Variance components and breeding values for growth traits from different statistical models.
Estimates of genetic parameters resulting from various analytical models for birth weight (BWT, n = 4,155), 205-d weight (WWT, n = 3,884), and 365-d weight (YWT, n = 3,476) were compared. Data consisted of records for Line 1 Hereford cattle selected for postweaning growth from 1934 to 1989 at ARS-USDA, Miles City, MT. Twelve models were compared. Model 1 included fixed effects of year, sex, age of dam; covariates for birth day and inbreeding coefficients of animal and of dam; and random animal genetic and residual effects. Model 2 was the same as Model 1 but ignored inbreeding coefficients. Model 3 was the same as Model 1 and included random maternal genetic effects with covariance between direct and maternal genetic effects, and maternal permanent environmental effects. Model 4 was the same as Model 3 but ignored inbreeding. Model 5 was the same as Model 1 but with a random sire effect instead of animal genetic effect. Model 6 was the same as Model 5 but ignored inbreeding. Model 7 was a sire model that considered relationships among males. Model 8 was a sire model, assuming sires to be unrelated, but with dam effects as uncorrelated random effects to account for maternal effects. Model 9 was a sire and dam model but with relationships to account for direct and maternal genetic effects; dams also were included as uncorrelated random effects to account for maternal permanent environmental effects. Model 10 was a sire model with maternal grandsire and dam effects all as uncorrelated random effects. Model 11 was a sire and maternal grandsire model, with dams as uncorrelated random effects but with sires and maternal grandsires assumed to be related using male relationships. Model 12 was the same as Model 11 but with all pedigree relationships from the full animal model for sires and maternal grandsires. Rankings on predictions of breeding values were the same regardless of whether inbreeding coefficients for animal and dam were included in the models. Heritability estimates were similar regardless of whether inbreeding effects were in the model. Models 3 and 9 best fit the data for estimation of variances and covariances for direct, maternal genetic, and permanent environmental effects. Other models resulted in changes in ranking for predicted breeding values and for estimates of direct and maternal heritability. Heritability estimates of direct effects were smallest with sire and sire-maternal grandsire models.


Probable epizootic chlamydiosis in wild California (Larus californicus) and ring-billed (Larus delawarensis) gulls in North Dakota.
During the summer of 1986, more than 400 California gulls (Larus californicus) and ring-billed gulls (Larvus delawarensis), primarily fledglings, died on an island in Lake Sakakawea near New Town, North Dakota (USA). Mortality was attributed largely to chlamydiosis. Necropsy findings in nine carcasses included splenomegaly (n = 9), hepatomegaly (n = 4), and pericarditis (n = 1). Livers from three California gulls and two ring-billed gulls, and spleens from the same five birds plus a third ring-billed gull were positive for Chlamydia psittaci by the direct immunofluorescence test. Chlamydia psittaci was isolated from separate pools of liver and spleen from one California gull and one ring-billed gull. This is believed to be the first record of epizootic chlamydiosis in gulls and the second report of epizootic chlamydial mortality in wild birds in North America.


Accumulation of acyl-enzyme in DD-peptidase-catalysed reactions with analogues of peptide substrates.
Thioester substrates can be used to study the hydrolysis and transfer reactions catalysed by beta-lactamases and DD-peptidases. With the latter enzymes, accumulation of the acyl-enzyme can be detected directly. The efficiency of various amines as acceptor substrates was in excellent agreement with previous results obtained with peptide substrates of the DD-peptidases. The results indicated the presence of a specific binding site for the acceptor substrates. Although most of the results agreed well with a simple partition model, more elaborate hypotheses will be needed to account for all the data presented.


Environmental and Experimental Factors Affecting Efficacy Testing of Nonporous Plastic Antimicrobial Surfaces.
Test methods for efficacy assessment of antimicrobial coatings are not modelled on a hospital environment, and instead use high humidity (>90%) high temperature (37 °C), and no airflow. Therefore, an inoculum will not dry, resulting in an antimicrobial surface exhibiting prolonged antimicrobial activity, as moisture is critical to activity. Liquids will dry quicker in a hospital ward, resulting in a reduced antimicrobial efficacy compared to the existing test, rendering the test results artificially favourable to the antimicrobial claim of the product. This study aimed to assess how hospital room environmental conditions can affect the drying time of an inoculum, and to use this data to inform test parameters for antimicrobial efficacy testing based on the hospital ward. The drying time of different droplet sizes, in a range of environmental conditions likely found in a hospital ward, were recorded (n = 630), and used to create a model to inform users of the experimental conditions required to provide a drying time similar to what can be expected in the hospital ward. Drying time data demonstrated significant (p < 0.05) variance when humidity, temperature, and airflow were assessed. A mathematical model was created to select environmental conditions for in vitro antimicrobial efficacy testing. Drying time in different environmental conditions demonstrates that experimental set-ups affect the amount of time an inoculum stays wet, which in turn may affect the efficacy of an antimicrobial surface. This should be an important consideration for hospitals and other potential users, whilst future tests predict efficacy in the intended end-use environment.


Structural bioinformatics insights into ATP binding mechanism in zebrafish (Danio rerio) cyclin-dependent kinase-like 5 (zCDKL5) protein.
In mammalian systems, the conserved cyclin-dependent protein kinases (CDKs) control the process of cell division and curb the transcription mechanism in response to diverse signaling events that are essential for the catalytic activity. In zebrafish, zCDKL5 portrays differential expression profiling in several tissues and presumed to play a vital role in the neuronal development. In this present study, the sequence-structure relationship and mode of ATP binding in zCDKL5 was unveiled through theoretical modeling, molecular docking, and MD simulations. Like human CDKs, the modeled zCDKL5 was found to be bipartite in nature, where, ATP binds to the central cavity of the catalytic domain through a strong network of H-bonding, electrostatic, and hydrophobic interactions. MD simulation portrayed that conserved residues, viz, Ile10, Gly11, Glu12, Val18, Val64, Glu81, Cys143, and Asp144 were indispensable for tight anchoring of ATP and contribute to the stability of the zCDKL5-ATP complex. MM/PBSA binding free energy analysis displayed that van der Waal energy (ΔG vwd ) and Electrostatic energy (ΔG ele ) were the major contributors towards the overall binding free energy. Thus, the comparative structural bioinformatics approach has shed new insights into the dynamics and ATP binding mechanism of zCDKL5. The results from the study will help to undertake further research on the role of phosphorylated CDKL5 in the onset of neurodevelopmental disorders caused by mutations in higher eukaryotic systems.


Teacher Mindsets Help Explain Where a Growth-Mindset Intervention Does and Doesn't Work.
A growth-mindset intervention teaches the belief that intellectual abilities can be developed. Where does the intervention work best? Prior research examined school-level moderators using data from the National Study of Learning Mindsets (NSLM), which delivered a short growth-mindset intervention during the first year of high school. In the present research, we used data from the NSLM to examine moderation by teachers' mindsets and answer a new question: Can students independently implement their growth mindsets in virtually any classroom culture, or must students' growth mindsets be supported by their teacher's own growth mindsets (i.e., the mindset-plus-supportive-context hypothesis)? The present analysis (9,167 student records matched with 223 math teachers) supported the latter hypothesis. This result stood up to potentially confounding teacher factors and to a conservative Bayesian analysis. Thus, sustaining growth-mindset effects may require contextual supports that allow the proffered beliefs to take root and flourish.


Delivery of vaccines to adults: correlations with physician knowledge and patient variables.
Our objective was to explore reasons why vaccines are not provided to adult patients receiving primary health care. The study setting was a primary health care clinic in a urban hospital staffed primarily by residents and teaching faculty. The patients were identified as all continuity care patients with a scheduled visit to the clinic during the 4-week study period in April 1995. The providers were all primary care providers for the patients during the study period. The providers were given two surveys before the study: one to assess their knowledge of published preventive health care guidelines and one to assess their perspective of the guidelines. During the study period, the charts of the patients were reviewed for the services they had received. An assessment was placed in each patient's chart for the provider's completion during the visit. The assessment enabled the provider to explain why services had not been provided. The results showed that influenza, pneumococcal, and diphtheria-tetanus vaccines were provided at varying rates. Each vaccine had a different profile as to noncompliance with guidelines. Lack of provider knowledge of the guideline was most apparent with pneumococcal vaccine. Providers' ambivalence regarding the scientific basis and/or clinical importance was most apparent with influenza vaccine. Patient refusal was a prominent cause with influenza vaccine in the elderly. Patient appointment behavior (opportunity for care and compliance) also seemed to play an important role. We conclude that explanations for nondelivery of vaccines to adults seem to be multiple. Lack of physician knowledge and physician perception of the guidelines provide some explanations. Patient-related factors including refusal, decreased opportunity for care, and noncompliance also play important roles in why vaccinations are not provided. Improvement in the rates at which immunizations to adults are provided will require interventions in multiple areas.


Chemical metrology.
The phrase chemical metrology generates a wide variety of responses from analytical chemists and a degree of confusion. This technical brief aims to dispel the mythology of metrology, explain important aspects and demonstrate the value of metrology to chemical measurements. It is shown that the basic principles of metrology have been applied since ancient times and served well for thousands of years as the key to consistent measurements. Application of the principles to physical measurements was formalised towards the end of the 19th century to meets the needs of industrialisation and global trade. The most recent change in global adoption of metrology took place at the end of the 20th century with the decision to extend the system to analytical chemistry. The brief describes how this decision is being implemented and the progress which has been made towards an international infrastructure for chemical and more recently biological measurements.


