistive switching behavior on the flexible plastic substrate as well. A cost-effective, environmentally benign memory device using chitosan satisfies the functional requirements of nonvolatile memory operations.


Exchange bias using a spin glass.
Exchange bias is commonly manifested as the hysteresis-loop shift observed when a ferromagnet is in contact with an antiferromagnet. Here, we report observations of exchange bias with unusual features of a ferromagnet in contact with a spin glass, demonstrating that this is a phenomenon of greater generality. The easily measured properties of the ferromagnet allow access to the internal magnetic degrees of freedom of the glass to which they are coupled. Our results show that a Co/CuMn bilayer system exhibits all the rich phenomena of coercivity enhancement, bias-field shifts and training effects associated with a conventional ferromagnet/antiferromagnet system. Nevertheless, striking differences arise, such as an orientation reversal of the bias field in a small temperature range just below the blocking temperature. We argue that all features can be understood within the context of a random-field model for long-ranged oscillatory Ruderman-Kittel-Kasuya-Yosida (RKKY) coupled spins.


Familial aggregation of multimorbidity in Sweden: national explorative family study.
To examine whether multimorbidity aggregates in families in Sweden. National explorative family study. Swedish Multigeneration Register linked to the National Patient Register, 1997-2015. Multimorbidity was assessed with a modified counting method of 45 chronic non-communicable diseases according to ICD-10 (international classification of diseases, 10th revision) diagnoses. 2 694 442 Swedish born individuals (48.73% women) who could be linked to their Swedish born first, second, and third degree relatives. Twins were defined as full siblings born on the same date. Multimorbidity was defined as two or more non-communicable diseases. Familial associations for one, two, three, four, and five or more non-communicable diseases were assessed to examine risks depending on the number of non-communicable diseases. Familial adjusted odds ratios for multimorbidity were calculated for individuals with a diagnosis of multimorbidity compared with relatives of individuals unaffected by multimorbidity (reference). An initial principal component decomposition followed by a factor analysis with a principal factor method and an oblique promax rotation was used on the correlation matrix of tetrachoric correlations between 45 diagnoses in patients to identify disease clusters. The odds ratios for multimorbidity were 2.89 in twins (95% confidence interval 2.56 to 3.25), 1.81 in full siblings (1.78 to 1.84), 1.26 in half siblings (1.24 to 1.28), and 1.13 in cousins (1.12 to 1.14) of relatives with a diagnosis of multimorbidity. The odds ratios for multimorbidity increased with the number of diseases in relatives. For example, among twins, the odds ratios for multimorbidity were 1.73, 2.84, 4.09, 4.63, and 6.66 for an increasing number of diseases in relatives, from one to five or more, respectively. Odds ratios were highest at younger ages: in twins, the odds ratio was 3.22 for those aged ≤20 years, 3.14 for those aged 21-30 years, and 2.29 for those aged >30 years at the end of follow-up. Nine disease clusters (factor clusters 1-9) were identified, of which seven aggregated in families. The first three disease clusters in the principal component decomposition were cardiometabolic disease (factor 1), mental health disorders (factor 2), and disorders of the digestive system (factor 3). Odds ratios for multimorbidity in twins, siblings, half siblings, and cousins for the factor 1 cluster were 2.79 (95% confidence interval 0.97 to 8.06), 2.62 (2.39 to 2.88), 1.52 (1.34 to 1.73), and 1.31 (1.23 to 1.39), and for the factor 2 cluster, 5.79 (4.48 to 7.48) 3.24 (3.13 to 3.36), 1.51 (1.45 to 1.57), and 1.37 (1.341.40). The results of this explorative family study indicated that multimorbidity aggregated in Swedish families. The findings suggest that map clusters of diseases should be used for the genetic study of common diseases to show new genetic patterns of non-communicable diseases.


Percutaneous vs. surgical placement of hepatic artery indwelling catheters for regional chemotherapy.
Intra-arterial hepatic chemotherapy based on floxuridine infusion is an effective treatment for hepatic metastases from colorectal cancer. The aim of the present study is the comparative analysis of surgical and percutaneous transaxillary approaches to implant a catheter into the hepatic artery for intra-arterial hepatic chemotherapy with floxuridine. Fifty-six patients received an arterial device for intra-arterial hepatic chemotherapy. Twenty-eight patients (LPT group) underwent laparotomy to implant the catheter into the hepatic artery, the other 28 patients (PCT group) received a percutaneous catheter into the hepatic artery through a transaxillary percutaneous access. Safety and efficacy of surgical and percutaneous transaxillary approaches were comparatively analyzed in terms of number of intra-arterial hepatic chemotherapy cycles administered, device-related complications causing suppression of intra-arterial hepatic chemotherapy, and biological costs of the procedures. Mean postoperative hospitalization was 8.2 +/- 2.2 days in the LPT group and 1.8 +/- 0.7 days in the PCT group (P < 0.0001), while mean analgesic requirements were 9.7 +/- 3.2 doses in the LPT group and 2 +/- 0.9 doses in the PCT group (P < 0.0001). Mean number of intra-arterial hepatic chemotherapy cycles administered was 6.5 +/- 4.2 in the LPT group and 4.3 +/- 3.4 in the PCT group (P = 0.038). The overall incidence of device-related complications causing suppression of intra-arterial hepatic chemotherapy was 42.7% in the PCT group and 7.1% in the LPT group (P = 0.005). Surgical implantation is still recommended when laparotomy has to be performed for other contextual procedures, such as colorectal or hepatic resection, while percutaneous transaxillary catheter placement is indicated for palliative or neoadjuvant intra-arterial hepatic chemotherapy.


