Use of introgression lines to determine the ecophysiological basis for changes in water use efficiency and yield in California processing tomatoes.
Field and greenhouse studies examined the effects of growth habit and chloroplast presence in leaf veins for their role in increasing agronomic water use efficiency and yields of California modern processing tomato (Solanum lycopersicum L.) cultivars. Five introgression lines (ILs), made with Solanum pennellii Cor. in the genetic background of cultivar M82, differ in genes that map to a region on Chromosome 5, including the SP5G gene (determinate vs. semideterminate (Det vs. SemiDet)) and the obv gene (presence (obscure) vs. absence (clear) of leaf vein chloroplasts (Obs vs. Clr)). The five ILs and M82 represented three of the four gene combinations (Det-Clr was unavailable). Det-Obs ILs had less leaf, stem and total aboveground biomass with earlier fruit set and ripening than SemiDet-Clr ILs. By harvest, total fruit biomass was not different among ILs. Photosynthetic rates and stomatal conductance were 4-7% and 13-26% higher, respectively, in Det-Obs ILs than SemiDet-Clr ILs. SemiDet-Obs ILs were intermediate for growth and gas exchange variables. The Det-Obs ILs had lower leaf N concentration and similar chlorophyll content per leaf area (but slightly higher per leaf mass) than SemiDet-Clr ILs. The Obs trait was associated with gains in leaf gas exchange-related traits. This study suggests that a more compact growth habit, less leaf biomass and higher C assimilation capacity per leaf area were relevant traits for the increased yields in cultivars with determinate growth. Developing new introgression libraries would contribute to understanding the multiple trait effects of desirable phenotypes.


Arabidopsis STAYGREEN-LIKE (SGRL) promotes abiotic stress-induced leaf yellowing during vegetative growth.
During leaf senescence in Arabidopsis, STAYGREEN 1 (SGR1) and SGR2 regulate chlorophyll degradation positively and negatively, respectively. SGR-LIKE (SGRL) is also expressed in pre-senescing leaves, but its function remains largely unknown. Here we show that under abiotic stress, Arabidopsis plants overexpressing SGRL exhibit early leaf yellowing and sgrl-1 mutants exhibit persistent green color of leaves. Under salt stress, SGR1 and SGRL act synergistically for rapid Chl degradation prior to senescence. Furthermore, SGRL forms homo- and heterodimers with SGR1 and SGR2 in vivo, and interacts with LHCII and chlorophyll catabolic enzymes. The role of SGRL under abiotic stress is discussed.


Identification and analysis of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene from glyphosate-resistant Ochrobactrum intermedium Sq20.
Glyphosate is a herbicide that acts by inhibition of the enzyme, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), involved in the catalysis of an essential step in the biosynthesis of aromatic amino acids. The objective of this study was the isolation of glyphosate-resistant bacterial strains and subsequent characterization of the gene(s) encoding glyphosate resistance in these isolates. Using an enrichment culture technique, a glyphosate-resistant bacterium, Ochrobactrum intermedium Sq20 was isolated from glyphosate-contaminated indigenous soil and characterized. An open reading frame (ORF) comprising of 1353 bp potentially encoding aroAO. intermediumSq20 was amplified from O. intermedium Sq20. It showed 97% homology with aroA genes from other Ochrobactrum spp. Physicochemical characterization revealed that aroAO. intermediumSq20 encodes a polypeptide of 450 amino acids with a calculated molecular mass of 48.9782 kDa and an isoelectric point of 5.21. Secondary structure prediction of AroAO. intermediumSq20 demonstrated a high percentage of random coils and α helices. Methodical optimization and validation of the protein structure helped to build a reliable protein model indicating the presence of 91.8% amino acid residues in most favoured regions. In addition, strain Sq20 was found to be capable of complete degradation of glyphosate at 500 mg L-1 initial concentration as the sole carbon and energy source within 4 days. A glyphosate-resistant bacterial strain O. intermedium Sq20 was discovered. Sequence analysis and structure modelling demonstrated that AroAO. intermediumSq20 closely resembles class II EPSPS and possesses high glyphosate resistance. This provides a good foundation for functional analysis of experimentally derived crystal structures. The cloning and characterization of AroAO. intermediumSq20 will further help in understanding its role at the molecular level and its potential use in the production of glyphosate-resistant transgenic crops. © 2017 Society of Chemical Industry.


Mitoxantrone dihydrochloride, an FDA approved drug, binds with SARS-CoV-2 NSP1 C-terminal.
One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of the NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed different spectroscopic technique-based binding assays of an anticancer drug mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular dynamics simulations of the docked complex with two different force fields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting the NSP1 protein of SARS-CoV-2.


Nebulized Budesonide vs. Placebo in Adults with Asthma Attack; a Double Blind Randomized Placebo-Controlled Clinical Trial.
Asthma is one of acute respiratory diseases leading to emergency department (ED) referral. Management of acute attack plays an important role in its outcome. This trial was designed to evaluate the effectiveness of nebulized budesonide versus placebo in moderate to severe acute asthma attack in adults in the ED. In this clinical trial, we enrolled patients with acute exacerbation of asthma and standard treatment of acute asthma attack was administered to all of them. 41 patients in our study were randomly entered into 2 groups. In one group, we prescribed nebulized budesonide and in the other group nebulized placebo (normal saline) was administered. Patients' demographic data, vital signs, symptoms' acuity and the time of symptom relief, patient and physician satisfaction were all recorded and compared between the 2 groups. All cases were followed and disease outcome, readmission, mortality and morbidity rates were documented. In this study, 20 patients were entered the budesonide group and 19 patients were enrolled in the placebo group. The mean age ranges were 55.70±15.30 and 60.32±18.41 years old respectively. Heart rate, respiratory rate and O2 saturation in the first group were improved significantly after the treatment in comparison to the second group (p<0.05). The mean time of recovery and length of hospital stay were better in the first group than the second group but this difference was not significant (p>0.05). The addition of nebulized budesonide to standard asthma treatment might result in more improvement in O2 saturation and less patient's distress.


Lipid nanocarriers (LNC) and their applications in ocular drug delivery.
The peculiar physio-anatomical structure of the eye and the poor physico-chemical properties of many drug molecules are often responsible for the inefficient treatment of ocular diseases by conventional dosage forms, and justify the development of innovative ocular drug delivery systems. Lipid-based nanocarriers (LNC) are among the newer and interesting colloidal drug delivery systems; they show the capability to improve the local bioavailability of drugs administered by various ocular routes and, therefore, their therapeutic efficacy. Furthermore, their extreme biodegradability and biocompatible chemical nature have secured them the title of 'nanosafe carriers.' This review treats the main features of LNC [namely, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid-drug conjugates (LDC)]; examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented.