Protective effects of flavonol isoquercitrin, against 6-hydroxy dopamine (6-OHDA)-induced toxicity in PC12 cells.
Free radicals-induced neurodegeneration is one of the many causes of Parkinson's disease (PD). This study investigated the neuroprotective effects of flavonol isoquercitrin against toxicity induced by 6-hydroxy-dopamine (6-OHDA) in rat pheochromocytoma (PC12) cells. PC12 cells were pretreated with different concentrations of isoquercitrin for 4, 8 and 12 hours and incubated with 6-OHDA for 24 hours to induce oxidative cell damage. A significant cytoprotective activity was observed in isoquercitrin pre-treated cells in a dose-dependent manner. There was a significant increase (P < 0.01) in the antioxidant enzymes namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione in isoquercitrin pretreated cells compared to cells incubated with 6-OHDA alone. Isoquercitrin significantly reduced (P < 0.01) lipid peroxidation in 6-OHDA treated cells. These results suggested that isoquercitrin protects PC 12 cells against 6-OHDA-induced oxidative stress. The present study suggests the protective role of isoquercitrin on 6-hydroxydopamine-induced toxicity by virtue of its antioxidant potential. Isoquercitrin could be a potential therapeutic agent against neurodegeneration in Parkinson's disease.


Selfish evolution of cytonuclear hybrid incompatibility in Mimulus.
Intraspecific coevolution between selfish elements and suppressors may promote interspecific hybrid incompatibility, but evidence of this process is rare. Here, we use genomic data to test alternative models for the evolution of cytonuclear hybrid male sterility in Mimulus In hybrids between Iron Mountain (IM) Mimulus guttatus × Mimulus nasutus, two tightly linked M. guttatus alleles (Rf1/Rf2) each restore male fertility by suppressing a local mitochondrial male-sterility gene (IM-CMS). Unlike neutral models for the evolution of hybrid incompatibility loci, selfish evolution predicts that the Rf alleles experienced strong selection in the presence of IM-CMS. Using whole-genome sequences, we compared patterns of population-genetic variation in Rf at IM to a neighbouring population that lacks IM-CMS. Consistent with local selection in the presence of IM-CMS, the Rf region shows elevated FST, high local linkage disequilibrium and a distinct haplotype structure at IM, but not at Cone Peak (CP), suggesting a recent sweep in the presence of IM-CMS. In both populations, Rf2 exhibited lower polymorphism than other regions, but the low-diversity outliers were different between CP and IM. Our results confirm theoretical predictions of ubiquitous cytonuclear conflict in plants and provide a population-genetic mechanism for the evolution of a common form of hybrid incompatibility.


Mindfulness as a strategy for coping with cue-elicited cravings for alcohol: an experimental examination.
Mindfulness has been identified as a promising strategy for managing cravings for alcohol and other drugs, but little controlled experimental research has directly studied whether this approach is effective. The current study systematically examined the effects of an acute mindfulness manipulation on craving for alcohol during prolonged exposure to alcohol cues. Heavy drinkers (N = 84, 50% male) underwent a prolonged alcohol cue exposure paradigm in a simulated bar environment and received either a mindfulness-based strategy, a distraction (DST)-based strategy (active control), or no strategy (passive control) to cope with alcohol cravings and discomfort associated with craving. No baseline differences were present between conditions. Manipulation checks revealed that participants in the 2 active conditions reported using the recommended strategies. Across groups, the initial exposure to alcohol cues was associated with significant increases in craving, urge distress, and heart rate. Mixed analyses of variance on these indices following the experimental manipulation revealed significant differences based on condition over the course of the bar laboratory protocol. The DST strategy was significantly more effective at acutely reducing craving and urge distress than the other 2 conditions, which did not significantly differ from each other. Contrary to our prediction, these findings suggest that an acute DSTstrategy is beneficial for coping with alcohol cravings. The potential importance of protracted mindfulness training to detect significant effects on in vivo craving, additional implications, and methodological considerations are discussed.


Nanoceria as Antioxidant: Synthesis and Biomedical Applications.
The therapeutic application of nanomaterials has been a focus of numerous studies in the past decade. Due to its unique redox properties, cerium oxide (ceria) is finding widespread use in the treatment of medical disorders caused by the reactive oxygen intermediates (ROI). The radical-scavenging role of ceria nanoparticles (nanoceria) have been established, as well as the autocatalytic ability of nanoceria to regenerate under various environmental conditions. The synthesis of nanoceria in biocompatible media has also been reported along with cell viability in order to determine the potential use of nanoceria in biomedical applications.


Interfacial evaluation of experimentally weakened roots restored with adhesive materials and fibre posts: an SEM analysis.
To evaluate the bonding interface in experimentally weakened roots reinforced with adhesive restorative materials and quartz fibre posts, varying the light-exposure time of the composite resin used for root reinforcement. Twelve extracted human maxillary incisors teeth were used. The crowns were removed and the roots were endodontically treated. After post space preparation, the roots were assigned to four groups. The thickness of the root dentine was reduced and adhesively restored with composite resin light-activated through a translucent fibre post for either 40s (group 1), 80s (group 2) or 120s (group 3). In the case of control (group 4), the roots were not weakened. One day after post cementation, the specimens were sectioned transversally in three slices and processed for scanning electron microscopic analysis to observe bonding interface formation, quality of the hybrid layer and density of resin tags using a four-step scale method. Formation of a hybrid layer and resin tags were evident in all groups. There was no statistically (p>0.05) significant difference between the regions analysed in each group (Friedman test) and between groups in each section depth (Kruskal-Wallis test). Furthermore, comparison of the flared/reinforced groups showed that the different times used for composite resin cure did not affect the results significantly (Kruskal-Wallis test, p=0.2139). Different light-exposure times used for composite resin polymerisation during root canal reinforcement did not affect significantly the formation and quality of the dentine/adhesive/composite resin bonding interface.


Personalized Fall Risk Assessment Tool by using the Data Treasure contained in Mobile Electronic Patient Records.
This work presents a novel approach for combining multiple Electronic Patient Records (EPRs) to a self-learning fall risk assessment tool. This tool is used by a new type of home-visiting nurses to track the fall risk of their patients. In order to provide personalized healthcare for elderly people, we combine multiple EPRs using an agent-based architecture, where each patient is represented by an associated agent. The patient agents are enabled to negotiate about possible fallrisk indicators recognized in the specific patient population under care. We use distributed information fusion and opinion aggregation techniques to elaborate new fall-risk indicators and in consequence to adapt the fall risk assessment tool.


Rotational Spectrum and Conformational Analysis of N-Methyl-2-Aminoethanol: Insights into the Shape of Adrenergic Neurotransmitters.
We describe an experimental and quantum chemical study for the accurate determination of the conformational space of small molecular systems governed by intramolecular non-covalent interactions. The model systems investigated belong to the biological relevant aminoalcohol's family, and include 2-amino-1-phenylethanol, 2-methylamino-1-phenylethanol, noradrenaline, adrenaline 2-aminoethanol, and N-methyl-2-aminoethanol. For the latter molecule, the rotational spectrum in the 6-18 and 59.6-74.4 GHz ranges was recorded in the isolated conditions of a free jet expansion. Based on the analysis of the rotational spectra, two different conformational species and 11 isotopologues were observed and their spectroscopic constants, including 14N-nuclear hyperfine coupling constants and methyl internal rotation barriers, were determined. From the experimental data a structural determination was performed, which was also used to benchmark accurate quantum chemical calculations on the whole conformational space. Atom in molecules and non-covalent interactions theories allowed the characterization of the position of the intramolecular non-covalent interactions and the energies involved, highlighting the subtle balance responsible of the stabilization of all the molecular systems.


Functional deprivation promotes amyloid plaque pathogenesis in Tg2576 mouse olfactory bulb and piriform cortex.
Cerebral hypometabolism and amyloid accumulation are principal neuropathological manifestations of Alzheimer's disease (AD). Whether and how brain/neuronal activity might modulate certain pathological processes of AD are interesting topics of recent clinical and basic research in the field, and may be of potential medical relevance in regard to both the disease etiology and intervention. Using the Tg2576 transgenic mouse model of AD, this study characterized a promotive effect of neuronal hypoactivity associated with functional deprivation on amyloid plaque pathogenesis in the olfactory pathway. Unilateral naris-occlusion caused beta-secretase-1 (BACE1) elevation in neuronal terminals in the deprived relative to the non-deprived bulb and piriform cortex in young adult mice. In parallel with the overall age-related plaque development in the forebrain, locally increased BACE1 immunoreactivity co-occurred with amyloid deposition first in the piriform cortex then within the bulb, more prominent on the deprived relative to the non-deprived side. Biochemical analyses confirmed elevated BACE1 protein levels, enzymatic activity and products in the deprived relative to non-deprived bulbs. Plaque-associated BACE1 immunoreactivity in the bulb and piriform cortex was localized preferentially to swollen/sprouting glutamatergic axonal terminals, with Abeta immunoreactivity occurring inside as well as around these terminals. Together, these findings suggest that functional deprivation or neuronal hypoactivity facilitates amyloid plaque formation in the forebrain in a transgenic model of AD, which operates synergistically with age effect. The data also implicate an intrinsic association of amyloid accumulation and plaque formation with progressive axonal pathology.


Primary adenocarcinoma of the middle ear.
Adenocarcinoma arising from the mucosa of the middle ear is a rare tumor. This report adds four new cases to the 13 cases that have been previously reported in the literature. These neoplasms tend to have a rather slow growth pattern and have an infrequent incidence of distant metastases. The observations that local recurrence is the major problem with adenocarcinoma of the middle ear suggest that aggressive locoregional treatment should be strongly considered.