Effects of arecoline on proliferation of oral squamous cell carcinoma cells by dysregulating c-Myc and miR-22, directly targeting oncostatin M.
Arecoline, the major alkaloid of areca nut, is known to induce oral carcinogenesis, however, its mechanism is still needed to elucidate. This study investigated the effects of arecoline on cell viability and cell-cycle progression of oral squamous cell carcinoma (OSCC) cells as well as a relevant cellular gene expression. The results showed that a low concentration of arecoline (0.025 μg/ml) increased OSCC cell viability, proportion of cells in G2/M phase and cell proliferation. Simultaneously, it induced IL-6, STAT3 and c-Myc expression. Interestingly, c-myc promoter activity was also induced by arecoline. MiR-22 expression in arecoline-treated OSCC cells was suppressed and comparable to an upregulated c-Myc expression. In arecoline-treated OSCC cells, oncostatin M (OSM) expression was significantly upregulated and inversely correlated with miR-22 expression. Likewise, OSM expression and its post-transcriptional activity were significantly decreased in miR-22-transfected OSCC and 293FT cells. This result demonstrated that miR-22 directly targeted OSM. Interestingly, miR-22 played an important role as a tumor suppresser on suppressing cell proliferation, migration and cell-cycle progression of OSCC cells. This result suggested the effect of arecoline to promote cell proliferation and cell-cycle progression of OSCC cells might be involved in induction of c-Myc expression and reduction of miR-22 resulting in OSM upregulation.


Retinol-binding protein 4 and new adipocytokines in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of hepatic dysfunction and is highly correlated with components of the metabolic syndrome such as obesity, insulin resistance and type 2 diabetes. Among others, nutritional factors, physical inactivity, genetic variants and visceral obesity have been identified as risk parameters for NAFLD. The complex pathophysiology of fatty liver degeneration, however, and especially the interaction between hepatocytes and adipose tissue has not been completely elucidated. Furthermore, it is not entirely understood whether insulin resistance generates fatty liver disease or vice versa. Nevertheless, adipocytokines are likely to be involved in the pathogenesis of NAFLD since they are secreted not only from adipose tissue but also from the liver. For several adipocytokines such as leptin, adiponectin, tumor necrosis factor-alpha, retinol binding protein 4 (RBP4) or fetuin-A a crucial role in the development and progression of fatty liver disease has been suggested. It has been accepted that obesity is an independent risk factor for NAFLD. Dysregulation of adipocytokines may represent an important mechanism linking increased fat mass in obesity with the development of fatty liver disease. Here, we discuss the association of RBP4 and other recently discovered adipocytokines and their relation with NAFLD.


Effects of alcohols and counterions on the phase behavior of 1-octyl-3-methylimidazolium chloride aqueous solution.
Phase behavior of ternary systems involving 1-octyl-3-methylimidazolium chloride ([C8mim]Cl), water, and different alcohols (1-hexanol, 1-octanol, 1-decanol, and 1-dodecanol) is investigated at 25 degrees C. With the use of polarized optical microscopy and small-angle X-ray scattering techniques, lyotropic lamellar phases (Lalpha) are identified in all systems, the formation of which is considered as a synergetic result of the hydrophobic force and the hydrogen-bonded network comprising an imidazolium ring, Cl-, water, and alcohols. In these Lalpha phases, alcohol molecules play important roles not only because they could partly penetrate into the palisade layer with their hydroxyl groups extruded to form the network at the aggregate interface, but also because they could partly locate themselves in the interior of the hydrophobic bilayers to twist with the alkyl chains of [C8mim]Cl. Influencing factors such as the carbon chain length and content of different alcohols on these Lalpha phases are discussed. With comparison to analogous ternary systems of [C8mim]BF4 and [C8mim]PF6, it is found that the strong interaction between counterions and alcohols favors the appearance of ordered assemblies.


Demography and evolution of an urban ethnic community: Polish Hill, Pittsburgh.
Polish Hill is an urban, ethnic enclave of approximately 3000 residents residing in a 25-block area of Pittsburgh. This paper documents changes in the fertility, morbidity, and mortality patterns in the community from the turn of the century to the present. The demographic reconstruction is based upon baptismal and marriage records, the administration of demographic proformae and population censuses. The high mortality, morbidity, and fertility variance suggest that the immigrant population has experienced a period of high opportunity for selection in the early 1900's and that Crow's index was gradually reduced to its present level.


Wegener autoantigen and myeloblastin are encoded by a single mRNA.
Myeloblastin is a serine protease that has been identified in the human leukemia cell line HL-60. Down-regulation of this protease can inhibit proliferation and induce differentiation of promyelocyte-like human leukemic cells. Proteinase 3, a serine protease of human neutrophils, has been identified as the Wegener autoantigen. A high level of homology between myeloblastin and proteinase 3 has suggested that they may be a single serine protease. We have recently completed the 5'-terminal nucleotide sequence of proteinase 3 and shown that its mRNA was also expressed in HL-60 cells and in cells from patients with acute myeloid leukemia. Here we demonstrate that myeloblastin and proteinase 3 are encoded by a single mRNA.


Antitumor agents 4. Characterization of free radicals produced during reduction of the antitumor drug 5H-pyridophenoxazin-5-one: an EPR study.
5H-Pyridophenoxazin-5-one (PPH), a new anticancer iminoquinone, is able to inhibit a large number of lymphoblastoid and solid tumor-derived cells at submicromolar concentrations. Molecular modeling calculations indicated that this compound might intercalate into the DNA double strand. This was also supported by nuclear magnetic resonance studies. Since free radicals arising from anticancer quinonic drugs have been proposed to be key species responsible for DNA cleavage, we have aimed to intercept and identify free radicals from PPH generated under bioreductive conditions. The first and second monoelectronic reduction potentials of PPH were measured by means of cyclic voltammetry: the reduction potential of PPH is compatible with its reduction by compounds such as NADH, and suggested that reduction of PPH may play a role in its cytotoxicity. The radical anion PPH(*)(-) was detected by means of electron paramagnetic resonance spectroscopy, and its identification was supported by DFT calculations. EPR experiments in the presence of spin traps 5,5-dimethylpyrroline N-oxide and 5-(diethoxyphosphoryl)-5-methylpyrroline N-oxide suggested the occurrence of an electron transfer between the radical anion of the drug and oxygen resulting in the formation of the superoxide anion (O(2)(*)(-)). The enthalpy of the reaction of PPH(*)(-) with O(2) was determined both in the gas phase and in solution at the B3LYP/6-31+G level using the isodensity PCM method, and the overall process in dimethyl sulfoxide was predicted to be slightly exothermic. We propose that the monoelectronic reduction of PPH in the proximity of DNA may eventually lead to radicals that could cause considerable damage to DNA, thus accounting for the high cytotoxic activity of the drug. Indeed, a comet assay (alkaline single-cell electrophoresis) showed that PPH causes free radical-induced DNA damage.