Epigenome engineering in cancer: fairytale or a realistic path to the clinic?
Epigenetic modifications such as histone post-transcriptional modifications, DNA methylation, and non-protein-coding RNAs organize the DNA in the nucleus of eukaryotic cells and are critical for the spatio-temporal regulation of gene expression. These epigenetic modifications are reversible and precisely regulated by epigenetic enzymes. In addition to genetic mutations, epigenetic modifications are highly disrupted in cancer relative to normal tissues. Many epigenetic alterations (epi-mutations) are associated with aberrations in the expression and/or activity of epigenetic enzymes. Thus, epigenetic regulators have emerged as prime targets for cancer therapy. Currently, several inhibitors of epigenetic enzymes (epi-drugs) have been approved for use in the clinic to treat cancer patients with hematological malignancies. However, one potential disadvantage of epi-drugs is their lack of locus-selective specificity, which may result in the over-expression of undesirable parts of the genome. The emerging and rapidly growing field of epigenome engineering has opened new grounds for improving epigenetic therapy in view of reducing the genome-wide "off-target" effects of the treatment. In the current review, we will first describe the language of epigenetic modifications and their involvement in cancer. Next, we will overview the current strategies for engineering of artificial DNA-binding domains in order to manipulate and ultimately normalize the aberrant landscape of the cancer epigenome (epigenome engineering). Lastly, the potential clinical applications of these emerging genome-engineering approaches will be discussed.


Vascular risk moderates associations between hippocampal subfield volumes and memory.
Advanced age and vascular risk negatively affect episodic memory. The hippocampus (HC) is a complex structure, and little is known about the roles of different HC regions in age-related memory declines. Using data from an ongoing longitudinal study, we investigated whether memory functions are related to volumes of specific HC subregions (CA1-2, CA3-4/dentate gyrus, and subiculum). Furthermore, we inquired if arterial hypertension, a common age-related vascular risk factor, modifies age-related differences in HC regional volumes, concurrent memory performance, and improvement in memory over multiple administrations. Healthy adults (n = 49, 52-82 years old) completed associative recognition and free recall tasks. In grouped path models, covariance structures differed between hypertensive and normotensive participants. Whereas larger CA3-4/dentate gyrus volumes predicted greater improvement in associative memory over repeated tests regardless of vascular risk, CA1-2 volumes were associated with improvement in noun recall only in hypertensive participants. Only among hypertensive participants, CA1-2 volumes negatively related to age and CA3-4/dentate gyrus and CA1-2 volumes were associated with performance at the last measurement occasion. These findings suggest that relatively small regions of the HC may play a role in age-related memory declines and that vascular risk factors associated with advanced age may modify that relationship.


Electron-opaque inclusions in the rat retinal pigment epithelium after treatment with chelators of zinc.
Sprague-Dawley male rats given intraperitoneal injections of zinc chelators, namely dithizone and 1,10-phenanthroline, had unusual osmiophilic inclusion bodies in their retinal pigment epithelium (RPE). These structures were not seen in untreated or vehicle-treated controls. The morphology of the inclusion bodies clearly distinguished them from cytoplasmic organelles observed normally in the RPE. The number of inclusion bodies is dose-dependent. The bodies do not have the morphological characteristics of lipid droplets seen infrequently in the untreated rat RPE. The results suggest that sequestration of zinc, either rapidly with injections of dithizone or more slowly with daily administration of 1,10-phenanthroline, exerts pronounced effects on the retinal pigment epithelial cells.


Rapid MRI evaluation of acute intracranial hemorrhage in pediatric head trauma.
Rapid MRI with ultrafast T2 sequences can be performed without sedation and is often used in place of computed tomography (CT) to evaluate pediatric patients for indications such as hydrocephalus. This study investigated the sensitivity of rapid magnetic resonance imaging (MRI) for detection and follow-up of acute intracranial hemorrhage in comparison to CT, which is commonly the first-line imaging. Patients presenting to a pediatric hospital with acute intracranial hemorrhage on CT and follow-up rapid MRI within 48 h were included. Rapid MRI studies consisted of three plane ultrafast T2 sequences either with or without axial gradient echo (GRE) sequences. Identification of hemorrhage on rapid MRI was assessed by readers both blinded and unblinded to prior CT results. One hundred two acute hemorrhages in 61 patients were identified by CT. Rapid MRI detection of subdural and epidural hemorrhages was modest in the absence of prior CT for comparison (sensitivity 61-74 %), but increased with review of the prior CT (sensitivity 80-86 %). Hemorrhage size was a significant predictor of detection (p < 0.0001). Three plane fast T2 images alone without GRE sequences were poor at detecting subarachnoid hemorrhage (sensitivity 10-25 %); rapid MRI with GRE sequences identified the majority of subarachnoid hemorrhage (sensitivity 71-93 %). GRE modestly increased detection of other extra-axial hemorrhages. Rapid MRI with GRE sequences is sensitive for most acute intracranial hemorrhages only when a prior CT is available for review. Rapid MRI is not adequate to replace CT in initial evaluation of intracranial hemorrhages but may be helpful in follow-up of known hemorrhages.


Perinatal health services organization for preterm births: a multinational comparison.
To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.


The clinical credibility of nurse educators: time the debate was put to rest.
The proverbial discussion surrounding the clinical credibility of nurse lecturers has almost become a preoccupation within the nursing literature and professional circles. It is not coincidental that it this has occurred alongside the cessation of hospital-based training and the associated reassignment of the responsibility for nurse education to institutes of higher education. This paper aims to put the debate to rest and proposes that the focus of the nurse lecturer should not be on establishing clinical credibility but on developing strong partnerships between academic and service areas. Such partnerships or communities of practice are more likely to facilitate high quality preparation of nursing students for future roles within a diverse and dynamic profession.


The effect of falling height on muscle activity and foot motion during landings.
The aims of this study were: (a) to examine the effect of falling height on the kinematics of the tibiotalar, talonavicular and calcaneocuboid joints and (b) to study the influence of falling height on the muscle activity of the leg during landings. Six female gymnasts (height: 1.63 +/- 0.04 m, weight: 58.21 +/- 3.46 kg) participated in this study. All six gymnasts carried out barefoot landings, falling from 1.0, 1.5 and 2.0 m height onto a mat. Three genlocked digital high speed video cameras (250 Hz) captured the motion of the left shank and foot. Surface electromyography (EMG) was used to measure muscle activity (1000 Hz) from five muscles (gastrocnemius medialis, tibialis anterior, peroneus longus, vastus lateralis and hamstrings) of the left leg. The kinematics of the tibiotalar, talonavicular and calcaneocuboid joints were studied. The lower-leg and the foot were modelled by means of a multi-body system, comprising seven rigid bodies. The falling height does not show any influence on the kinematics neither of the tibiotalar nor of the talonavicular joints during landing. The eversion at the calcaneocuboid joint increases with increasing falling height. When augmenting falling height, the myoelectric activity of the muscles of the lower limb increases as well during the pre-activation phase as during the landing itself. The muscles of the lower extremities are capable of stabilizing the tibiotalar and the talonavicular joints actively, restricting their maximal motion by means of a higher activation before and after touchdown. Maximal eversion at the calcaneocuboid joint increases about 52% when landing from 2.0 m.