Measurement of IR laser backscatter spectra from sulfuric acid and ammonium sulfate aerosols.
An optical system employing a tunable carbon dioxide laser has been used to investigate backscatter signatures of aerosols as a function of wavelength. Submicron sulfuric acid or ammonium sulfate aerosols are produced with a vapor-condensation aerosol generator. The aerosol is contained in a 1-m long windowless aerosol chamber, and laser radiation backscattered from the irradiated aerosol is collected and measured as the laser is tuned from 9.2 to 10.8 microm. The volume backscatter coefficient is calculated from the lidar equation to yield the theoretical IR spectrum of the aerosol. The measured spectral signature is compared with the theoretical signature, which is computed from Mie theory. Backscatter signatures show excellent agreement with calculated signatures. The spectral signature of ammonium sulfate is readily distinguished from that of sulfuric acid for the conditions of the experiment. Because of vapor pressure characteristics of sulfuric acid, it is possible to concentrate the acid in the generator over time and look for a change in the acid concentration in the aerosol. Not only has this concentration process been observed optically, but under these experimental conditions the acid concentration in the aerosol can be determined by observing backscatter at just two wavelengths.


Molecular identification of viral agents associated with acute conjunctivitis: a prospective controlled study.
Viral conjunctivitis are the most frequent infections in ophthalmology clinics. The diagnosis is usually relying on clinical findings and medical history. However, topical antibiotics are often used unnecessarily addition to symptomatic treatment because of unsure agents. We aimed to detect the Adenovirus, Coxsackievirus and Enterovirus from conjunctiva and pharyngeal samples of patients. The conjunctiva and pharyngeal samples of the patients with conjunctivitis were taken by Virocult transport media and kept at -80̊C up to study day. Adenovirus spp, Enterovirus 70 and Enterovirus 71, Coxsackie A24 and Coxsackie A16 were detected by real-time PCR. Samples from healthy health care workers of ophthalmology clinic were used for control group. A total of 176 samples (conjunctival and pharyngeal samples of 62 patient and 26 healthy subjects) were included. The mean age of 34 (55.7%) male and 27 (44.3%) female patients was 34±17. Twenty five (40.3%) of the patients were receiving antibiotic drops at first visit. The main etiologic agent in conjunctival samples was found to be Adenovirus (46/62, 74.2%) followed by Enterovirus 70 (4/62, 6.4%) and Enterovirus 71 (4/62, 6.4%). Coxsackievirus 16 and 24 were also found in 2 patients (1/62 each, 1.6%). Pharyngeal samples were also positive for Adenovirus (20/62, 32.3%), Enterovirus 70 and 71 (7/62, 11.3% and 5/62, 8.1% respectively), Coxsackievirus 16 and 24 (2/62, 3.2% and 1/61, 1.6%). It is very difficult in viral conjunctivitis to make clinical differentiation caused by different agents because of common clinical signs and symptoms. In routine clinical work, the viral conjunctivitis usually related with Adenovirus. But almost one fourth of the patients' conjunctivitis were not related to Adenovirus, which shows the importance of the laboratory diagnostics. True diagnosis plays an important role on prevention of contamination and unnecessary use of antibiotics in viral conjunctivitis.


Leptospirosis in Hawaii: shifting trends in exposure, 1907-1984.
Leptospirosis was first recognized as an occupational disease of sugar plantation workers in Hawaii in 1907. Since then, shifts have been noted in the animal transmission cycles, the occupational groups at risk, and an increasing recognition of cases associated with avocational exposure. Surveys of the small mammal populations indicate rats, mice, and mongooses are the most important vectors in Hawaii. Serologic surveys of workers in high-risk occupations show antibody prevalence rates ranging from 12 to 82 percent. The epidemiology of leptospirosis in Hawaii is described, based on 182 cases reported to the Hawaii Department of Health from 1970-1984. The most common infecting serovar was mankarso in the Icterohaemorrhagiae serogroup; other serovars in the Icterohaemorrhagiae group were also frequently implicated as causing disease. The manifestations of disease noted by physicians in Hawaii are similar to those observed in the continental U.S. Fever, myalgia, and headache were the most common symptoms reported in the majority of cases in Hawaii; jaundice was noted in the records of 24 percent. Recommendations made to interrupt the cycle of transmission and reduce the chances of exposure in occupational settings include the control of rodent populations and vaccination of domestic animals. Personal hygiene among workers is to be encouraged, and the development of prophylactic measures is suggested either by immunization or by chemoprophylaxis.


Optical Genome Mapping Reveals Novel Structural Variants in Lymphoblastic Lymphoma.
Accurate histologic and molecular genetic diagnosis is critical for the pathogenesis study of pediatric patients with lymphoblastic lymphoma (LBL). Optical genome mapping (OGM) as all-in-one process allows the detection of most major genomic risk markers, which addresses some of the limitations associated with conventional cytogenomic testing, such as low resolution and throughput, difficulty in ascertaining genomic localization, and orientation of segments in duplication, inversions, and insertions. Here, for the first time, we examined the cytogenetics of 5 children with LBL using OGM. OGM was used to analyze 5 samples of pediatric LBL patients treated according to the modified NHL-BFM95 backbone regimen. Whole-exon Sequencing (WES) was used to confirm the existence of structural variants (SVs) identified by OGM with potentially clinical significance on MGI Tech (DNBSEQ-T7) platform. According to the fusion exon sequences revealed by WES, the HBS1L::AHI1 fusion mRNA in case 4 was amplified by cDNA-based PCR. In total, OGM identified 251 rare variants (67 insertions, 129 deletions, 3 inversion, 25 duplications, 15 intrachromosomal translocations, and 12 interchromosomal translocations) and 229 copy number variants calls (203 gains and 26 losses). Besides all of the reproducible and pathologically significant genomic SVs detected by conventional cytogenetic techniques, OGM identified more SVs with definite or potential pathologic significance that were not detected by traditional methods, including 2 new fusion genes, HBS1L::AHI1 and GRIK1::NSDHL, which were confirmed by WES and/or Reverse Transcription-Polymerase Chain Reaction. Our results demonstrate the feasibility of OGM to detect genomic aberrations, which may play an important role in the occurrence and development of lymphomagenesis as an important driving factor.


Synthesis of Quercetin-imprinted Polymer Spherical Particles with Improved Ability to Capture Quercetin Analogues.
Molecularly imprinted polymers (MIPs) are composed of specific cavities able to selectively recognise a template molecule. Used as chromatographic sorbents, MIPs may not trap related structures due to the high rigidity of their cross-linking. To improve the capture of quercetin analogues by modulating the synthesis strategy for a quercetin-imprinted polymer (Qu MIP). An additional comonomer bearing a short oligoethylene glycol (OEG) unit was used to prepare a Qu MIP that was compared to a traditional one formulated in a similar fashion, but without the OEG-comonomer. The Qu MIPs were prepared in bead form through fluorocarbon suspension polymerisation. After solid phase extraction (SPE) assessment of their imprinted cavities, the MIPs were evaluated by HPLC for their recognition properties towards quercetin and other polyphenols, including flavonoids, phenolic acids and curcumin. The Qu MIPs were finally SPE-tested on a white onion extract. The incorporation of OEG units modulated the selectivity of the Qu MIP by improving the recognition of quercetin related structures (12-61% increase in the imprinting effect for distant analogues). It also allowed limiting or suppressing non-specific hydrophobic interactions (decrease of about 10% in the rate of quercetin retention on the non-imprinted polymer). The SPE application of the MIP to a white onion extract indicates its interest for the selective extraction of quercetin and its analogues. The OEG-modified Qu MIP appears to be an attractive tool to discover new drug candidates from natural sources by extracting, amongst interfering compounds, structural analogues of quercetin. Copyright © 2017 John Wiley & Sons, Ltd.


Rare earth deposits in a deceased movie projectionist. A new case of rare earth pneumoconiosis?
The subject described in this case report, a movie projectionist, had approximately 25 years of occupational exposure to carbon arc lamp fumes. The carbon arc deposits were visible in histological sections as small granules within macrophages of the tracheobronchial lymph nodes and hepatic Kupffer's cells. Electron microprobe analysis by energy dispersive analysis of x-rays showed the granules to be composed of the rare earth elements cerium, lanthanum and neodymium, which are the major constituents of carbon arc rods. Tissue concentrations, as determined by inductively coupled plasma spectroscopy, were approximately 250-2000 times those of unexposed controls, and there was evidence of their redistribution throughout the reticuloendothelial system. There were no respiratory symptoms, or radiographic or histological pulmonary changes attributable to the progressive accumulation of the rare earth elements, and as such the patient cannot be considered to have suffered from pneumoconiosis. Twenty-one published cases of rare earth pneumoconiosis, mainly in photoengravers exposed to carbon arc fumes, are reviewed and suggest that rare earth oxides are not innocuous dusts. With the increasingly widespread use of rare earth elements there is a likelhood that further occupational groups may have significant but unrecognised exposure.


Increased agonist affinity is induced in tetranitromethane-modified muscarinic receptors.
Tetranitromethane (TNM) modifies the muscarinic receptors from rat cerebral cortex. The modified receptor possesses an increased binding affinity (6-9-fold) toward several agonists such as acetylcholine, carbamoylcholine, arecoline, etc. The binding of antagonists (Bmax and Kd) is only slightly altered. The effects of TNM treatment can be prevented by atropine, thus indicating that TNM modifies residue(s) at the binding site. We carried out a series of successive chemical modifications which indicated that the modified residue(s) is (are) most probably a tyrosyl and not a cysteinyl residue. This conclusion gains support from the pH profile of agonist binding, which suggests the involvement of a residue with an apparent pK comparable to that of the phenolic hydroxyl of a nitrotyrosyl residue. The binding properties of the modified receptor, when compared to those of the native one, clearly indicate that the response to TNM modification with respect to the binding of agonists such as acetylcholine and carbamoylcholine is different from that when oxotremorine and its analogue are employed. This is interpreted as being the result of different binding modes exhibited by the various agonists. Nitration of the receptors can be prevented by the presence of an antagonist but not by an agonist. We propose that this differential response is due to the formation of ligand-receptor complexes that differ with respect to the microenvironment of the modified tyrosyl residue.