Mortality Associated with Bacteremia Due to Colistin-Resistant Klebsiella pneumoniae with High-Level Meropenem Resistance: Importance of Combination Therapy without Colistin and Carbapenems.
Combination therapy including colistin and a carbapenem has been found to be associated with lower mortality in the treatment of bloodstream infections (BSI) due to KPC-producing Klebsiella pneumoniae when the isolates show a meropenem or imipenem MIC of <16 mg/liter. However, the optimal treatment of BSI caused by colistin- and high-level carbapenem-resistant KPC-producing K. pneumoniae is unknown. A prospective cohort study including episodes of bacteremia caused by colistin-resistant and high-level meropenem-resistant (MIC ≥ 64 mg/liter) KPC-producing K. pneumoniae diagnosed from July 2012 to February 2016 was performed. The impact of combination therapy on crude 30-day mortality was analyzed by Cox regression using a propensity score as a covariate to control for indication bias and in an inverse probability of treatment weighting (IPTW) cohort. The study sample comprised 104 patients, of which 32 (30.8%) received targeted monotherapy and 72 (69.2%) received targeted combination therapy; none of them received either colistin or a carbapenem. The 30-day crude mortality rate was 30.8% (43.8% in patients treated with monotherapy and 25% in patients receiving combination therapy). In the Cox regression analysis, 30-day mortality was independently associated with septic shock at BSI onset (hazard ratio [HR], 6.03; 95% confidence interval [CI], 1.65 to 21.9; P = 0.006) and admission to the critical care unit (HR, 2.87; 95% CI, 0.99 to 8.27; P = 0.05). Targeted combination therapy was associated with lower mortality only in patients with septic shock (HR, 0.14; 95% CI, 0.03 to 0.67; P = 0.01). These results were confirmed in the Cox regression analysis of the IPTW cohort. Combination therapy is associated with reduced mortality in patients with bacteremia due to colistin-resistant KPC-producing K. pneumoniae with high-level carbapenem resistance in patients with septic shock.


In vitro rejoining of double strand breaks induced in cellular DNA by bleomycin and restriction endonucleases.
We have previously described a cell-free assay that can be employed to study rejoining of radiation-induced DNA double-stranded breaks (dsb) in 'naked' DNA prepared from agarose-embedded cells using an extract of HeLa cells as a source of enzymes. Rejoining of dsb in this assay is absolutely dependent on cell extract and proceeds, under optimal reaction conditions, to an extent and with kinetics similar to those observed in intact cells. Here, we extend these experiments and demonstrate that the assay also supports rejoining of bleomycin and restriction endonuclease-induced dsb, agents that generate dsb with known ends. Rejoining of bleomycin-induced dsb proceeds to an extent and with kinetics similar to those observed with radiation-induced dsb. The kinetics of rejoining of restriction endonuclease-induced dsb are also similar to those of radiation-induced dsb. However, more and more dsb remain unrejoined as the extent of DNA fragmentation increases when enzymes cutting the DNA at frequent intervals are used. Dsb with blunt ends are rejoined with a similar efficiency to dsb with cohesive ends. Rejoining of restriction endonuclease-induced dsb is, in the presence of cell extract, more efficient than in the presence of T4 DNA ligase, suggesting the action in the overall reaction of activities in addition to DNA ligases. The experiments presented generalize the utility of the assay in studying the enzymology of dsb rejoining after treatment with radiomimetic drugs and restriction endonucleases and should be useful in the elucidation of the enzymatic requirements of dsb repair.


Quality assurance of the multileaf collimator with helical tomotherapy: design and implementation.
Quality assurance (QA) of the multileaf collimator (MLC) is a critical step for the delivery of intensity modulated radiation therapy treatment plan. While QA procedures for motor-driven MLC have been published extensively, those for binary MLCs such as the one used for helical tomotherapy have not been presented in the literature, as this is still a fairly new technology. In this study, seven test patterns for the MLC QA of a helical tomotherapy unit have been designed and implemented. The seven test patterns check the MLC alignment, MLC leakage, MLC timing and MLC leaf position error in detail. Those patterns can be easily implemented in any center with a helical tomotherapy unit as part of the routine QA. The QA procedures can be performed using existing QA resources such as solid water phantom and EDR2 film. A software toolkit called "Tomo MLC QA" has been developed to assist in generating the QA procedures and analyzing the results. Our results showed that the helical tomotherapy MLC is very robust, exhibiting interleaf leakage of 0.53% +/-0.09%. Several issues with the MLC have been found and discussed. The QA results also illustrate the utilization and usefulness of the proposed QA procedures.


IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells.
Interleukin (IL)-10 expression is induced in activated hepatic stellate cells (HSC) in vitro and in vivo. We analyzed expression of IL-10 receptor (IL-10R) and coreceptor cytokine receptor family (CRF2-4) in HSC. We aimed to clone and sequence partial cDNA for rat IL-10R and CRF2-4, determine their expression in activated rat HSC in vivo and in vitro, and examine the biological responsiveness of HSC to exogenous IL-10. PCR cloning and sequencing of partial rat IL-10R and CRF2-4 cDNAs revealed 86% homology with corresponding mouse sequences. In hepatic macrophages, Northern blot with cloned IL-10R cDNA detected an expected 3.5-kb transcript, and IL-10R and CRF2-4 mRNAs showed steady constitutive expression after in vitro lipopolysaccharide treatment or cholestatic liver injury. IL-10R mRNA expression, as confirmed by immunohistochemistry, was induced 20.1- and 8.6-fold in HSC from cholestatic livers and 7-day culture-activated HSC, respectively but CRF2-4 mRNA levels were unchanged. Under serum-free conditions, IL-10 had minimal effects on collagen production but reduced DNA synthesis, matrix metalloprotease-2 mRNA levels, and activity in HSC. With serum, IL-10 inhibited both collagen production and DNA synthesis but had no effect on procollagen-alpha(1)(I) mRNA levels. This shows concomitant induction of IL-10R but not CRF2-4 to that of IL-10 by activated HSC in vitro and in vivo and associated acquisition of the responsiveness to IL-10, entailing complex effects on HSC.