Repeatability for Gaussian and non-Gaussian data: a practical guide for biologists.
Repeatability (more precisely the common measure of repeatability, the intra-class correlation coefficient, ICC) is an important index for quantifying the accuracy of measurements and the constancy of phenotypes. It is the proportion of phenotypic variation that can be attributed to between-subject (or between-group) variation. As a consequence, the non-repeatable fraction of phenotypic variation is the sum of measurement error and phenotypic flexibility. There are several ways to estimate repeatability for Gaussian data, but there are no formal agreements on how repeatability should be calculated for non-Gaussian data (e.g. binary, proportion and count data). In addition to point estimates, appropriate uncertainty estimates (standard errors and confidence intervals) and statistical significance for repeatability estimates are required regardless of the types of data. We review the methods for calculating repeatability and the associated statistics for Gaussian and non-Gaussian data. For Gaussian data, we present three common approaches for estimating repeatability: correlation-based, analysis of variance (ANOVA)-based and linear mixed-effects model (LMM)-based methods, while for non-Gaussian data, we focus on generalised linear mixed-effects models (GLMM) that allow the estimation of repeatability on the original and on the underlying latent scale. We also address a number of methods for calculating standard errors, confidence intervals and statistical significance; the most accurate and recommended methods are parametric bootstrapping, randomisation tests and Bayesian approaches. We advocate the use of LMM- and GLMM-based approaches mainly because of the ease with which confounding variables can be controlled for. Furthermore, we compare two types of repeatability (ordinary repeatability and extrapolated repeatability) in relation to narrow-sense heritability. This review serves as a collection of guidelines and recommendations for biologists to calculate repeatability and heritability from both Gaussian and non-Gaussian data.


The Reliability and Validity Study of Turkish Version of the Death Depression Scale-Revised Among Nurses.
The study aimed to establish the reliability and validity of the Turkish version of the Death Depression Scale-Revised (DDS-R) with a sample of 284 nurses. Cronbach's coefficient for the whole scale was .909 and the sub-dimension values were calculated as .934, .798, .715, and .537. The test-retest reliability coefficient was found to be .880. The content validity index (CVI) of the scale was calculated as .86. The results of the exploratory factor analysis showed that 62.254% variance was explained in 4 sub-dimensions of the scale (existential vacuum, death emptiness, other death, death sadness). Confirmatory factor analysis revealed that a four-dimensional structure yielded a good fit (X2/df = 3.124, RMSEA = .087). TDDS-R was found to be a valid and reliable measurement tool in determining the death depression levels of nurses.


Residual catatonic state following neuroleptic malignant syndrome.
Neuroleptic malignant syndrome (NMS) is usually a self-limited disorder, with most cases resolving within 2 weeks after antipsychotic drug discontinuation. However, the course of NMS may not always be short-lived. In this report, the authors describe five patients who developed a residual catatonic state that persisted after acute hyperthermic symptoms of NMS had subsided and compare them with 27 similar cases in the literature. Two of our patients recovered gradually with supportive treatment. Three patients were treated with electroconvulsive therapy (ECT). Of these, two showed a positive response, although one died later of intercurrent pneumonia. A third patient did not respond to ECT, but recovered gradually thereafter. Although dopamine agonists or benzodiazepines have been advocated for the treatment of residual symptoms in previous case reports, ECT was the treatment most often associated with a rapid response and no mortality, even in patients refractory to pharmacotherapy. In conclusion, catatonic and parkinsonian symptoms of NMS may persist as a residual state lasting for weeks to months after more fulminant acute symptoms abate. These residual symptoms may be more likely to develop in patients with pre-existing structural brain disorders. Although patients may improve gradually with supportive care or pharmacotherapy, ECT can often be highly effective in treating the residual catatonic state that follows NMS.


H-Ras nanocluster stability regulates the magnitude of MAPK signal output.
H-Ras is a binary switch that is activated by multiple co-factors and triggers several key cellular pathways one of which is MAPK. The specificity and magnitude of downstream activation is achieved by the spatio-temporal organization of the active H-Ras in the plasma membrane. Upon activation, the GTP bound H-Ras binds to Galectin-1 (Gal-1) and becomes transiently immobilized in short-lived nanoclusters on the plasma membrane from which the signal is propagated to Raf. In the current study we show that stabilizing the H-Ras-Gal-1 interaction, using bimolecular fluorescence complementation (BiFC), leads to prolonged immobilization of H-Ras.GTP in the plasma membrane which was measured by fluorescence recovery after photobleaching (FRAP), and increased signal out-put to the MAPK module. EM measurements of Raf recruitment to the H-Ras.GTP nanoclusters demonstrated that the enhanced signaling observed in the BiFC stabilized H-Ras.GTP nanocluster was attributed to increased H-Ras immobilization rather than to an increase in Raf recruitment. Taken together these data demonstrate that the magnitude of the signal output from a GTP-bound H-Ras nanocluster is proportional to its stability.


Secret lifestyles of pyrophilous fungi in the genus Sphaerosporella.
Pyrophilous fungi form aboveground fruiting structures (ascocarps) following wildfires, but their ecology, natural history, and life cycles in the absence of wildfires are largely unknown. Sphaerosporella is considered to be pyrophilous. This study explores Sphaerosporella ascocarp appearance following a rare 2016 wildfire in the Great Smoky Mountains National Park (GSMNP), compares the timing of ascocarp formation with recovery of Sphaerosporella DNA sequences in soils, and explores the association of Sphaerosporella with post-fire Table Mountain pine (Pinus pungens) seedlings. Burned sites in the GSMNP were surveyed for pyrophilous fungal ascocarps over 2 years. Ascocarps, mycorrhizae, and endophyte cultures were evaluated morphologically and by Sanger sequencing of the nuclear ribosomal ITS gene region (fungal barcode; Schoch et al., 2012). DNA from soil cores was subjected to Illumina sequencing. The timing and location of post-fire Sphaerosporella ascocarp formation was correlated with recovery of Sphaerosporella DNA sequences in soils. Genetic markers (fungal barcode) of Sphaerosporella were also recovered from mycorrhizal root tips and endophyte cultures from seedlings of Pinus pungens. This study demonstrates that Sphaerosporella species, in the absence of fire, are biotrophic, forming both mycorrhizal and endophytic associations with developing Pinus pungens seedlings and may persist in nature in the absence of wildfire as a conifer symbiont. We speculate that Sphaerosporella may fruit only after the host plant is damaged or destroyed and that after wildfires, deep roots, needle endophytes, or heat-resistant spores could serve as a source of soil mycelium.


Optimal design of clinical trials comparing several treatments with a control.
Clinical trials are often designed to compare several treatments with a common control arm in pairwise fashion. In this paper we study optimal designs for such studies, based on minimizing the total number of patients required to achieve a given level of power. A common approach when designing studies to compare several treatments with a control is to achieve the desired power for each individual pairwise treatment comparison. However, it is often more appropriate to characterize power in terms of the family of null hypotheses being tested, and to control the probability of rejecting all, or alternatively any, of these individual hypotheses. While all approaches lead to unbalanced designs with more patients allocated to the control arm, it is found that the optimal design and required number of patients can vary substantially depending on the chosen characterization of power. The methods make allowance for both continuous and binary outcomes and are illustrated with reference to two clinical trials, one involving multiple doses compared to placebo and the other involving combination therapy compared to mono-therapies. In one example a 55% reduction in sample size is achieved through an optimal design combined with the appropriate characterization of power.