How Computational Modeling Can Force Theory Building in Psychological Science.
Psychology endeavors to develop theories of human capacities and behaviors on the basis of a variety of methodologies and dependent measures. We argue that one of the most divisive factors in psychological science is whether researchers choose to use computational modeling of theories (over and above data) during the scientific-inference process. Modeling is undervalued yet holds promise for advancing psychological science. The inherent demands of computational modeling guide us toward better science by forcing us to conceptually analyze, specify, and formalize intuitions that otherwise remain unexamined-what we dub open theory. Constraining our inference process through modeling enables us to build explanatory and predictive theories. Here, we present scientific inference in psychology as a path function in which each step shapes the next. Computational modeling can constrain these steps, thus advancing scientific inference over and above the stewardship of experimental practice (e.g., preregistration). If psychology continues to eschew computational modeling, we predict more replicability crises and persistent failure at coherent theory building. This is because without formal modeling we lack open and transparent theorizing. We also explain how to formalize, specify, and implement a computational model, emphasizing that the advantages of modeling can be achieved by anyone with benefit to all.


Biolistic transformation of haploid isolated microspores of barley (Hordeum vulgare L.).
Transgenic barley plants were produced by the direct delivery of plasmid DNA into isolated microspores of barley cv. Igri using high velocity microprojectiles. The plasmid pAHC25 contained the uidA and bar genes, each under the control of a maize Ubi1 promoter. Bombarded microspores were cultured and selected on solid medium containing varying concentrations (2-5 mg/L) of the Basta herbicide active agent bialaphos. The effectiveness of selection with bialaphos depended on its interaction with the medium component glutamine. Six transgenic plants (R0) were obtained, and the presence of the uidA and bar genes and their integration into nuclear DNA in transformed R0 plants were confirmed by PCR and Southern blot analysis. Phosphinothricin acetyltransferase activity was observed in all six R0 transgenic plants, whereas none showed β-glucuronidase (GUS) activity in histochemical GUS assays. Two of the six R0 plants were haploid and sterile; one of them was trisomic and partially sterile; the remainder were diploid, but one of them was also sterile. Inheritance of the transgenes in progeny of three seed-producing transgenic plants was investigated. Southern blot analysis of genomic DNA from R1 plants showed that the introduced bar and uidA genes were hemizygous and stably cotransmitted to the R1 progeny derived from self-pollination. Analysis of Basta resistance and the integration of the bar gene by PCR analysis in R1 plants indicated that the bar gene was being inherited and expressed as a single dominant trait. Fluorescent in situ hybridization was performed on chromosomes of the trisomic plant to confirm the presence of transgenes in the genome.


Challenges in modeling complexity of neglected tropical diseases: a review of dynamics of visceral leishmaniasis in resource limited settings.
Neglected tropical diseases (NTD), account for a large proportion of the global disease burden, and their control faces several challenges including diminishing human and financial resources for those distressed from such diseases. Visceral leishmaniasis (VL), the second-largest parasitic killer (after malaria) and an NTD affects poor populations and causes considerable cost to the affected individuals. Mathematical models can serve as a critical and cost-effective tool for understanding VL dynamics, however, complex array of socio-economic factors affecting its dynamics need to be identified and appropriately incorporated within a dynamical modeling framework. This study reviews literature on vector-borne diseases and collects challenges and successes related to the modeling of transmission dynamics of VL. Possible ways of creating a comprehensive mathematical model is also discussed. Published literature in three categories are reviewed: (i) identifying non-traditional but critical mechanisms for VL transmission in resource limited regions, (ii) mathematical models used for dynamics of Leishmaniasis and other related vector borne infectious diseases and (iii) examples of modeling that have the potential to capture identified mechanisms of VL to study its dynamics. This review suggests that VL elimination have not been achieved yet because existing transmission dynamics models for VL fails to capture relevant local socio-economic risk factors. This study identifies critical risk factors of VL and distribute them in six categories (atmosphere, access, availability, awareness, adherence, and accedence). The study also suggests novel quantitative models, parts of it are borrowed from other non-neglected diseases, for incorporating these factors and using them to understand VL dynamics and evaluating control programs for achieving VL elimination in a resource-limited environment. Controlling VL is expensive for local communities in endemic countries where individuals remain in the vicious cycle of disease and poverty. Smarter public investment in control programs would not only decrease the VL disease burden but will also help to alleviate poverty. However, dynamical models are necessary to evaluate intervention strategies to formulate a cost-effective optimal policy for eradication of VL.


Giant primary retroperitoneal myxoid leiomyoma: a case report.
Leiomyomas are benign smooth muscle tumors that usually arise from the uterus. We present a patient with a 6-month history of vague abdominal discomfort, occasional nausea, vomiting and urinary incontinence. On examination, there was an extremely large firm unpainfull palpable abdominal mass. Laboratory investigation revealed mild leukocytosis and blood creatinine elevation. Abdominopelvic ultrasonography and computed tomography revealed a massive well bordered, encapsulated intraabdominal tumor, extending from the pelvis to epigastrium and almost completely fulfilling the pelvic and abdominal cavity. At laparotomy, tumor arising from the retroperitoneum was excised in toto. Histopathological examination disclosed that the tumor was composed mainly of smooth muscle cells and very rare fibrous connective tissue elements with myxomatous alteration and with no mitotic activity. The negative results of numerous additional parameters analyzed (pancytokeratin, epithelial membrane antigen, S100 protein, CD68, CD34, desmin, aktin) ruled out different origin of a tumor. One year after resection the patient had no complaints and no radiological evidence of tumor recurrence. Considering current limitations in radiological diagnosis, in toto resection of these tumors is necessary to rule out malignancy.


Management of endocrinological problems in children on home invasive mechanical ventilation.
Children with home invasive mechanical ventilation (HIMV) face numerous difficulties, including endocrine problems that can arise as a consequence of their condition. Endocrine problems seen in children treated with HIMV may develop due to the underlying disease, drugs used, or prolonged mechanical ventilation. This manuscript will review the most common endocrine problems encountered in children with HIMV, including problems in glucose metabolism, thyroid dysfunction, bone metabolism, adrenal dysfunctions, growth, and puberty. Close monitoring, multidisciplinary care, and regular assessments are essential to optimize the endocrine system functions of children requiring home mechanical ventilation. By understanding these complications, it can develop effective management strategies to optimize the health and well-being of these vulnerable individuals.


Mathematical model and tool to explore shorter multi-drug therapy options for active pulmonary tuberculosis.
Standard treatment for active tuberculosis (TB) requires drug treatment with at least four drugs over six months. Shorter-duration therapy would mean less need for strict adherence, and reduced risk of bacterial resistance. A system pharmacology model of TB infection, and drug therapy was developed and used to simulate the outcome of different drug therapy scenarios. The model incorporated human immune response, granuloma lesions, multi-drug antimicrobial chemotherapy, and bacterial resistance. A dynamic population pharmacokinetic/pharmacodynamic (PK/PD) simulation model including rifampin, isoniazid, pyrazinamide, and ethambutol was developed and parameters aligned with previous experimental data. Population therapy outcomes for simulations were found to be generally consistent with summary results from previous clinical trials, for a range of drug dose and duration scenarios. An online tool developed from this model is released as open source software. The TB simulation tool could support analysis of new therapy options, novel drug types, and combinations, incorporating factors such as patient adherence behavior.


An algorithmic approach to mechanical hip pain.
As our understanding of hip pathology evolves, the focus is shifting toward earlier identification of hip pathology. Therefore, it is vitally important to elucidate intra-articular versus extra-articular pathology of hip pain in every step of the patient encounter: history, physical examination, and imaging. The objective was to address the following research questions: (1) Can an algorithmic approach to physical examination of a painful non-arthritic hip provide a more accurate diagnosis and improved treatment plan? (2) Does an anatomical layered concept of clinical diagnosis improve diagnostic accuracy? (3) What are the diagnostic tools necessary for the accurate application of a four-layer (osteochondral, inert, contractile, and neuromechanical) diagnosis? An unrestricted computerized search of MEDLINE was conducted. Different terms were used in various combinations. An algorithmic approach to physical examination of a painful nonarthritic hip, including history, physical examination (specific tests), and advanced imaging allow for better interpretation of debilitating intra- and extra-articular disorders and their effect on core performance. Additionally, it improves our understanding as to how underlying abnormal joint mechanics may predispose the hip joint and the associated hemipelvis to asymmetric loads. These abnormal joint kinematics (layer I) can lead to cartilage and labral injury (layer II), as well as resultant injury to the musculotendinous (layer III) and neural structures (layer IV) about the hip joint and the hemipelvis. The layer concept is a systematic means of determining which structures about the hip are the source of hip pathology and how to best implement treatment. A clear understanding of the differential diagnosis of hip pain through a detailed and systematic physical examination, diagnostic imaging assessment, and the interpretation of how mechanical factors can result in such a wide range of compensatory injury patterns about the hip can facilitate the diagnosis and treatment recommendations.


Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner.
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.See related commentary by Gabrilovich et al., p. 1100.This article is highlighted in the In This Issue feature, p. 1079.


Subcutaneous Implantable Cardioverter-Defibrillator Technology.
The advent of subcutaneous implantable cardioverter-defibrillator (ICD) systems represents a paradigm shift for the detection and therapy of ventricular tachyarrhythmias. Despite advances in transvenous lead technology, problems remain that notably include requirement for technical expertise; periprocedural complications during implantation and explantation; and long-term lead failure. Although subcutaneous ICD systems may mitigate some of these risks, they provide new shortcomings, such as inability to provide pacing therapy for bradyarrhythmias, ventricular tachyarrhythmias, and cardiac resynchronization. Ongoing clinical evaluation and development are required before the role of subcutaneous ICDs as an adjunctive or primary therapy can be defined. This article examines studies investigating the subcutaneous ICD and discusses its possible advantages and disadvantages as compared with current transvenous ICD systems.