[Radiotherapy for Bone Metastases].
Appropriate use of radiotherapy leads to a better patient care. Oncologists may wonder when to apply radiotherapy for painful bone metastases, what patients should particularly be offered radiotherapy, when to apply re-irradiation, when to apply radiotherapy to malignant spinal cord compression, or whether to apply radiotherapy to prevent symptoms. This paper aims to offer non-radiation oncologist physicians knowledge to help them better refer patients to radiation oncology.


Actin filament mechanics in the laser trap.
Numerous biological processes, including muscular contraction, depend upon the mechanical properties of actin filaments. One such property is resistance to bending (flexural rigidity, EI). To estimate EI, we attached the ends of fluorescently labelled actin filaments to two microsphere 'handles' captured in independent laser traps. The positions of the traps were manipulated to apply a range of tensions (0-8 pN) to the filaments via the microsphere handles. With increasing filament tension, the displacement of the microspheres was inconsistent with a microsphere-filament system that is rigid. We maintain that this inconsistency is due to the microspheres rotating in the trap and the filaments bending near either attachments to accommodate this rotation. Fitting the experimental data to a simple model of this phenomena, we estimate actin's EI to be approximately 15 x 10(3) pNnm2, a value within the range of previously reported results, albeit using a novel method. These results both: support the idea that actin filaments are more compliant than historically assumed; and, indicate that without appropriately pretensioning the actin filament in similar laser traps, measurements of unitary molecular events (e.g. myosin displacement) may be significantly underestimated.


Pre-infusion single-dose mesenchymal stem cells promote platelet engraftment and decrease severe acute graft versus host disease without relapse in haploidentical peripheral blood stem cell transplantation.
Mesenchymal stem cells (MSCs) may be used to treat steroid-refractory graft versus host disease (GVHD). However, the effects of MSCs in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) have not been confirmed in randomized studies. We conducted a randomized clinical study to investigate the effects of pre-infusion (1 × 106 cells/kg) MSCs on hematopoietic recovery, Epstein-Barr and cytomegalovirus infection, GVHD, and relapse in patients undergoing haplo-PBSCT. Fifty patients with acute leukemia or myelodysplastic syndrome were randomly divided into an MSC group administered 1 × 106 MSCs/kg 4 to 6 hours before infusion of peripheral stem cells and a control group without MSCs. Mean platelet engraftment time was significantly faster in the MSC compared with the control group (12.28 vs 13.29 days). The mean neutrophil engraftment time was comparable in both groups (10.76 ± 2.40 vs. 10.29 ± 1.72 days). Grade II or above acute GVHD was significantly decreased in the MSC compared with the control group (12% vs. 36%). There were no significant differences in relapse rate or overall survival between the groups. These results suggest that pre-infusion single-dose MSCs promote platelet engraftment and decrease severe acute GVHD without increasing relapse rate.


Analysis of organic compounds' degradation and electricity generation in anaerobic fluidized bed microbial fuel cell for coking wastewater treatment.
A single-chambered packing-type anaerobic fluidized microbial fuel cell (AFBMFC) with coking wastewater (CWW) as fuel was built to treat CWW, which not only has high treating efficiency, but also can convert organic matter in wastewater into electricity. AFBMFC was constructed by using anaerobic sludge that was domesticated as inoculation sludge, which was used to biochemically treat CWW. The organic compounds in CWW were extracted by liquid-liquid extraction step by step every day. The extraction phase was concentrated by a rotary evaporator and a nitrogen sweeping device and was analyzed by GC-MS. And the electricity-generation performances of AFBMFC were investigated. The results show that the composition of CWW was complicated, which mainly contains hydrocarbons, phenols, nitrogenous organic compounds, alcohols and aldehydes, esters and acids and so on. After a cycle of anaerobic biochemical treatment, the content of organic compounds in the effluent decreased significantly. After the treatment of AFBMFC, 99.9% phenols, 98.4% alcohol and aldehydes and 95.3% nitrogenous compounds were biodegraded. In the effluent, some new compounds (such as tricosane and dibutyl phthalate) were produced. The chemical oxygen demand (COD) of CWW decreased from 3372 to 559 mg/L in the closed-circuit microbial fuel cell, and the COD removal was 83.4 ± 1.0%. The maximum power density of AFBMFC was 2.13 ± 0.01 mW m-2.


Toxic Metabolic Encephalopathy in Hospitalized Patients with COVID-19.
Toxic metabolic encephalopathy (TME) has been reported in 7-31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase-polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020. TME was diagnosed in patients with altered mental status off sedation or after an adequate sedation washout. Patients with structural brain disease, seizures, or primary neurological diagnoses were excluded. The coprimary outcomes were the prevalence of TME stratified by etiology and in-hospital mortality (excluding comfort care only patients) assessed by using a multivariable time-dependent Cox proportional hazards models with adjustment for age, race, sex, intubation, intensive care unit requirement, Sequential Organ Failure Assessment scores, hospital location, and date of admission. Among 4491 patients with COVID-19, 559 (12%) were diagnosed with TME, of whom 435 of 559 (78%) developed encephalopathy immediately prior to hospital admission. The most common etiologies were septic encephalopathy (n = 247 of 559 [62%]), hypoxic-ischemic encephalopathy (HIE) (n = 331 of 559 [59%]), and uremia (n = 156 of 559 [28%]). Multiple etiologies were present in 435 (78%) patients. Compared with those without TME (n = 3932), patients with TME were older (76 vs. 62 years), had dementia (27% vs. 3%) or psychiatric history (20% vs. 10%), were more often intubated (37% vs. 20%), had a longer hospital length of stay (7.9 vs. 6.0 days), and were less often discharged home (25% vs. 66% [all P < 0.001]). Excluding comfort care patients (n = 267 of 4491 [6%]) and after adjustment for confounders, TME remained associated with increased risk of in-hospital death (n = 128 of 425 [30%] patients with TME died, compared with n = 600 of 3799 [16%] patients without TME; adjusted hazard ratio [aHR] 1.24, 95% confidence interval [CI] 1.02-1.52, P = 0.031), and TME due to hypoxemia conferred the highest risk (n = 97 of 233 [42%] patients with HIE died, compared with n = 631 of 3991 [16%] patients without HIE; aHR 1.56, 95% CI 1.21-2.00, P = 0.001). TME occurred in one in eight hospitalized patients with COVID-19, was typically multifactorial, and was most often due to hypoxemia, sepsis, and uremia. After we adjustment for confounding factors, TME was associated with a 24% increased risk of in-hospital mortality.