Hepatotoxicity due to hydroxycut: a case series.
Muscletech Hydroxycut (Iovate Health Sciences Research, Oakville, Ontario, Canada) was a popular weight-loss supplement that was recalled by the manufacturer in May 2009 on the basis of reports of hepatotoxicity associated with this supplement. We sought to characterize the clinical presentation of Hydroxycut-associated liver injury and to adjudicate these cases for causal association with Hydroxycut. We assessed the causality and grading of severity of liver injury using methodology developed by the Drug-Induced Liver Injury Network (DILIN) study. Eight patients who developed liver injury after taking Hydroxycut treated at different medical centers were identified. All were hospitalized, and three of eight patients required liver transplantation. Nine other cases with adequate clinical information were obtained from the FDA MedWatch database, including one fatal case of acute liver failure. Usual symptoms were jaundice, fatigue, nausea, vomiting, and abdominal pain. Most patients exhibited a hepatocellular pattern of injury. Adjudication for causality revealed eight cases as definite, five highly likely, two probable, and two were considered to be possible. Hydroxycut has been clearly implicated as a cause for severe liver injury that may lead to acute liver failure and death. Weight-loss supplements represent a class of dietary supplements that should be regarded as capable of causing severe hepatic toxicity when the usual causes of identified liver injury cannot be otherwise elucidated.


Morphology and proton diffusion in a coarse-grained model of sulfonated poly(phenylenes).
A coarse-grained model previously used to simulate Nafion using dissipative particle dynamics (DPD) is modified to describe sulfonated Diels-Alder poly(phenylene) (SDAPP) polymers. The model includes a proton-hopping mechanism similar to the Grotthuss mechanism. The intramolecular parameters for SDAPP are derived from atomistic molecular dynamics (MD) simulation using the iterative Boltzmann inversion. The polymer radii of gyration, domain morphologies, and cluster distributions obtained from our DPD model are in good agreement with previous atomistic MD simulations. As found in the atomistic simulations, the DPD simulations predict that the SDAPP nanophase separates into hydrophobic polymer domains and hydrophilic domains that percolate through the system at sufficiently high sulfonation and hydration levels. Increasing sulfonation and/or hydration leads to larger proton and water diffusion constants, in agreement with experimental measurements in SDAPP. In the DPD simulations, the proton hopping (Grotthuss) mechanism becomes important as sulfonation and hydration increase, in qualitative agreement with experiment. The turning on of the hopping mechanism also roughly correlates with the point at which the DPD simulations exhibit clear percolated, hydrophilic domains, demonstrating the important effects of morphology on proton transport.


Outrage and algorithms: Shifting drug-related stigma in a digital world.
Illicit drug dependence is one of the most stigmatised health conditions worldwide and the harmful impacts of stigma for people who use drugs are well documented. The use of stigmatising language about drugs in traditional media is also well documented. The increasing use of digital media platforms has revolutionised the way we communicate, and extended the reach of our messages. However, there are issues specific to the ways in which these platforms operate that have the potential to increase drug-related stigma. This paper outlines the importance of language, narrative, and imagery in reducing this stigma. It discusses the challenges digital media platforms present to achieving this goal, including the use of engagement strategies that trigger fear and increase stigma, the potential for amplifying stigmatising messages by using algorithms, and the potential for dissemination of misinformation. Key strategies to frame conversations about drug use are presented including 1) appeal to values of fairness and equity rather than scaring people; 2) avoid correcting misinformation as it strengthens unhelpful stigmatising frames of drug use; and 3) create a new narrative, focusing on the diversity of experiences of people who use drugs. Internationally we are at a critical juncture with respect to drug policy reform, and efforts to reduce drug-related stigma are central to building support for these reforms. The extensive reach of digital media platforms represents an important opportunity to communicate about illicit drug use. The challenge is to do so in a way that minimises stigma. If we are to achieve change, a narrative that puts values, people, health care and equity at the centre of the conversation is critical.


Ultrasonography alone for diagnosis of breast cancer in women under 40.
Recent guidelines suggest that ultrasonography should be used as the primary imaging modality in women under 40 years of age with mammography being offered if further imaging is required. The aim of this study was to assess the adequacy of ultrasonography and the utility of mammography in this patient group by reviewing the role these imaging techniques had in the diagnosis of breast cancer in our unit. All breast cancers diagnosed in patients 39 years or younger from June 2009 to June 2011 were reviewed. This was a retrospective review of presentation, clinical findings, imaging modality (ultrasonography, mammography, magnetic resonance imaging [MRI]) and histology. Mammography was the primary imaging modality until May 2011 in women between 35 and 39 years of age. Both invasive and intraductal carcinoma were included in the study but lobular carcinoma in situ was excluded. A total of 2,495 patients were referred to the symptomatic breast clinic in this age group during the study period. Thirty women were identified with either invasive cancer (n=27) or ductal carcinoma in situ (n=3). Twenty-eight patients underwent mammography, graded as uncertain, suspicious or malignant in the majority. Malignancy was missed in one patient. All 30 patients underwent ultrasonography, reported as uncertain, suspicious or malignant, an indication for diagnostic core biopsy. Ultrasonography alone did not miss any cancers but did fail to detect multifocal disease in one patient. In this study group, ultrasonography was reliable as the primary imaging modality for women under 40, identifying all cancers in this cohort. Mammography and/or MRI remain essential adjuncts to accurately determine multifocality and/or the extent of disease.


Use of social media for cancer prevention and early diagnosis: scoping review protocol.
Social media platforms offer unique opportunities for health promotion messages focusing on cancer prevention and early diagnosis. However, there has been very little synthesis of the evaluation of such campaigns, limiting the ability to apply learning to the design of future social media campaigns. We aimed to provide a broad overview of the current research base on social media interventions for cancer prevention and early diagnosis, to identify knowledge gaps and to inform policy, practice and future research questions. We will use scoping review methodology to explore the available evidence on social media interventions for cancer prevention and early diagnosis, with a focus on methodological approaches. Quantitative and qualitative studies and reports will be identified through searching several research databases, through internet searching for grey literature and by screening the citations of studies included in the review. All identified studies will undergo independent title and abstract screening and full-text screening against inclusion and exclusion criteria. We plan to chart the data from included studies to record the characteristics of the social media interventions, resources, activities, outputs, outcomes and impact. Charted data will be collated and summarised using a narrative synthesis. The interpretation and implications of the findings will be enhanced by consultation with relevant stakeholders such as public health organisations, cancer charities, and patient and public involvement groups when preliminary results are available. Ethical approval is not required for this scoping review. The results will be used to identify research questions for future systematic reviews and to inform the development of future social media interventions. We will disseminate findings in peer-reviewed journals and at relevant conferences.