Sea Ice Dynamics Drive Benthic Microbial Communities in McMurdo Sound, Antarctica.
Climate change is driving dramatic variability in sea ice dynamics, a key driver in polar marine ecosystems. Projected changes in Antarctica suggest that regional warming will force dramatic shifts in sea ice thickness and persistence, altering sea ice-associated primary production and deposition to the seafloor. To improve our understanding of the impacts of sea ice change on benthic ecosystems, we directly compared the benthic microbial communities underlying first-year sea ice (FYI) and multi-year sea ice (MYI). Using two tractable coastal habitats in McMurdo Sound, Antarctica, where FYI (Cape Evans) and MYI (New Harbour) prevail, we show that the structure and composition of the benthic microbial communities reflect the legacy of sea ice dynamics. At Cape Evans, an enrichment of known heterotrophic algal polysaccharide degrading taxa (e.g., Flavobacteriaceae, unclassified Gammaproteobacteria, and Rubritaleaceae) and sulfate-reducing bacteria (e.g., Desulfocapsaceae) correlated with comparatively higher chlorophyll a (14.2±0.8μgg-1) and total organic carbon content (0.33%±0.04), reflecting increased productivity and seafloor deposition beneath FYI. Conversely, at New Harbour, an enrichment of known archaeal (e.g., Nitrosopumilaceae) and bacterial (e.g., Woeseiaceae and Nitrospiraceae) chemoautotrophs was common in sediments with considerably lower chlorophyll a (1.0±0.24μgg-1) and total organic carbon content (0.17%±0.01), reflecting restricted productivity beneath MYI. We also report evidence of a submarine discharge of sub-permafrost brine from Taylor Valley into New Harbour. By comparing our two study sites, we show that under current climate-warming scenarios, changes to sea ice productivity and seafloor deposition are likely to initiate major shifts in benthic microbial communities, with heterotrophic organic matter degradation processes becoming increasingly important. This study provides the first assessment of how legacy sea ice conditions influence benthic microbial communities in Antarctica, contributing insight into sea ice-benthic coupling and ecosystem functioning in a polar environment.


Parent/caregiver perceptions and practice of child water safety at the beach.
Lack of appropriate supervision is a persistent risk factor in most child drowning incidents. The risks to young children associated with swimming at beaches place a premium on close and constant supervision by caregivers. However, little is known about caregiver supervisory practice and perceptions of child water safety at beaches. Adults (N = 769) in charge of children under 10 years of age were surveyed at 18 New Zealand beaches during the summer of 2007 to ascertain caregiver perceptions of their water safety skills, risk of drowning for their child and their supervisory behaviours. Most parents (78%) estimated that they could swim 100 m non-stop in open water, almost one half (48%) had been certified in cardio-pulmonary resuscitation and one quarter (24%) had received some rescue/lifesaving training. More than one quarter (29%) failed to provide appropriate supervision for their under 5-year olds at the beach. Almost half (46%) of caregivers did not provide close supervision for their 5-9 year olds. Although there were no significant differences between males and female self-reported supervision, male caregivers were more likely to rate their 5-9 year olds as good swimmers and less likely to estimate a high risk of drowning for that age group. To address shortcomings in caregiver supervision, it is suggested that water safety education initiatives emphasise how to provide close and constant supervision of young children at beaches. Furthermore, a focus on the necessity for caution when estimating risk and ability to cope with open water conditions is recommended.


Model of HIV-1 disease progression based on virus-induced lymph node homing and homing-induced apoptosis of CD4+ lymphocytes.
Several proposed theories have described the progression of HIV infection. Even so, no concrete evidence supports any as comprehensive, including, for example, why the CD4+ T-cell counts fall from 1000/mm3 of blood to roughly 100/mm3 over an average 10-year period, whereas concomitant viral loads are relatively constant, increasing by several orders of magnitude in late-stage disease. Here, we develop and validate a theoretical model that altered lymphocyte circulation patterns between the lymph system and blood due to HIV-induced enhanced lymph-node homing and subsequent apoptosis of resting CD4+ T cells can explain many aspects of HIV-1 disease progression. These results lead to a recalculation of the CD4+ lymphocyte dynamics during highly active antiretroviral therapy, and also suggest new targets for therapy.


Microbial contamination of removable prosthodontic appliances from laboratories and impact of clinical storage.
Decontamination of dental instruments has recently been the subject of considerable debate. However, little information is available on the potential bacterial colonisation of dental appliances returning from dental laboratories and their need for decontamination. This study investigated the extent and nature of microbial contamination of removable prosthodontic appliances produced at different dental laboratories and stored in two clinical teaching units (CTU 1 and CTU 2) of a dental hospital and school. Forty consecutive dental prosthodontic appliances that were being stored under varying conditions in the two clinical teaching units were selected for study; the appliances having been produced 'in-house' (hospital laboratory) or 'out-of-house' (external commercial laboratory). Two appliances, that were known to have undergone decontamination before storage, were used as controls. Swabs were taken according to a standard protocol and transferred to the microbiological laboratory with bacterial growth expressed as colony forming units (cfu) per cm(2). Microbial sampling yielded growth from 23 (58%) of the 40 appliances studied (CTU 1, n = 22; CTU 2, n = 18), with 38% of these having a high level of contamination (>42,000 cfu/cm(2)). The predominant bacteria isolated were Bacillus spp. (57%), pseudomonads (22%) and staphylococci (13%). Fungi of the genus Candida were detected in 38% of the samples. There was no significant difference in contamination of the appliances in relation to either their place of production or the CTU (p >0.05). However, the level of contamination was significantly higher (p = 0.035) for those appliances stored in plastic bag with fluid (n = 16) compared to those stored on models (n = 19). No growth was recovered from the two appliances that had undergone decontamination before storage. The research showed that appliances received from laboratories are often contaminated and therefore there is a need for routine disinfection of such items before use and a review of storage conditions required.


Evolinc: A Tool for the Identification and Evolutionary Comparison of Long Intergenic Non-coding RNAs.
Long intergenic non-coding RNAs (lincRNAs) are an abundant and functionally diverse class of eukaryotic transcripts. Reported lincRNA repertoires in mammals vary, but are commonly in the thousands to tens of thousands of transcripts, covering ~90% of the genome. In addition to elucidating function, there is particular interest in understanding the origin and evolution of lincRNAs. Aside from mammals, lincRNA populations have been sparsely sampled, precluding evolutionary analyses focused on their emergence and persistence. Here we present Evolinc, a two-module pipeline designed to facilitate lincRNA discovery and characterize aspects of lincRNA evolution. The first module (Evolinc-I) is a lincRNA identification workflow that also facilitates downstream differential expression analysis and genome browser visualization of identified lincRNAs. The second module (Evolinc-II) is a genomic and transcriptomic comparative analysis workflow that determines the phylogenetic depth to which a lincRNA locus is conserved within a user-defined group of related species. Here we validate lincRNA catalogs generated with Evolinc-I against previously annotated Arabidopsis and human lincRNA data. Evolinc-I recapitulated earlier findings and uncovered an additional 70 Arabidopsis and 43 human lincRNAs. We demonstrate the usefulness of Evolinc-II by examining the evolutionary histories of a public dataset of 5,361 Arabidopsis lincRNAs. We used Evolinc-II to winnow this dataset to 40 lincRNAs conserved across species in Brassicaceae. Finally, we show how Evolinc-II can be used to recover the evolutionary history of a known lincRNA, the human telomerase RNA (TERC). These latter analyses revealed unexpected duplication events as well as the loss and subsequent acquisition of a novel TERC locus in the lineage leading to mice and rats. The Evolinc pipeline is currently integrated in CyVerse's Discovery Environment and is free for use by researchers.


Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection.
Because complement activation in the subacute or chronic phase after stroke was recently shown to stimulate neural plasticity, we investigated how complement activation and complement inhibition in the acute phase after murine stroke interacts with subsequent rehabilitation therapy to modulate neuroinflammation and neural remodeling. We additionally investigated how complement and complement inhibition interacts with tissue plasminogen activator (tPA), the other standard of care therapy for stroke, and a U.S. Food and Drug Administration preclinical requirement for translation of an experimental stroke therapy. CR2fH, an injury site-targeted inhibitor of the alternative complement pathway, significantly reduced infarct volume, hemorrhagic transformation, and mortality and significantly improved long-term motor and cognitive performance when administered 1.5 or 24 h after middle cerebral artery occlusion. CR2fH interrupted a poststroke inflammatory process and significantly reduced inflammatory cytokine release, microglial activation, and astrocytosis. Rehabilitation alone showed mild anti-inflammatory effects, including reduced complement activation, but only improved cognitive recovery. CR2fH combined with rehabilitation significantly potentiated cognitive and motor recovery compared with either intervention alone and was associated with higher growth factor release and enhanced rehabilitation-induced neuroblast migration and axonal remodeling. Similar outcomes were seen in adult, aged, and female mice. Using a microembolic model, CR2fH administered in combination with acute tPA therapy improved overall survival and enhanced the neuroprotective effects of tPA, extending the treatment window for tPA therapy. A human counterpart of CR2fH has been shown to be safe and nonimmunogenic in humans and we have demonstrated robust deposition of C3d, the CR2fH targeting epitope, in ischemic human brains after stroke.SIGNIFICANCE STATEMENT Complement inhibition is a potential therapeutic approach for stroke, but it is not known how complement inhibition would interact with current standards of care. We show that, after murine ischemic stroke, rehabilitation alone induced mild anti-inflammatory effects and improved cognitive, but not motor recovery. However, brain-targeted and specific inhibition of the alternative complement pathway, when combined with rehabilitation, significantly potentiated cognitive and motor recovery compared with either intervention alone via mechanisms involving neuroregeneration and enhanced brain remodeling. Further, inhibiting the alternative pathway of complement significantly enhanced the neuroprotective effects of thrombolytic therapy and markedly expanded the therapeutic window for thrombolytic therapy.