Tapered enlarged ends in multimode optical fibers.
Radiation characteristics of multimode fibers with enlarged tapers were investigated on a number of samples obtained by varying the fiber drawing speed with a given law corresponding to a prefixed taper profile. The characterization of the fibers was made by near- and far-field intensity pattern measurements as well as by measuring the losses introduced by the taper. With a suitable choice of parameters the taper constitutes a reasonable low-loss component useful, for example, for either efficient coupling to large-spot high-power density sources or connecting fibers of different sizes. Conversely at the exit of the fiber the taper can be used for beam shaping which is of interest for mechanical or surgical applications.


Applying resource bricolage theory to the city integration of new-generation migrant workers in China.
New-generation migrant workers in Chinese cities are struggling with a lack of urban resources, such as capital, skills, and relationships. To cope with the pressure of these resource constraints, new-generation migrant workers obtain urban development opportunities through resource bricolage. Based on a questionnaire survey of 365 new-generation migrant workers, we used a multiple regression analysis to study the mechanism underlying the effects of resource bricolage on the city integration of new-generation migrant workers. There were four findings: (1) resource bricolage had a significant positive effect on career growth and city integration; (2) career growth had a mediation effect on the relationship between resource bricolage and city integration; (3) environmental dynamism had a positive moderating effect on the relationship between resource bricolage and city integration for new-generation migrant workers; and (4) resource bricolage and environmental dynamism had a moderating effect on city integration through the mediation effect of career growth. The results suggest that resource bricolage promotes the career growth of new-generation migrant workers and further promotes their city integration, and that the environmental dynamism faced by workers is the external condition for promoting integration through resource bricolage. The study emphasizes the importance of resource bricolage in new-generation migrant workers' city integration.


What physiological role(s) does the alternative oxidase perform in animals?
Although the alternative oxidase, AOX, was known to be widespread in the animal kingdom by 2004, its exact physiological role in animals remains poorly understood. Here we present what evidence has accumulated thus far, indicating that it may play a role in enabling animals to resist various kinds of stress, including toxins, abnormal oxygen or nutrient levels, protein unfolding, dessication and pathogen attack. Much of our knowledge comes from studies in model organisms, where any benefits from exogenously expressed AOX may be masked by its unregulated expression, which may itself be stressful. The further question arises as to why AOX has been lost from some major crown groups, namely vertebrates, insects and cephalopods, if it plays important roles favouring the survival of other animals. We conclude by presenting some speculative ideas addressing this question, and an outline of how it might be approached experimentally.


Strong nonlinear coupling between an ultracold atomic ensemble and a nanomechanical oscillator.
A new type of collective nonlinear coupling is presented via the indirect interaction between an ultracold atomic ensemble and a nanomechanical oscillator. More intriguingly, its interaction strength is enhanced largely with a factor of the atomic number, and thus, reaches a strong coupling regime within current experimental parameters. For the large atomic number, this obtained nonlinear coupling describes the interaction between the phonon and a pair of quasiparticle. Physically, this pair of quasiparticle is excited from the ultracold atomic ensemble when a phonon is emitted and vice versa. Based on these collective excitations, the nonlinear optical processes with the χ(2) term are simulated successfully.


[Sleep and anesthesia--Part 1, Recent findings in research].
We described how modern neuroscience has elucidated what is sleep and its implication, and also reviewed histological and current trends in search of sleep mechanism from view of neurocirculatory or hormonary basis studies. We conclude that anesthesia and sleep share some neuronal structure in their action and mechanism of anesthesia could be elucidated through sleep study. In addition, anesthesia-related sleep disturbance must be settled to serve satisfied quality of life of patients and to save economic and medical resources.


Comparative evaluation of immunofluorescent antibody and new immunoblot tests for the specific detection of antibodies against Besnoitia besnoiti tachyzoites and bradyzoites in bovine sera.
Besnoitia besnoiti, an apicomplexan parasite causes economically important disease in cattle in many countries of Africa and Asia is re-emerging in Europe. Serological identification of infected cattle is important because introduction of these animals into naive herds seems to play a major role in the transmission of the parasite. We report new, simplified immunoblot-based serological tests for the detection of B. besnoiti-specific antibodies. Antigens were used under non-reducing conditions in the immunoblots, because reduction of the antigen with beta-mercaptoethanol diminished the antigenicity in both, tachyzoites and bradyzoites. Ten B. besnoiti tachyzoite and ten bradyzoite antigens of 15-45 kDa molecular weight were recognized by B. besnoiti infected cattle, but not or only weakly detected by cattle infected with related protozoan parasites, Neospora caninum, Toxoplasma gondii, Sarcocystis cruzi, Sarcocystis hominis, or Sarcocystis hirsuta. The sensitivity and specificity of B. besnoiti immunoblots were determined with sera from 62 German cattle with clinically confirmed besnoitiosis and 404 sera from unexposed German cattle including 214 sera from animals with a N. caninum-specific antibody response. Using a new scoring system, the highest specificity (100%) and sensitivity (90%) of the immunoblots were observed when reactivity to at least four of the ten selected tachyzoite or bradyzoite antigens was considered as positive. When a cut-off based on this scoring system was applied to both the tachyzoite- and the bradyzoite-based immunoblots, there was an almost perfect agreement with the indirect fluorescent antibody test with a titre of 200 as the positive cut-off. We identified and partially characterized 10 tachyzoite and 10 bradyzoite B. besnoiti antigens which may help to develop new specific and sensitive serological tests based on individual antigens and in the identification of possible vaccine candidates.