Dopamine affects short-term memory corruption over time in Parkinson's disease.
Cognitive deficits are a recognised component of Parkinson's disease (PD). However, particularly within the domain of short-term memory, it is unclear whether these impairments are masked, or caused, by patients' dopaminergic medication. The effect of medication on pure maintenance in PD patients has rarely been explored, with most assessments examining maintenance intercalated between other executive tasks. Moreover, few studies have utilised methods that can measure the quality of mental representations, which can enable the decomposition of recall errors into their underlying neurocognitive components. Here, we fill this gap by examining pure maintenance in PD patients in high and low dopaminergic states. Participants had to encode the orientation of two stimuli and reproduce these orientations after a short (2 s) or long (8 s) delay. In addition, we also examined the performance of healthy, age-matched older adults to contextualise these effects and determine whether PD represents an exacerbation of the normal ageing process. Patients showed improved recall OFF compared to ON their dopaminergic medication, but only for long-duration trials. Moreover, PD patients OFF their medication actually performed at a level superior to age-matched controls, indicative of a paradoxical enhancement of memory in the low dopaminergic state. The application of a probabilistic model of response selection suggested that PD patients made fewer misbinding errors in the low, compared with high, dopaminergic state for longer-delay trials. Thus, unexpectedly, the mechanisms that prevent memoranda from being corrupted by misbinding over time appear to be enhanced in PD patients OFF dopaminergic medication. Possible explanations for this paradoxical effect are discussed.


Population pressures, system-level inertia and healthy aging policy revisited.
Chappell and Hollander provide support for a set of policy directives formulated for an aging population. An integrated continuum of care model is the fulcrum of the policy prescription, given evidence-based support for its cost-effectiveness; improved quality of care and quality of life; and the success of similar models found in Denmark, Japan and other countries. This commentary addresses the underlying assumptions of these policy recommendations, identifies the major barriers to their implementation and suggests solutions. Improving our understanding of the dynamics of population aging as it relates to health and healthcare use is a necessary requirement to reaching the aims set out by the authors.


The use of pure FSH alone or in combination for ovulation stimulation in in vitro fertilization.
The experience of the Norfolk Program, from the beginning of 1981 until mid 1984, is reviewed. Two groups of patients are compared. The initial experience goes from the very beginning until early 1984 in which knowledge has accumulated; the patients treated afterwards up to mid 1984 where the previous experience was used to monitor them in a more accurate way is reviewed as a separate category. Different protocols, in each group, are compared: concomitant combination of hFSH/hMG (protocol # 1), sequential combination of the two gonadotropins (protocol # 2), and pure FSH administration (protocol # 3). Several parameters were used in the evaluation of the results: 1) day of laparoscopy, 2) volume of the follicles obtained, 3) number of preovulatory oocytes obtained, 4) number of immature oocytes obtained, 5) number of atretic oocytes induced, 6) number of oocytes with abnormal zona pellucida, 7) fertilization rate of preovulatory and immature oocytes, 8) abnormal fertilization rate of preovulatory and immature oocytes, 9) cleavage rate of the normally fertilized preovulatory immature oocytes, 10) transfer rate, single and multiple, 11) follicular and luteal phases as evaluated by estradiol levels in the preovulatory phase and by E2 and progesterone in the post ovulatory phase, 12) pregnancy rate. Pure FSH seems to prolong somewhat the follicular phase. Preovulatory oocytes derived from small follicles may originate pregnancies that may end in abortion. The concomitant combination rendered a larger number of preovulatory oocytes. The number of immature oocytes tend to be higher in the pure FSH stimulated group, but this seems to depend on the way FSH is used. The normal fertilization rate for preovulatory oocytes tends to be similar as the criteria used in the stimulation protocol improved. The abnormal fertilization rate for both types of oocytes decreased in the latest series. The number of embryos transferred was higher in the concomitant combination stimulation. Shortening the hMG/hCG interval in the pure FSH category seems to induce a deficient follicular phase except in cases with rapid high response. When using the hFSH/hMG combination the values of estradiol in the follicular phase tend to be much higher than when the original pure hMG protocol is used. This does not seem to be true when pure FSH stimulation is used. The number of multiple transfers increased substantially in both types of stimulation as experience increased.(ABSTRACT TRUNCATED AT 400 WORDS)


Ownership type and community benefits of women's health centers.
An important aspect of the changing health care system is the growth of women's health centers--organizations that design and deliver services to women. This growth has generated interest in the behavior of centers, especially because of increasing awareness of women's health issues. Using data from the 1994 National Survey of Women's Health Centers, the authors examined the association between ownership of centers and 12 measures of community benefits, and 296 nonprofit and 108 for-profit centers were compared. Overall, the nonprofits performed better than the for-profits in terms of serving underserved women, delivering comprehensive primary care services, providing training for health professionals and education services for clients and the community, and involving the community in center governance. Among women's health centers, the results show that ownership matters, and indicate the importance of supporting providers who serve the underserved and developing a standard of community benefits.


Brugada syndrome and right ventricle morphofunctional abnormalities on echocardiography in young male with family anamnesis of sudden cardiac death.
First presented by Brugada and Brugada in 1992, Brugada Syndrome (BrS) is a primary electrical disease of the heart that causes sudden cardiac death or life-threatening ventricular arrhythmias. This disease is hereditary autosomic dominant transmitted and genetically determined. The syndrome has been linked to mutations in SCN5A, the gene encoding for the a-subunit of the sodium channel. Electrocardiogram (ECG) abnormalities indicating Brugada syndrome, include repolarization and depolarization abnormalities in the absence of identifiable structural cardiac abnormalities or other conditions or agents known to lead to ST-segment elevation in the right precordial leads (V1-V3). Intravenous administration of sodium channel blocking drugs may modify the ECG pattern. Ajmaline, flecainide, procainamide and propafenone exaggerate the ST-segment elevation or unmask it when it is initially absent. An implantable cardioverter-defibrillator (ICD) is the only proven effective device treatment for the disease. Although BrS is primary electrical disease, some authors have suggested the presence of morphological and functional abnormalities mainly located in the right ventricle (RV), notably in the outflow tract (RVOT). In this short report we will present a young male, with predisposition and positive family history of sudden cardiac death, with complete diagnostic procedure including propafenon testing unmasking Brugada syndrome. An echosonography revealed dilated apical right ventricle, suggesting BrS is not only electrical disorder, but may include morphofunctional abnormalities, described in previous reports. In addition, we reviewed the possible connection between Brugada syndrome and morphological abnormalities in RV.


Method for depletion of mitochondria DNA in human bronchial epithelial cells.
Mitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines that are depleted of mitochondrial DNA. One week of ethidium bromide (EtBr) treatment led to ∼95 % reduction of mtDNA copy number (mtDNA-CN) in cells, which was further reduced by addition of 25 µM 2',3'-dideoxycytidin (ddC). Treatment for up to three weeks with EtBr and ddC led to near complete loss of mtDNA. The basal oxygen consumption rate (OCR) of mtDNA-depleted BET-1A and BEAS-2B cells dropped to near zero. Glycolysis measured by extracellular acidification rate (ECAR) increased ∼two-fold in cells when mtDNA was eliminated. BET-1A ρ0 and BEAS-2B ρ0 cells were cultured for two months, frozen and thawed, cultured for two more months, and maintained near zero mtDNA-CN. Mitochondrial DNA-depleted BET-1A ρ0 and BEAS-2B ρ0 cell lines are viable, lack the capacity for aerobic respiration, and increase glycolysis.•BET-1A and BEAS-2B cells were treated with ethidium bromide (EtBr) with or without 2',3'-dideoxycytidine (ddC) to create cells lacking mitochondrial DNA (mtDNA).•Cells' mtDNA copy number relative to nuclear DNA (nDNA) were verified by quantitative polymerase chain reaction (qPCR).•Cells were also assessed for oxidative phosphorylation by measures of oxygen consumption using the Seahorse analyzer.