Drivers for Rift Valley fever emergence in Mayotte: A Bayesian modelling approach.
Rift Valley fever (RVF) is a major zoonotic and arboviral hemorrhagic fever. The conditions leading to RVF epidemics are still unclear, and the relative role of climatic and anthropogenic factors may vary between ecosystems. Here, we estimate the most likely scenario that led to RVF emergence on the island of Mayotte, following the 2006-2007 African epidemic. We developed the first mathematical model for RVF that accounts for climate, animal imports and livestock susceptibility, which is fitted to a 12-years dataset. RVF emergence was found to be triggered by the import of infectious animals, whilst transmissibility was approximated as a linear or exponential function of vegetation density. Model forecasts indicated a very low probability of virus endemicity in 2017, and therefore of re-emergence in a closed system (i.e. without import of infected animals). However, the very high proportion of naive animals reached in 2016 implies that the island remains vulnerable to the import of infectious animals. We recommend reinforcing surveillance in livestock, should RVF be reported is neighbouring territories. Our model should be tested elsewhere, with ecosystem-specific data.


Macroscopic current generated by local division and apoptosis in a minimal model of tissue dynamics.
It has been known that the motion of self-propelled particles inside an asymmetric channel can be rectified to give rise to a macroscopic and unidirectional current. In this paper, we show that division and apoptosis process alone (which are ubiquitous in all living systems), without any self-propulsion, are sufficient to give rise to a macroscopic and unidirectional current in a similar channel. More specifically, we consider a minimal computational model of two-dimensional living tissues, with two active ingredients: local particle division and apoptosis, and we found a net steady state current along the channel. This mechanism is fundamentally different from that of self-propelled particles, since this requires the system to be dense. Finally, our results might have applications in tissue engineering such as controlling tissue growth via a geometrically non-uniform substrate.


Optimized assay for transposase-accessible chromatin by sequencing (ATAC-seq) library preparation from adult Drosophila melanogaster neurons.
Assay for transposase-accessible chromatin by sequencing (ATAC-seq) is rapidly becoming the assay of choice to investigate chromatin-mediated gene regulation, largely because of low input requirements, a fast workflow, and the ability to interrogate the entire genome in an untargeted manner. Many studies using ATAC-seq use mammalian or human-derived tissues, and established protocols work well in these systems. However, ATAC-seq is not yet widely used in Drosophila. Vinegar flies present several advantages over mammalian systems that make them an excellent model for ATAC-seq studies, including abundant genetic tools that allow straightforward targeting, transgene expression, and genetic manipulation that are not available in mammalian models. Because current ATAC-seq protocols are not optimized to use flies, we developed an optimized workflow that accounts for several complicating factors present in Drosophila. We examined parameters affecting nuclei isolation, including input size, freezing time, washing, and possible confounds from retinal pigments. Then, we optimized the enzymatic steps of library construction to account for the smaller Drosophila genome size. Finally, we used our optimized protocol to generate ATAC-seq libraries that meet ENCODE quality metrics. Our optimized protocol enables extensive ATAC-seq experiments in Drosophila, thereby leveraging the advantages of this powerful model system to understand chromatin-mediated gene regulation.


Nonspecific bronchial reactivity and its relationship to the clinical expression of asthma. A longitudinal study.
The contribution of nonspecific bronchial reactivity to the day-to-day clinical expression of asthma is uncertain. We have examined this relationship in a longitudinal study of eight children and 12 adults. Measurements of reactivity to methacholine were made every 2 to 3 wk over a period of 12 to 18 months, deriving the dose that caused a 20% fall in FEV1 (PD20). Throughout the study, all patients kept a daily record of symptoms and treatment and twice daily measurements of peak expiratory flow (PEF). A significant relationship was found between subjects' overall reactivity (median PD20) and both their average day-to-day variation in morning PEF (Spearman's rho = -0.53, p = 0.016) and diurnal variation in PEF (Spearman's rho = -0.60, p = 0.004). However, examining the temporal relationship between reactivity and asthma within subjects, individual PD20 measurements were not consistently related to concurrent asthma severity: in only six subjects did changes in PD20 generally reflect simultaneous trends in symptoms or PEF. In several patients, exacerbations of asthma occurred in the absence of bronchial hyperreactivity (PD20 greater than 12.8 mumol). We conclude that nonspecific bronchial reactivity is only one mechanism underlying airflow obstruction in asthma, and that its relationship to the clinical state of asthma is not sufficiently close to be of practical clinical use.


Linkage failures in ecological studies.
Ecological studies require a methodological theory distinct from that used in individual-level epidemiological studies. This article discusses the special problems that need to be considered when planning ecological studies or using the results of such studies. Ecological studies are much more sensitive to bias from model mis-specification than are results from individual-level studies. For example, deviations from linearity in the underlying individual-level regressions can lead to inability to control for confounding in ecological studies, even if no misclassification is present. Conditions for confounding differ in individual-level and ecological analyses. For ecological analyses of means, for example, a covariate will not be a confounder if its mean value in a study region is not associated with either (i) the mean exposure level across regions, or (ii) the mean outcome (disease rate) across regions. On the other hand, effect modification across areas can induce ecological bias even when the number of areas is very large and there is no confounding. In contrast to individual-level studies, independent and nondifferential misclassification of a dichotomous exposure usually leads to bias away from the null hypothesis in aggregate data studies. Failure to standardize disease, exposure and covariate data for other confounders (not included in the regression model) can lead to bias. It should be borne in mind that there is no method available to identify or measure ecological bias. While this conclusion may sound like a general criticism of ecological studies, it is not. It does, however, serve as a reminder of the problems that need to be considered when one designs, analyses, or critically evaluates ecological studies.


Metagenome-assembled genomes of phytoplankton microbiomes from the Arctic and Atlantic Oceans.
Phytoplankton communities significantly contribute to global biogeochemical cycles of elements and underpin marine food webs. Although their uncultured genomic diversity has been estimated by planetary-scale metagenome sequencing and subsequent reconstruction of metagenome-assembled genomes (MAGs), this approach has yet to be applied for complex phytoplankton microbiomes from polar and non-polar oceans consisting of microbial eukaryotes and their associated prokaryotes. Here, we have assembled MAGs from chlorophyll a maximum layers in the surface of the Arctic and Atlantic Oceans enriched for species associations (microbiomes) with a focus on pico- and nanophytoplankton and their associated heterotrophic prokaryotes. From 679 Gbp and estimated 50 million genes in total, we recovered 143 MAGs of medium to high quality. Although there was a strict demarcation between Arctic and Atlantic MAGs, adjacent sampling stations in each ocean had 51-88% MAGs in common with most species associations between Prasinophytes and Proteobacteria. Phylogenetic placement revealed eukaryotic MAGs to be more diverse in the Arctic whereas prokaryotic MAGs were more diverse in the Atlantic Ocean. Approximately 70% of protein families were shared between Arctic and Atlantic MAGs for both prokaryotes and eukaryotes. However, eukaryotic MAGs had more protein families unique to the Arctic whereas prokaryotic MAGs had more families unique to the Atlantic. Our study provides a genomic context to complex phytoplankton microbiomes to reveal that their community structure was likely driven by significant differences in environmental conditions between the polar Arctic and warm surface waters of the tropical and subtropical Atlantic Ocean. Video Abstract.


Biosynthesis and metabolic engineering of glucosinolates.
Glucosinolates are amino acid-derived natural plant products found throughout the Capparales order. Glucosinolates and their degradation products have a wide range of biological activities, e.g. in plant defense as deterrents against insect and fungi. The conversion of amino acids to aldoximes is a key step in glucosinolate biosynthesis. This step is catalyzed by cytochromes P450 from the CYP79 family. The post-aldoxime enzymes in the glucosinolate pathway have high substrate-specificity for the functional group and low substrate-specificity for the side chain. Therefore, we have been able to metabolically engineer new glucosinolate profiles into Arabidopsis by altering the levels of endogenous CYP79s and by introducing exogenous CYP79s. The approach has great potential for design of metabolically engineered plants with improved pest resistance and increased nutritional value.


Persistent abdominal pain. Treatment by lumbar sympathetic lysis.
The organic and psychological problems of patients suffering from chronic abdominal pain are described and three case histories of patients who had undergone multiple surgery for their abdominal pain are presented. All three were treated by lumbar sympathetic lysis, resulting in relief of their pain. The possible reasons for this success are discussed.


The feasibility of maximum length sequences to reduce acquisition time of the middle latency response.
Maximum length sequences (MLS) have been used to improve the signal-to-noise ratio (SNR) of otoacoustic emissions [Thornton, J. Acoust. Soc. Am. 94, 132-136 (1993)] and the auditory brainstem response [Thornton and Slaven, Br. J. Audiol. 27, 205-210 (1993)]. By implication, a shorter recording time would be required to give equal signal-to-noise ratio (SNR). This study aimed to establish whether it is also possible to improve the SNR of the auditory-evoked potential termed the middle latency response (MLR) using maximum length sequences (MLS). Recordings of 180 s each were made using a conventional recording rate and MLS rates of 42, 89, and 185 clicks/s. Three different stimulus intensities were used in the range 30 to 70 dB nHL. The rate of 89 clicks/s was found to produce most improvement in SNR for both the Na-Pa region of the MLR and the Na-Pb region. This improvement in SNR using MLS implies that an MLS rate of 89 clicks/s would produce a fourfold reduction in recording time for equal SNR over conventional recording for the Pa-Nb region of the MLR at a stimulus intensity of 70 dB nHL. The latency of the Nb wave was found to reduce significantly using MLS. An MLR could not be recorded from every subject in this study, but more subjects had an identifiable response for MLS than for conventional recordings. Use of MLS to record the MLR appears to offer the potential for reduction in test time and better wave identification.