Bibliometric Analysis of the Top 50 Most Influential Studies on Patellar Tendon Injury.
There is a wide range of literature on patellar tendon injury, making it increasingly difficult to stay informed on the most influential studies in this field. It is essential to be familiar with the foundational articles of patellar tendon injury research to understand the current state of the literature and deliver high quality care. To objectively identify the 50 most influential articles relating to patellar tendon injury and conduct a bibliometric analysis to identify key features of these articles. Cross-sectional study. The Clarivate Analytics Web of Knowledge database was utilized to gather metrics on the 50 most cited articles on patellar tendon injury on June 27, 2022. The information extracted from each article included publication year, number of citations, author information, article type, level of evidence, country of origin, journal name, study focus, and industry influence. The top 50 studies were cited a total of 8543 times and published between 1977 and 2015. The majority of articles were published after 2003, and the majority of citations were accrued after 2011. The most prevalent article types were cohort studies (n = 23), and the majority of studies were of evidence level 2 (n = 14) or 4 (n = 13). Australia and the United States (US) each published the most studies (n = 11). Only 4 (8%) studies focused on patellar tendon rupture, and 12 (24%) of the top 50 studies were associated with industry. The majority of the top 50 most influential articles in patellar tendon injury were published and accumulated citations in the past 10 to 20 years. Non-US countries, institutions, and journals published many of the top 50 studies, reflecting a global interest and commitment to research in this field. Patellar tendon rupture and surgical repair represents a minority of research in the top 50 studies and could be a point of growth in the future.


Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms.
The effective development of new drugs relies on the identification of genes that are related to the symptoms of toxicity. Although many researchers have inferred toxicity markers, most have focused on discovering toxicity occurrence markers rather than toxicity severity markers. In this study, we aimed to identify gene markers that are relevant to both the occurrence and severity of toxicity symptoms. To identify gene markers for each of four targeted liver toxicity symptoms, we used microarray expression profiles and pathology data from 14,143 in vivo rat samples. The gene markers were found using sparse linear discriminant analysis (sLDA) in which symptom severity is used as a class label. To evaluate the inferred gene markers, we constructed regression models that predicted the severity of toxicity symptoms from gene expression profiles. Our cross-validated results revealed that our approach was more successful at finding gene markers sensitive to the aggravation of toxicity symptoms than conventional methods. Moreover, these markers were closely involved in some of the biological functions significantly related to toxicity severity in the four targeted symptoms.


Role of intrarenal angiotensin II and alpha-adrenoceptors in renal vasoconstriction with acute hypoxemia and hypercapnic acidosis in conscious dogs.
To evaluate our previous observation of renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied 13 conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 meq/day for 4 days). Five dogs were studied during combined acute hypoxemia (PaO2, 37 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2, 59 +/- 1 mm Hg; pH 7.20 +/- 0.01). Each dog was studied during infusion of 1) the intrarenal vehicle (n = 5), 2) the intrarenal alpha 1-antagonist prazosin (0.2 micrograms.kg-1.min-1, n = 5), 3) intrarenal [Sar1,Ala8]angiotensin II (70 ng.kg-1.min-1, n = 5), and 4) intrarenal prazosin and [Sar1,Ala8]angiotensin II (n = 4). Immediate induction of combined hypoxemia and hypercapnic acidosis after control measurements during intrarenal vehicle infusion resulted in a decrease in effective renal plasma flow and glomerular filtration rate, increase in renal vascular resistance, and decrease in filtered sodium load in the first 20 minutes of the blood gas derangement. Intrarenal administration of [Sar1,Ala8]angiotensin II failed to reverse the effects of the combined blood gas derangement on renal function. In contrast, intrarenal prazosin administration either alone or in combination with [Sar1,Ala8]angiotensin II abrogated the increase in renal vascular resistance, decrease in glomerular filtration rate, and fall in filtered sodium load. These studies identify a major role for alpha 1-adrenoceptors in the renal vasoconstriction during combined hypoxemia and hypercapnic acidosis.


Fault-tolerant control strategy of six-phase permanent magnet synchronous motor based on deadbeat current prediction.
The fault-tolerant control after phase loss is crucial in the studies of the six-phase permanent magnet synchronous motor (PMSM), and the one phase loss is the most frequent phase loss fault. To improve the system instability caused by nonlinear and time-varying perturbations of inductance parameters in a double-Y phase shifted 30° six-phase PMSM, an improved deadbeat predictive current fault-tolerant control (DPC-FTC) method is proposed in this study. The transformation matrix after single-phase open-phase is first reduced and reconstructed, and the reduced-dimensional voltage equation is derived. Based on this equation, the deadbeat current predictive control is then used to predict the expected voltage using the current feedback value and the reference value, so as to shorten the response time and improve the overall control effect. The voltage equation after parameter perturbation is rewritten, and the current discrete transfer function under constant expected voltage before and after parameter perturbation is calculated. Afterwards, to further improve the low stability of fault-tolerant control after phase loss, which is caused by the inductance parameter perturbation of the control system, the weight coefficient is introduced in order to enhance the deadbeat predictive current control so that it splits and optimizes the direct-quadrature axis current. The stability of the system is then analyzed. By changing the weight coefficient, the fault-tolerant control system has a wider stable working range. Finally, the simulation model and experimental platform are completed. The results show that the improved DPC-FTC method improves the permissible inductor parameter uptake range by a factor of 1/β, reduces the current static difference by 32.05% and 46.02% when the inductor parameter is mismatched by a factor of 2, reduces the current oscillation and effectively reduces the sensitivity of system stability to inductor parameter uptake.


[Importance of pH- and osmolarity-dependent changes in deformability- determining factors on the filterability of human erythrocytes].
The deformability of erythrocytes was characterized by measuring their filterability through cellulose filters under low pressure, their cellular geometry and elastic membrane properties. A decreased filterability of suspensions of washed erythrocytes with increasing pH (5.5-7.9) and osmolarity (220-510) was found. The influence of RBC-deformability determining factors on the measured quantity (relative time of filtration) was determined. It is concluded that the viscosity of the cell interior has a predominating influence on the filterability through cellulose filters among all experimentally changed factors determining the deformability. The influence of the cell volume on the filterability is small compared with that of secondary effects of volume changes (dilution or concentration of hemoglobin, changes of cell volume concentration at constant hematocrit). The influence on the erythrocyte volume increases with decreasing pore size.