Phenylphosphonate surface functionalisation of MgMn2O4 with 3D open-channel nanostructures for composite slurry-coated cathodes of rechargeable magnesium batteries operated at room temperature.
Spinel-type MgMn2O4, prepared by a propylene-oxide-driven sol-gel method, has a high surface area and structured bimodal macro- and mesopores, and exhibits good electrochemical properties as a cathode active material for rechargeable magnesium batteries. However, because of its hydrophilicity and significant water adsorption properties, macroscopic aggregates are formed in composite slurry-coated cathodes when 1-methyl-2-pyrrolidone (NMP) is used as a non-aqueous solvent. Functionalising the surface with phenylphosphonate groups was found to be an easy and effective technique to render the structured MgMn2O4 hydrophobic and suppress aggregate formation in NMP-based slurries. This surface functionalisation also reduced side reactions during charging, while maintaining the discharge capacity, and significantly improved the coulombic efficiency. Uniform slurry-coated cathodes with active material fractions as high as 93 wt% can be produced on Al foils by this technique employing carbon nanotubes as an electrically conductive support. A coin-type full cell consisting of this slurry-coated cathode and a magnesium alloy anode delivered an initial discharge capacity of ∼100 mA h g-1 at 25 °C.


[Predictive microbiology and risk assessment].
Predictive microbiology (predictive modelling PM), in spite of its limits and short-comings, may often contribute to a reduction of the problems arising when HACCP systems are established or microbiological risk assessment is done. Having identified the agents which constitute a risk and the contamination rate and density in the raw material, the influences of production steps and storage on these microorganisms have to be examined. Finally, there should be an exposure assessment, i.e. an estimate of the contamination density in the final product at the time of consumption. Should the exposure assessment together with data from dose response assessments reveal a potential for intake of inacceptable numbers of organisms, the risk identified has to be characterized. As a consequence, risk management should result in a modification of the composition of the product and/or of the production process so that the risk does not surpass an acceptable limit. For this approach it is indispensable to have product- and process-specific information on the multiplication of pathogens prior to heat treatment, on reduction of their density by thermal treatment and on growth or dying of organisms having survived heat treatment or penetrated into the product after heat treatment as post-process contaminant. Commonly, challenge tests are conducted to provide such information. But they are time consuming and, as their results are only valid for the specific product tested and the conditions prevailing during the experiment, the have to be repeated if there is any modification of intrinsic or extrinsic factors. At least partially, the PM may replace the challenge tests. The efficiency of the models is rated particularly high if they are used already at the stage of product development when the question has to be answered whether a planned recipe or process of production are already save or have to be modified to become save.


Cloning and sequencing of the xylose isomerase and xylulose kinase genes of Escherichia coli.
A 4.2-kilobase-pair fragment of the Escherichia coli chromosome which contains the genes for xylose isomerase and xylulose kinase was cloned into plasmid pBR322. The hybrid plasmid (designated pECX14) complements strains deficient in either or both of the two enzymes. Deletion derivatives of pECX14 were used to localize the two genes on the cloned fragment. The entire nucleotide sequence of the cloned fragment was determined. Open reading frames which, if translated, would encode proteins of molecular weights 54,000 and 52,000 were found. These were identified as the isomerase and kinase structural genes, respectively.


Oestrogen effects on kainate-induced toxicity in primary cultures of rat cortical neurons.
Oestrogens protect neurons against excitatory amino acid-induced toxicity; however data on their interaction with particular subtype of glutamate receptors are sparse. Therefore in the present study we investigated oestrogen effects on kainate neurotoxicity in primary cortical neurons. The data showed that both oestradiol-17 beta and oestrone (100 nM and 200 nM) reduced kainate toxicity by ca. 40%. Since tamoxifen only partly inhibited the above effects, we suggest that both genomic and non-genomic mechanisms are involved in the anti-kainate action of oestrogens.


Logical word learning: The case of kinship.
We examine the conceptual development of kinship through the lens of program induction. We present a computational model for the acquisition of kinship term concepts, resulting in the first computational model of kinship learning that is closely tied to developmental phenomena. We demonstrate that our model can learn several kinship systems of varying complexity using cross-linguistic data from English, Pukapuka, Turkish, and Yanomamö. More importantly, the behavioral patterns observed in children learning kinship terms, under-extension and over-generalization, fall out naturally from our learning model. We then conducted interviews to simulate realistic learning environments and demonstrate that the characteristic-to-defining shift is a consequence of our learning model in naturalistic contexts containing abstract and concrete features. We use model simulations to understand the influence of logical simplicity and children's learning environment on the order of acquisition of kinship terms, providing novel predictions for the learning trajectories of these words. We conclude with a discussion of how this model framework generalizes beyond kinship terms, as well as a discussion of its limitations.


Revisiting demographic processes in cattle with genome-wide population genetic analysis.
The domestication of the aurochs took place approximately 10,000 years ago giving rise to the two main types of domestic cattle known today, taurine (Bos taurus) domesticated somewhere on or near the Fertile Crescent, and indicine (Bos indicus) domesticated in the Indus Valley. However, although cattle have historically played a prominent role in human society the exact origin of many extant breeds is not well known. Here we used a combination of medium and high-density Illumina Bovine SNP arrays (i.e., ~54,000 and ~770,000 SNPs, respectively), genotyped for over 1300 animals representing 56 cattle breeds, to describe the relationships among major European cattle breeds and detect patterns of admixture among them. Our results suggest modern cross-breeding and ancient hybridisation events have both played an important role, including with animals of indicine origin. We use these data to identify signatures of selection reflecting both domestication (hypothesized to produce a common signature across breeds) and local adaptation (predicted to exhibit a signature of selection unique to a single breed or group of related breeds with a common history) to uncover additional demographic complexity of modern European cattle.


Decreased Rhes mRNA levels in the brain of patients with Parkinson's disease and MPTP-treated macaques.
In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinson's disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation.


Toward evidence-based literacy interventions for children with severe and multiple disabilities.
Children with severe and multiple disabilities constitute a heterogeneous population that typically experiences significant and lifelong difficulties in learning to read and write. These difficulties appear to be both intrinsic and environmental in nature. Children with severe and multiple disabilities struggle particularly with vocabulary acquisition and phonological awareness. Home, preschool, and school environments may limit literacy learning opportunities by making literacy a lower priority than the child's competing health, self-care, and therapeutic needs; by providing limited access to adapted print materials or tools; by providing limited access to communication supports; or by providing little time for literacy learning. Children with severe and multiple disabilities who have demonstrated literacy learning progress are often taught in technology-supported environments offering a wide range of word study, text-based reading and writing instruction, and opportunities for print exploration. Sufficient evidence exists for clinicians and educators to begin providing more successful literacy instruction to individual children and classrooms by comparing their children and intervention contexts with those reported in the limited body of research in this area.


Binding assays with molecularly imprinted polymers--why do they work?
The design of homologous displacement ligand binding assays based on molecularly imprinted polymers (MIP) is discussed in terms of the MIP adsorption isotherm. It is shown that only MIPs having a binding isotherm with varying slope are suitable for the assay, but there is no need to interpret the isotherm in terms of site affinity and population. One can calculate the calibration plot of the binding assay from the isotherm and vice versa.