HLA transgenic mice provide evidence for a direct and dominant role of HLA class II variation in modulating the severity of streptococcal sepsis.
Our epidemiologic studies on invasive Group A Streptococci (GAS) infections identified specific HLA class II haplotypes/alleles conferring high-risk or protection from streptococcal toxic shock syndrome with a strong protection conferred by the DRB1*15/DQB1*06 haplotype. We used HLA-transgenic mice to provide an in vitro and in vivo validation for the direct role of HLA class II allelic variation in streptococcal toxic shock syndrome. When splenocytes from mice expressing the protective HLA-DQB1*06 (DQ6) allele were stimulated with a mixture of streptococcal superantigens (SAgs), secreted by the prevalent M1T1 strain, both proliferative and cytokine responses were significantly lower than those of splenocytes from mice expressing the neutral DRB1*0402/DQB1*0302 (DR4/DQ8) alleles (p < 0.001). In crisscross experiments, the presentation of SAgs to pure T cells from either the DQ6 or the DR4/DQ8 mice resulted in significantly different levels of response depending on the HLA type expressed on the APCs. Presentation by HLA-DQ6 APCs elicited significantly lower responses than the presentation by HLA-DR4/DQ8 APCs. Our in vitro data were supported by in vivo findings, as the DQ6 mice showed significantly longer survival post-i.v. infection with live M1T1 GAS (p < 0.001) and lower inflammatory cytokine responses as compared with the DR4/DQ8 mice (p < 0.01). The data presented here provide evidence for a direct role of HLA class II molecules in modulating responses to GAS SAgs and underscore the dominant role of HLA class II allelic variation in potentiating the severity of GAS systemic infections.


BAYESIAN METHODS FOR MULTIPLE MEDIATORS: RELATING PRINCIPAL STRATIFICATION AND CAUSAL MEDIATION IN THE ANALYSIS OF POWER PLANT EMISSION CONTROLS.
Emission control technologies installed on power plants are a key feature of many air pollution regulations in the US. While such regulations are predicated on the presumed relationships between emissions, ambient air pollution, and human health, many of these relationships have never been empirically verified. The goal of this paper is to develop new statistical methods to quantify these relationships. We frame this problem as one of mediation analysis to evaluate the extent to which the effect of a particular control technology on ambient pollution is mediated through causal effects on power plant emissions. Since power plants emit various compounds that contribute to ambient pollution, we develop new methods for multiple intermediate variables that are measured contemporaneously, may interact with one another, and may exhibit joint mediating effects. Specifically, we propose new methods leveraging two related frameworks for causal inference in the presence of mediating variables: principal stratification and causal mediation analysis. We define principal effects based on multiple mediators, and also introduce a new decomposition of the total effect of an intervention on ambient pollution into the natural direct effect and natural indirect effects for all combinations of mediators. Both approaches are anchored to the same observed-data models, which we specify with Bayesian nonparametric techniques. We provide assumptions for estimating principal causal effects, then augment these with an additional assumption required for causal mediation analysis. The two analyses, interpreted in tandem, provide the first empirical investigation of the presumed causal pathways that motivate important air quality regulatory policies.


Proficiency testing for creatine kinase isoenzyme CK-2 (CK-MB) in Ontario.
Three surveys of the measurement and interpretation of creatine kinase (CK; EC 188.8.131.52) isoenzyme 2 (CK-MB) were conducted in Ontario, Canada, in 1989. Of the clinical laboratories participating, 66% used immunological methods and 24% used electrophoretic methods. Although reference ranges and interpretative routines varied widely, 95% of the laboratories reported correct interpretations for 10 of the 15 vials tested. The only major problems occurred with samples with very low total CK activity. Within-survey duplicate results compared well, and 89% of the laboratories had consistent between-survey results, even for specimens with low total CK activity. Errors were proportional to the frequency of use of the different analytical methods. The lyophilized testing material gave higher results with methods for measuring the mass of CK-2, suggesting that the material contained inactive but immunologically intact CK-2. The surveys indicate that laboratories should review their protocols for measuring CK-2 when only a single sample from the patient is available.


Crystal structure of a silyl cation with no coordination to anion and distant coordination to solvent.
The crystal structure of a stable silyl cation, triethylsilylium, in the form of its tetrakis (pentafluorophenyl)borate salt [Et(3)Si(+) (C(6)F(5))(4)B(-)] (Et, ethyl) shows no coordination between cation and anion. The closest silicon-fluorine distance is greater than 4 angstroms. A toluene solvent molecule is close enough to cause some deviations from planarity at the silicon, but the silicon-toluene distance is well beyond the sum of the silicon and carbon covalent radii. The toluene molecule is essentially planar and undistorted, as expected if little or no positive charge has been transferred from silicon to toluene.


Antihypertensive potential of Brassica rapa leaves: An in vitro and in silico approach.
Aim: Plants contain many essential constituents and their optimization can result in the discovery of new medicines. One such plant is Brassica rapa that is commonly used as a vegetable to fulfill daily food requirements worldwide. This study intends to screen the phytochemicals, antihypertensive potential, GC-MS, and in silico analysis of the leaves of Brassica rapa. Methods: Powdered leaves were subjected to proximate analysis followed by estimation of primary metabolites. Extracts were obtained by hot and cold extraction and investigated for secondary metabolites. All crude extracts were screened for their antihypertensive potential using an angiotensin-converting enzyme (ACE) inhibition assay. GC-MS analysis was carried out to standardize the extract, and an antihypertensive metabolite was confirmed using an in silico approach. Results: Physicochemical evaluation resulted in moisture content (9.10% ± 0.1), total ash value (18.10% ± 0.6), and extractive values (water 9.46% ± 0.5 and alcohol soluble 4.99% ± 0.1), while phytochemical investigation revealed primary metabolites (total proteins 11.90 mg/g ± 0.9; total fats 3.48 mg/g ± 0.5; and total carbohydrates 57.45 mg/g ± 1.2). Methanol extract showed the highest number of secondary metabolites including polyphenols 93.63 mg/g ± 0.6; flavonoids 259.13 mg/g ± 0.6; and polysaccharides 56.63 mg/g ± 1.4, while water extract (70 mg/g ± 2) was rich in glycosaponins. Methanol extract showed the highest antihypertensive potential by inhibiting ACE (79.39%) amongst all extracts, compared to the standard drug captopril, which inhibited 85.81%. Standardization of methanol extract via GC-MS analysis revealed potent phytoconstituents, and a molecular docking study confirmed that oleic acid is the main antihypertensive metabolite. Conclusion: We conclude that leaves of Brassica rapa can successfully lower hypertension by inhibiting ACE, however; in vivo investigations are required to confirm this antihypertensive activity.


Physical Contacts Between Mitochondria and WPBs Participate in WPB Maturation.
Weibel-Palade bodies (WPBs) are endothelial cell-specific cigar-shaped secretory organelles containing various biologically active molecules. WPBs play crucial roles in thrombosis, hemostasis, angiogenesis, and inflammation. The main content of WPBs is the procoagulant protein vWF (von Willebrand factor). Physical contacts and functional cross talk between mitochondria and other organelles have been demonstrated. Whether an interorganellar connection exists between mitochondria and WPBs is unknown. We observed physical contacts between mitochondria and WPBs in human umbilical vein endothelial cells by electron microscopy and living cell confocal microscopy. We developed an artificial intelligence-assisted method to quantify the duration and length of organelle contact sites in live cells. We found there existed physical contacts between mitochondria and WPBs. Disruption of mitochondrial function affected the morphology of WPBs. Furthermore, we found that Rab3b, a small GTPase on the WPBs, was enriched at the mitochondrion-WPB contact sites. Rab3b deficiency reduced interaction between the two organelles and impaired the maturation of WPBs and vWF multimer secretion. Our results reveal that Rab3b plays a crucial role in mediating the mitochondrion-WPB contacts, and that mitochondrion-WPB coupling is critical for the maturation of WPBs in vascular endothelial cells.


Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study.
Limited evidence suggests that the risk of acute myocardial infarction (AMI) may be increased shortly after total hip replacement (THR) and total knee replacement (TKR) surgery. However, risk of AMI in these patients has not been compared against matched controls who have not undergone surgery. The objective of this study was to evaluate the timing of AMI in patients undergoing THR or TKR surgery compared with matched controls. Retrospective, nationwide cohort study within the Danish national registries. All patients who underwent a primary THR or TKR (n = 95,227) surgery from January 1, 1998, through December 31, 2007, were selected and matched to 3 controls (no THR or TKR) by age, sex, and geographic region. All study participants were followed up for AMI, and disease- and medication history-adjusted hazard ratios (HRs) were calculated. During the first 2 postoperative weeks, the risk of AMI was substantially increased in THR patients compared with controls (adjusted HR, 25.5; 95% CI, 17.1-37.9). The risk remained elevated for 2 to 6 weeks after surgery (adjusted HR, 5.05; 95% CI, 3.58-7.13) and then decreased to baseline levels. For TKR patients, AMI risk was also increased during the first 2 weeks (adjusted HR, 30.9; 95% CI, 11.1-85.5) but did not differ from controls after the first 2 weeks. The absolute 6-week risk of AMI was 0.51% in THR patients and 0.21% in TKR patients. Risk of AMI is substantially increased in the first 2 weeks after THR (25-fold) and TKR (31-fold) surgery compared with controls. Risk assessment of AMI should be considered during the first 6 weeks after THR surgery and during the first 2 weeks after TKR surgery.


Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation - a follow-up study.
Non-functioning pituitary adenomas (NFA) are the commonest type of pituitary macroadenoma. Although the initial definitive management of these tumours is almost always trans-sphenoidal surgery, the use of postoperative radiotherapy remains controversial. Radiotherapy has been shown to significantly reduce the risk of tumour regrowth. An audit of patients with NFAs treated with trans-sphenoidal surgery without irradiation was performed at our centre five years ago, and suggested that careful selection and follow-up could avoid the need for adjuvant radiotherapy. We have repeated this audit to assess the longer term effects of this management strategy. The case notes and imaging of the original cohort of 65 of 73 patients (50 males, mean age 52) who had undergone trans-sphenoidal surgery (TSA) for NFA between July 1979 and 1992, had not received irradiation and were followed up by imaging were reviewed. Tumour regrowth was defined as enlargement of the pituitary tumour. Mean follow-up was 76 months (range 12-173). Pituitary tumour regrowth has occurred in 21 of the 65 patients (32%) during a mean follow-up of 76 months compared with 8/73 (11%) in 1994 (P = 0.002). The tumour regrowth was detected at a mean of 5.4 years (range 2-14 years). Lifetable analysis of the whole unirradiated group showed 82% recurrence free survival at 5 years (95% confidence limits 72-92%), and 56% at 10 years (95% confidence limits 38-74%). Eight (12%) patients required a second surgical procedure (6 TSA and 2 craniotomies). There was no relationship between recurrence and whether a total surgical removal was thought to have been performed. Despite careful selection of patients with non-functioning pituitary adenomas, tumour regrowth occurs in a significant proportion. These results show that continued follow-up in these patients is essential as significantly more patients showed evidence of tumour regrowth at this second assessment compared with the 1994 data. Until we are able to predict which tumours are likely to regrow postoperatively, radiotherapy should be considered for all patients with non-functioning pituitary adenomas as even in carefully selected cases, the regrowth rate is approaching 50% at 10 years.


A thaumatin-like protein, Rj4, controls nodule symbiotic specificity in soybean.
Soybeans exhibit a nitrogen-fixing symbiosis with soil bacteria of the genera Bradyrhizobium and Ensifer/Sinorhizobium in a unique organ, the root nodule. It is well known that nodulation of soybean is controlled by several host genes referred to as Rj (rj) genes. Among these genes, a dominant allele, Rj4, restricts nodulation with specific bacterial strains such as B. elkanii USDA61 and B. japonicum Is-34. These incompatible strains fail to invade the host epidermal cells as revealed by observations using DsRed-labeled bacteria. Here, we describe the molecular identification of the Rj4 gene by using map-based cloning with several mapping populations. The Rj4 gene encoded a thaumatin-like protein (TLP) that belongs to pathogenesis-related (PR) protein family 5. In rj4/rj4 genotype soybeans and wild soybeans, we found six missense mutations and two consecutive amino acid deletions in the rj4 gene as compared with the Rj4 allele. We also found, using hairy root transformation, that the rj4/rj4 genotype soybeans were fully complemented by the expression of the Rj4 gene. Whereas the expression of many TLPs and other PR proteins is induced by biotic/abiotic stress, Rj4 gene expression appears to be constitutive in roots including root nodules.


[Psychiatric and psychological aspects of Fahr syndrome].
The following article reports findings concerning a man who first developed symptoms in his late twenties that were later diagnosed as bilateral basal ganglia calcification. The man, now 53 years of age, shows symptoms of an alteration of his personality with despondency and nearly a total loss of drive. Earlier clinical reports assumed that the man's condition was due to a deterioration of his intelligence. The findings presented here, however, show that he had a normal IQ, and that the supposed deterioration of intelligence was only due to his loss of drive.


Preclinical Gold Complexes as Oral Drug Candidates to Treat Leishmaniasis Are Potent Trypanothione Reductase Inhibitors.
The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 μM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 μM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.


Reduced mortality, paraplegia, and stroke with stent graft repair of blunt aortic transections: a modern meta-analysis.
Stent grafting has become the first-line approach to traumatic thoracic aortic transections (TTAT) in some trauma centers due to a perceived decrease in morbidity and mortality compared with standard open repair. We reviewed contemporary outcomes of patients undergoing endovascular repair of TTAT (endoTTAT) and those undergoing open repair (openTTAT) to determine if current reported results support first-line use of endoTTAT. Retrospective, nonrandomized studies published in English (>5 cases/report) involving TTAT listed in PubMed between 2001 and 2006 were systematically reviewed. Periprocedural outcomes between endoTTAT and openTTAT were analyzed. Mean follow-up was 22.9 months for endoTTAT (reported for 22 of 28 studies) and 48.6 months for openTTAT (reported for 5 of 12 studies). For statistical analysis, t tests were used. We analyzed 33 articles reporting 699 procedures in which 370 patients treated with endoTTAT and 329 patients managed with openTTAT. No statistical differences were found between patient groups in mean age (41.3 vs 38.8 years, P < .10), injury severity score (39.8 vs 36.0, P < .10), or technical success rates of the procedure (96.5% vs 98.5%, P = .58). In contrast, mortality was significantly lower in the endoTTAT group (7.6% vs 15.2%, P = .0076) as were rates of paraplegia (0% vs 5.6%, P < .0001) and stroke (0.85% vs 5.3%, P = .0028). The most common procedure-related complications for each technique were iliac artery injury during endoTTAT and recurrent laryngeal nerve injury after openTTAT. To our knowledge, no large multicenter prospective randomized trial comparing endoTTAT and openTTAT has been published in the literature. This meta-analysis of pooled data serves as a surrogate, demonstrating a significant reduction in mortality, paraplegia, and stroke rates in patients who undergo endoTTAT; however, the long-term durability of endoTTAT remains in question.


The effect of mixed liquor suspended solids (MLSS) on biofouling in a hybrid membrane bioreactor for the treatment of high concentration organic wastewater.
Biofouling is a crucial factor in membrane bioreactor (MBR) applications, particularly for high organic loading operations. This paper reports a study on biofouling in an MBR to establish a relationship between critical flux, Jc, mixed liquor suspended solids (MLSS) (ranging from 5 to 20 g L-1) and volumetric loading rate (6.3 kg COD m-3 h-1) of palm oil mill effluent (POME). A lab-scale 100 L hybrid MBR consisting of anaerobic, anoxic, and aerobic reactors was used with flat sheet microfiltration (MF) submerged in the aerobic compartment. The food-to-microorganism (F/M) ratio was maintained at 0.18 kg COD kg-1 MLSSd-1. The biofouling tendency of the membrane was obtained based on the flux against the transmembrane pressure (TMP) behaviour. The critical flux is sensitive to the MLSS. At the MLSS 20 g L-1 the critical flux is about four times lower than that for the MLSS concentration of 5 g L-1. The results showed high removal efficiency of denitrification and nitrification up to 97% at the MLSS concentration 20 g L-1. The results show that the operation has to compromise between a high and a low MLSS concentration. The former will favour a higher removal rate, while the latter will favour a higher critical flux.


Amiloride added together with bumetanide completely blocks mouse 3T3-cell exit from G0/G1-phase and entry into S-phase.
In this study we tested the hypothesis that stimulation of univalent-cation fluxes which follow the addition of growth factors are required for cell transition through the G1-phase of the cell cycle. The effect of two drugs, amiloride and bumetanide, were tested on exit of BALB/c 3T3 cells from G0/G1-phase and entry into S-phase (DNA synthesis). Amiloride, an inhibitor of the Na+/H+ antiport, only partially inhibited DNA synthesis induced by serum. Bumetanide, an inhibitor of the Na+/K+ co-transport, only slightly suppressed DNA synthesis by itself, but when added together with amiloride completely blocked cell transition through G1 and entry into S-phase. Similar inhibitory effects of the two drugs were found on the induction of ornithine decarboxylase (ODC) (a marker of mid-G1-phase) in synchronized cells stimulated by either partially purified fibroblast growth factor (FGF) or serum. To test this hypothesis further, cells arrested in G0/G1 were stimulated by serum, insulin or FGF. All induced similar elevations of cellular K+ content during the early G1-phase of the cell cycle. However, serum and FGF, but not insulin, released the cells from the G0/G1 arrest, as measured by ODC enzyme induction. This result implies that the increase in cellular K+ content may be necessary but not sufficient for induction of early events during the G1-phase. The synergistic inhibitory effects of amiloride and bumetanide on the two activities stimulated by serum growth factors, namely ODC induction (mid-G1) and thymidine incorporation into DNA (S-phase), suggested that the amiloride-sensitive Na+/H+ antiport system together with the bumetanide-sensitive Na+/K+ transporter play a role in the mitogenic signal.


Mapping the Diagnosis Axis of an Interface Terminology to the NANDA International Taxonomy.
Background. Nursing terminologies are designed to support nursing practice but, as with any other clinical tool, they should be evaluated. Cross-mapping is a formal method for examining the validity of the existing controlled vocabularies. Objectives. The study aims to assess the inclusiveness and expressiveness of the nursing diagnosis axis of a newly implemented interface terminology by cross-mapping with the NANDA-I taxonomy. Design/Methods. The study applied a descriptive design, using a cross-sectional, bidirectional mapping strategy. The sample included 728 concepts from both vocabularies. Concept cross-mapping was carried out to identify one-to-one, negative, and hierarchical connections. The analysis was conducted using descriptive statistics. Results. Agreement of the raters' mapping achieved 97%. More than 60% of the nursing diagnosis concepts in the NANDA-I taxonomy were mapped to concepts in the diagnosis axis of the new interface terminology; 71.1% were reversely mapped. Conclusions. Main results for outcome measures suggest that the diagnosis axis of this interface terminology meets the validity criterion of cross-mapping when mapped from and to the NANDA-I taxonomy.


Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.
Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor-initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.