LIPUS promotes synthesis and secretion of extracellular matrix and reduces cell apoptosis in human osteoarthritis through upregulation of SOX9 expression.
Increasing studies have illustrated that low-intensity pulsed ultrasound (LIPUS) has a therapeutic effect in experimental animal models of osteoarthritis (OA). However, the function of the LIPUS on human chondrocytes of OA remains unclear. The aim of the current study was to observe the effect and explore the mechanism of LIPUS treatment on proliferation, apoptosis, and extracellular matrix (ECM) production of chondrocytes in vitro. Results showed that LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities markedly inhibited the apoptosis of chondrocytes compared with the 0 mW/cm2 intensity; however, the effect of LIPUS stimulation at 0, 30, 60, and 90 mW/cm2 intensities on the proliferation of chondrocytes had no significant difference. Furthermore, the mRNA and protein levels of COL2A1 and ACAN were upregulated in chondrocytes treated with LIPUS stimulation at 30, 60, and 90 mW/cm2 intensities. The concentration of COL2A1 and ACAN in supernatants of chondrocytes in the 30, 60, and 90 mW/cm2 groups were obviously higher than those in the 0 mW/cm2 group. In addition, activation of SOX9 mRNA and protein expression were observed in the 30, 60, and 90 mW/cm2 groups compared with the 0 mW/cm2 group. In summary, our data demonstrated that LIPUS promotes ECM synthesis and secretion and reduces apoptosis of human OA by activation of SOX9, indicating LIPUS might bea promising therapy for the treatment of OA.


Negative valence systems: sustained threat and the predatory imminence continuum.
This review describes the relationship between the National Institute of Mental Health (U.S.A.) Research Domain Criteria (RDoC) Negative Valence System related to responses to threat and the Predatory Imminence Continuum model of antipredator defensive behavior. While the original RDoC constructs of Potential Threat (anxiety) and Acute Threat (fear) fit well with the pre-encounter and post-encounter defense modes of the predatory imminence model, the Sustained Threat construct does not. Early research on the bed nuclei of the stria terminalis (BST) suggested that when fear responding needed to be sustained for a prolonged duration this region was important. However, follow-up studies indicated that the BST becomes critical not because responses needed to be sustained but rather when the stimuli triggering fear were more difficult to learn about, particularly when aversive stimuli were difficult to accurately predict. Instead, it is argued that the BST and the hippocampus act to expand the range of conditions that can trigger post-encounter defense (Acute Threat). It is further suggested that sustained threat refers to situations where the predatory imminence continuum becomes distorted causing defensive behavior to intrude into times when organisms should be engaging in other adaptive behaviors. Stress is seen as something that can cause a long-term disturbance of the continuum and this disturbance is a state of sustained threat.


Silver nanoparticles modify the hypothalamic-pituitary-interrenal axis and block cortisol response to an acute stress in zebrafish, Danio rerio.
The present study aimed at assessing the effects of exposure to silver nanoparticle (AgNP) and a subsequent acute stress on the expression of various genes involved in the hypothalamus-pituitary-interrenal (HPI) axis in zebrafish, Danio rerio. The fish were exposed to 0 (Control), 0.1 (LC), 0.4 (MC), and 1.2 (HC) mg Ag/L (as AgNP) over a 2-week period, followed by an acute air exposure stress. The whole body cortisol and the expression of selected genes in the fish brain and kidney were analyzed, before and after the acute stress. The results showed that AgNP increased basal cortisol levels and the expression of corticotropin releasing factor, prohormone convertase 1, pro-opiomelanocortin, and melanocortin 2 receptor; however, it suppressed/inhibited whole body cortisol, brain corticotropin releasing factor responses, pro-opiomelanocortin, and the kidney melanocortin 2 receptor responses to the acute stress. AgNP down-regulated the expression of the steroidogenic acute regulatory protein, but it intensified the gene expression in response to the acute stress. Before the acute stress, LC treatment exhibited an up-regulation in Cytochrome P450-11A-1 expression, but MC and HC treatments induced down-regulation. After the acute stress, the AgNP-exposed fish exhibited decreased Cytochrome P450-11A-1 expressions, compared with the Control. Exposure to AgNP significantly increased Cytochrome P450-11B expression. However, after the acute stress, LC treatment exhibited an up-regulation, but MC and HC treatments exhibited down-regulation in the Cytochrome P450-11B gene expression. In conclusion, AgNP suppressed cortisol response to stress, which appears to be a consequence of alterations in the HPI axis at the transcriptomic levels.


Cross-sectional Area of the Achilles Tendon in a Cohort of Elite Military Warriors Using Standard Ultrasound Techniques.
The prevalence of Achilles tendon (AT) pathology is common and can result in disability. Understanding normal AT properties can improve our ability to prevent AT injuries. We examined the cross-sectional area of the AT at multiple levels in an asymptomatic population of Army Rangers. This is a prospective cohort study composed of 41 voluntarily recruited United States Army Rangers deployed in a combat theater. All subjects were members of the Ranger Regiment participating in more than 20 h of intense bipedal non-sport weekly training with no history of AT pathology. While standing, each subject had bilateral AT calcaneal tuberosity insertions (0 cm) marked, along with skin markings made at 2 cm, 4 cm, and 6 cm superior to the AT insertion. AT diameter was measured at each level in the coronal and sagittal planes using ultrasound. Mean sagittal diameter of the AT was 4.4 mm, 4.3 mm, 4.2 mm, and 3.9 mm at 0 cm, 2 cm, 4 cm, and 6 cm, respectively. Mean coronal diameter of the AT was 19.3 mm, 14.7 mm, 13.8 mm, and 14.5 mm at 0 cm, 2 cm, 4 cm, and 6 cm, respectively. The cross-sectional area was calculated as 0.66 cm2, 0.5 cm2, 0.46 cm2, and 0.44 cm2 at 0 cm, 2 cm, 4 cm, and 6 cm, respectively. Our data suggest that increased non-sport activity may not increase the cross-sectional area of the AT. Identifying the normal diameter at multiple levels throughout the most commonly injured area may improve the provider's ability to identify early disease processes and apply targeted interventions to help slow or prevent progression and possible rupture. Level III-V.