Learning to Predict Ischemic Stroke Growth on Acute CT Perfusion Data by Interpolating Low-Dimensional Shape Representations.
Cerebrovascular diseases, in particular ischemic stroke, are one of the leading global causes of death in developed countries. Perfusion CT and/or MRI are ideal imaging modalities for characterizing affected ischemic tissue in the hyper-acute phase. If infarct growth over time could be predicted accurately from functional acute imaging protocols together with advanced machine-learning based image analysis, the expected benefits of treatment options could be better weighted against potential risks. The quality of the outcome prediction by convolutional neural networks (CNNs) is so far limited, which indicates that even highly complex deep learning algorithms are not fully capable of directly learning physiological principles of tissue salvation through weak supervision due to a lack of data (e.g., follow-up segmentation). In this work, we address these current shortcomings by explicitly taking into account clinical expert knowledge in the form of segmentations of the core and its surrounding penumbra in acute CT perfusion images (CTP), that are trained to be represented in a low-dimensional non-linear shape space. Employing a multi-scale CNN (U-Net) together with a convolutional auto-encoder, we predict lesion tissue probabilities for new patients. The predictions are physiologically constrained to a shape embedding that encodes a continuous progression between the core and penumbra extents. The comparison to a simple interpolation in the original voxel space and an unconstrained CNN shows that the use of such a shape space can be advantageous to predict time-dependent growth of stroke lesions on acute perfusion data, yielding a Dice score overlap of 0.46 for predictions from expert segmentations of core and penumbra. Our interpolation method models monotone infarct growth robustly on a linear time scale to automatically predict clinically plausible tissue outcomes that may serve as a basis for more clinical measures such as the expected lesion volume increase and can support the decision making on treatment options and triage.


[Adjuvant treatment of canine splenic hemangiosarcoma with autologous dendritic cell therapy - a prospective, randomized double-blind study].
Canine splenic hemangiosarcomas (HSA) are malignant mesenchymal tumors with a high tendency for metastasis. Median survival times after splenectomy followed by adjuvant chemotherapy usually range between 5 and 8 months. The aim of this prospective randomized double-blinded study was to examine the efficacy of a commercially available dendritic cell therapy (PetBioCell) following splenectomy. In addition, possible side effects of this therapy were evaluated. Twenty-one dogs with histologically confirmed splenic HSA without metastasis (stages I or II) were included in the study. Ten dogs received the dendritic cell therapy, and 11 dogs received a placebo. Injections were administered according to the manufacturer's instructions monthly for the first 3 months and then every 3 months until death. Survival times and toxicoses of both groups were compared. Follow-up data were available for all 21 patients; the observation period ranging until euthanasia or metastasis-related death. One patient that had received the dendritic cell therapy was euthanized due to prostatitis and experienced the longest survival time (668 days). One dog in the placebo-group lived for 448 days after splenectomy. The median survival times in the dendritic cell therapy and the placebo group amounted to 74 and 126 days, respectively. There was no significant difference in tumor-free interval (t(18) = 1.4, p = 0.911) and survival times (t(19) = -0.094, p = 0.463) between the 2 groups. Toxicoses reported in both groups were mild and self-limiting. Immunotherapy using autologous, immature and unprimed dendritic cells according to the PetBioCell method failed to show efficacy on tumor-free interval and survival time in the presented dog population with splenic hemangiosarcoma.


Determining Need for School-Based Physical Therapy Under IDEA: Commonalities Across Practice Guidelines.
The Individuals with Disabilities Education Act (IDEA) includes physical therapy (PT) as a related service that may be provided to help students with disabilities benefit from their education. However, the IDEA does not provide specific guidance for the provision of school-based PT, resulting in variations in practice across the United States. The authors examined 22 state and local education agency guidelines available online to find commonalities related to the determination of a student's need for PT. Seven commonalities found: educational benefit, team decision, need for PT expertise, establishment of Individualized Education Program (IEP) goal before determining need for PT, distinction between medical and educational PT, the student's disability adversely affects education, and the student's potential for improvement. These commonalities are discussed in relation to current PT and special education literature. This article suggests applying these commonalities as procedural requirements and questions for discussion during an IEP team meeting.


Bax mutations are an infrequent event in indolent lymphomas and in mantle cell lymphoma.
The Bax gene is one of the most important genes involved in apoptosis regulation. Recently, it has been proposed that inactivating mutations of this death agonist may contribute to the pathogenesis of human tumors. This study was aimed at defining the status of the Bax gene in indolent lymphomas. Fifty paraffin-embedded biopsies from indolent lymphomas (10 small lymphocytic lymphomas, 5 immunocytomas, 20 follicular lymphomas and 15 marginal zone lymphomas) and 10 mantle cell lymphomas ( MCL ) were studied. All six exons of the Bax gene, together with their flanking sequences, underwent mutational analysis by PCR-SSCP followed by direct sequencing of positive cases. Moreover, Bax protein expression was investigated in all samples by immunohistochemical analysis. All analyzed cases showed wild type Bax gene alleles and variable levels of Bax protein expression. This study indicates that deregulation of apoptotic control in indolent lymphomas and MCL is not caused by Bax mutations and that other molecular mechanisms must, therefore, be involved.


Obesity decreases time to claudication and delays post-exercise hemodynamic recovery in elderly peripheral arterial disease patients.
Althoughobesity is usually observed in peripheral arterial disease (PAD) patients, the effects of the association between these diseases on walking capacity are not well documented. The main objectives of this study were to determine the effects of obesity on exercise tolerance and post-exercise hemodynamic recovery in elderly PAD patients. 46 patients with stable symptoms of intermittent claudication were classified according to their body mass index (BMI) into normal group (NOR) = BMI <28.0 and obese or in risk of obesity group (OBE) = BMI >or=28.0. All patients performed a progressive graded treadmill test. During exercise, ventilatory responses were evaluated and pre- and post-exercise ankle and arm blood pressures were measured. Exercise tolerance and oxygen consumption at total walking time were similar between OBE and NOR. However, OBE showed a lower claudication time (309 +/- 151 vs. 459 +/- 272 s, p = 0.02) with a similar oxygen consumption at this time. In addition, OBE presented a longer time for ankle brachial index recovery after exercise (7.8 +/- 2.8 vs. 6.3 +/- 2.6 min, p = 0.02). Obesity in elderly PAD patients decreased time to claudication, and delayed post-exercise hemodynamic recovery. These results suggest that muscle metabolic demand, and not total workload, is responsible for the start of the claudication and maximal exercise tolerance in PAD patients. Moreover, claudication duration might be responsible for the time needed to a complete hemodynamic recovery after exercise.