Microsatellite unstable colorectal cancer cell lines with truncating TGFbetaRII mutations remain sensitive to endogenous TGFbeta.
Disruptions to the TGFbeta signalling pathway have been implicated in most human adenocarcinomas. As cancers progress, many acquire resistance to the growth-suppressing properties of TGFbeta while retaining sensitivity to its tumour-promoting effects. Microsatellite unstable colorectal cancers (MSI-H CRCs) possess truncating mutations in the type II TGFbeta receptor (TGFbetaRII) gene that have been assumed to render these tumours insensitive to TGFbeta. However, numerous reports of TGFbetaRII bypass exist and this study was thus undertaken in order to clarify the true extent of TGFbeta sensitivity in MSI-H CRCs. Using stimulation with exogenous TGFbeta, we demonstrated that, while MSI-H CRCs are capable of binding soluble TGFbeta, two out of three cell lines examined remain refractory to its signalling effects. In contrast, use of a specific inhibitor of the type I TGFbeta receptor (TGFbetaRI) revealed that all remain sensitive to signalling by endogenously produced TGFbeta. Specifically, autocrine signalling via TGFbetaRI mediates constitutive activation of Smad2 as well as repression of Erk signalling. Real-time PCR confirmed that these effects are sufficient to affect the expression level of various TGFbeta-modulated genes. An invasion assay revealed that autocrine TGFbetaRI signalling also promotes the invasion capacity of MSI-H CRCs to an extent similar to that seen in their non-MSI-H counterparts. Independent TGFbetaRI signalling, however, has no effect on the rate of proliferation of MSI-H CRC cells. Together, these results demonstrate that MSI-H CRC cell lines are not completely refractory to TGFbeta, despite lacking functional TGFbetaRII. In addition to clarifying the true consequences of natural TGFbetaRII loss and the independent function of TGFbetaRI, our results highlight the selective nature of TGFbeta resistance developed by cancers.


Legal perceptions and medical decision making.
Medicine and law are more closely intertwined than ever before, particularly regarding issues of life-sustaining treatment for the elderly. The legal system's potential as a positive force in medical decision making has been limited by pervasive misperceptions by physicians of its processes and role. Identifying these myths and misperceptions is a first step toward a more effective partnership of medicine and law on behalf of the dying or demented patient.


Health inequalities associated with neighbourhood deprivation in the Quebec population with hypertension in primary prevention of cardiovascular disease.
Although a number of studies look at prevalence, incidence, treatment, mortality and morbidity in relation to hypertension, few have taken into account the effect of residential neighbourhood on these health indicators in the population diagnosed with hypertension. The objective of this study was to measure and compare prevalence, mortality, morbidity, use of medical resources and treatments in relation to the level of material and social deprivation of the area of residence, in a population with a diagnosis of hypertension in primary prevention for cardiovascular disease (CVD) in Quebec in 2006-2007. This study is based on a secondary analysis of the medical administrative data of the Quebec health insurance board, the Régie de l'assurance maladie du Québec, for a cohort of 276 793 patients aged 30 years or older who had been diagnosed with hypertension in 2006 or 2007, but who did not have a known diagnosis of CVD. The health indicators adjusted for age and sex are prevalence, death, a cardiovascular event, physician visits, emergency department visits and use of antihypertensives. Twenty-five types of areas of residence were obtained by crossing the material and social deprivation quintiles. Compared with patients living in materially and socially advantaged areas, those living in deprived areas were at 46% higher risk of a cardiovascular event, 47% higher risk of being frequent emergency department visitors and 31% higher risk of being frequent users of a general practitioner's services, but 25% lower risk of being frequent users of medical specialists' services. Little or no variation was observed in the use of antihypertensives. This study reveals the existence, in a CVD primary prevention context, of large variations in a number of health indicators among hypertensive patients owing to the material and social deprivation of residential neighbourhood. It is therefore important to take the socioeconomic context into account when planning interventions to prevent CVDs and their consequences.


Multishell structures of virus coat proteins.
Under conditions of low ionic strength and a pH ranging between about 3.7 and 5.0, solutions of purified coat proteins of cowpea chlorotic mottle virus (CCMV) form spherical multishell structures in the absence of viral RNA. The outer surfaces of the shells in these structures are negatively charged, whereas the inner surfaces are positively charged due to a disordered cationic N-terminal domain of the capsid protein, the arginine-rich RNA-binding motif that protrudes into the interior. We show that the main forces stabilizing these multishells are counterion release combined with a lower charge density in the RNA-binding motif region of the outer shells due to their larger radii of curvature, arguing that these compensate for the outer shells not being able to adopt the smaller, optimal, radius of curvature of the inner shell. This explains why the structures are only stable at low ionic strengths at pHs for which the outer surface is negatively charged and why the larger outer shells are not observed separately in solution. We show how to calculate the free energy of shells of nonoptimal radius of curvature from the elastic properties of the native shell. The spacing between shells is determined mainly by the entropic elasticity of the RNA-binding motifs. Although we focus on CCMV multishells, we also predict the solution conditions under which multishells formed by CCMV coat protein mutants with a lower RNA-binding motif charge are stable, and we examine other viruses as well. We conclude that at a given surface charge density, the boundaries separating regions of stable multishells with different numbers of shells shift to lower ionic strengths upon either increasing the length of the RNA-binding motif, increasing the stiffness of the shells, or decreasing the charge per RNA-binding motif.


The development of pyrimethamine resistance by Plasmodium falciparum.
Sixteen patent P. falciparum infections (McLendon and Panama strains) in non-immunes were treated with single doses of pyrimethamine. The schizontocidal and sporontocidal response to the initial dose was rapid.Seven blood-induced infections, of which three were treated with 100 mg and four with 50 mg, did not relapse. Of seven cases observed after 25-mg treatment, five relapsed.Delayed treatment of the relapsing infections (Panama strain) with single doses of 25 mg or 50 mg, and subsequently 100 mg, had virtually no schizontocidal or sporontocidal effect. In one case the resistant infection was transmitted by mosquitos to another patient; the subsequent infection was also highly resistant to the drug.It is concluded that under the experimental conditions of this study resistance to pyrimethamine by P. falciparum may occur rapidly after a single dose of 25 mg, being manifested during relapses on the second challenge with the drug. Increasing the drug dosage does not overcome the resistance. The resistant character is readily transmitted by mosquitos.