Clinical characteristics of silent corticotrophic adenomas and creation of an internet-accessible database to facilitate their multi-institutional study.
Silent corticotrophic adenomas (SCAs) of the pituitary gland present as clinically nonfunctioning sellar lesions, with normal serum and urine hormone testing results, but stain positively for adrenocorticotropic hormone in immunohistochemical analyses. These tumors are now more readily recognized, but determination of their natural history and responses to treatment is difficult because of their rarity. We report the diagnoses and outcomes for a series of patients with SCAs, and we describe the creation of an Internet-accessible database (www.hsc.virginia.edu/neuro/neurosurgery/pituitary.html) for collection of multi-institutional data on these lesions. The medical records of patients with documented SCAs who were treated at the University of Virginia between 1991 and 2002 were reviewed. A comprehensive data collection form was then created and posted online. Twenty-seven patients with SCAs were identified, with a female predominance (70%, P = 0.04). Headache was the most common presenting symptom (70%), followed by visual field deficits (52%), acute or subacute pituitary apoplexy (33%), cavernous sinus syndrome (18.5%), and hypopituitarism (11.1%). Extrasellar extension was noted for 92.6% of patients on preoperative magnetic resonance imaging scans. Transsphenoidal surgery was performed for all patients. Follow-up information was available for all patients (median, 60 mo; range, 3-254 mo). Postoperatively, 33% of patients received radiotherapy. Recurrence was noted for 37% of all patients and 41.7% of patients who did not receive postoperative radiotherapy. SCAs, although clinically nonfunctioning, may behave like aggressive adrenocorticotropic hormone-secreting adenomas and therefore should receive vigorous follow-up monitoring, with consideration being given to the recommendation of radiotherapy in cases with residual tumor.


Understanding health-related quality of life measures used in early-stage non-small cell lung cancer clinical trials: A review.
Health-related quality of life (HRQoL) is an important consideration in cancer clinical research, which can be substantially influenced by cancer treatment procedures and medications. The treatment landscape for early-stage (stage I-III) non-small cell lung cancer (NSCLC) is rapidly evolving. In this light, it is important to evaluate the most suitable instruments for HRQoL assessment and timing. Given there is often a requirement for patients with early-stage disease to receive long-term treatment to reduce the risk of disease recurrence after surgery, maintenance or improvement in HRQoL is an important goal of both neoadjuvant and adjuvant treatments. Key challenges with assessing HRQoL relate to the suitability of existing instruments to measure relevant treatment-related adverse effects, consistency in HRQoL assessment approach between similar studies, gaps in data collection and reporting, and interpretation of longitudinal data. Frequent assessments during and after treatment are warranted to capture the true impact of treatment and disease progression on HRQoL, and changes in the relative importance of these factors over time. There is scope for improving existing HRQoL approaches, including ease of use and integration of digital tools to facilitate analysis and interpretation, to enhance the experience of both patients and healthcare professionals. In this narrative review, we discuss key considerations for HRQoL assessment and evaluate the tools currently available to measure HRQoL in NSCLC, many of which were designed with advanced disease in mind. We focus on the key challenges of measuring HRQoL for the specific needs of patients with early-stage disease, and consider future perspectives, to determine the most appropriate HRQoL instruments and analysis methods to use in early-stage NSCLC clinical trials.1.


Danazol for lupus thrombocytopenia.
Danazol therapy was used in the treatment of three consecutive patients with lupus-associated thrombocytopenia refractory to high-dose prednisone therapy (two patients) or in whom high-dose prednisone therapy was considered contraindicated (one patient). Treatment was associated in each case with an increase in platelet count but was complicated in two of three patients by the development of a diffuse maculopapular rash that promptly resolved following discontinuation of danazol therapy. Retreatment of one patient with danazol was associated with immediate recurrence of the rash. We suggest that danazol therapy deserves further evaluation in the treatment of lupus-associated thrombocytopenia, but advise that patients be carefully monitored for rash.


Genetic, immunological, and cytotoxic comparisons of Legionella proteolytic activities.
Several strains of Legionella pneumophila and other species of Legionella with proteolytic activities were compared by assays, including Southern hybridizations and Western immunoblots, to determine their proteolytic, hemolytic, and cytotoxic activities. Only proteases from strains of L. pneumophila were both hemolytic and cytotoxic, and proteolytic activities extracted from other species of Legionella possessed only hemolytic activity. A 4.0-kilobase DNA sequence encoding the 38-kilodalton metalloprotease from L. pneumophila Philadelphia 1 that we showed previously was responsible for the observed hemolytic and cytotoxic phenotypes (F. D. Quinn and L. S. Tompkins, Mol. Microbiol., 3:797-805, 1989) was used in Southern hybridizations to probe chromosomal DNA from several strains of L. pneumophila and other Legionella species. The probe hybridized to the chromosomal DNA of all serogroups of L. pneumophila but not to any strains of L. dumoffii, L. micdadei, L. feeleii, or L. jordanis that we examined. Additionally, Western immunoblots done with rabbit antisera made to the cloned L. pneumophila protease demonstrated cross-reactions among 38-kilodalton proteins from strains of L. pneumophila, but no reactions were observed with proteins from other species of Legionella. Similarly, the cloned protease from L. pneumophila reacted with convalescent-phase sera from patients infected with L. pneumophila, but not with antisera isolated from patients infected with other Legionella species. Thus, despite some similarities among the proteolytic activities of members of the genus Legionella, including proteolytic and hemolytic phenotypes, metal requirements for zinc or iron, sensitivity to EDTA, and temperature and pH optima, we documented distinct genetic, immunological, and cytotoxicity differences among the proteolytic activities produced by Legionella species.


Effect of Fontan-Associated Morbidities on Survival With Intact Fontan Circulation.
Although survival after the Fontan operation has improved, little is known about the burden of major medical morbidities associated with the modern total cavopulmonary connection (TCPC). A total of 773 consecutive patients who underwent a first Fontan operation at our institution between 1992 and 2009 were retrospectively reviewed. All subjects underwent TCPC (53% lateral tunnel, 47% extracardiac conduit). Median length of follow-up was 5.3 years (interquartile range 1.4 to 11.2), and 30% had follow-up >10 years. Freedom from a composite medical morbidity outcome (protein-losing enteropathy, plastic bronchitis, serious thromboembolic event, or tachyarrhythmia) was 47% at 20 years (95% confidence interval [CI] 38 to 55). Independent risk factors for morbidity included pre-Fontan atrioventricular valve regurgitation (hazard ratio [HR] 1.7, 95% CI 1.2 to 2.4, p = 0.001), pleural drainage >14 days (HR 1.5, 95% CI 1.01 to 2.2, p = 0.04), and longer cross-clamp time (HR 1.2 per 10 minutes, 95% CI 1.06 to 1.3, p = 0.004) at the time of TCPC. Surgical era, Fontan type, and ventricular morphology were not associated with the composite outcome. Presence of Fontan-associated morbidity was associated with a 36-fold increase in the risk of subsequent Fontan takedown, heart transplantation, or death (95% CI 17 to 76, p <0.001). For patients without any component of the composite outcome, freedom from Fontan failure was 98% at 20 years (95% CI 96 to 99). Medical morbidities after TCPC are common and significantly reduce the longevity of the Fontan circulation. However, for those patients who remain free from the composite morbidity outcome, 20-year survival with intact Fontan circulation is encouraging.


Understanding cancer mechanisms through network dynamics.
Cancer is a complex, multifaceted disease. Cellular systems are perturbed both during the onset and development of cancer, and the behavioural change of tumour cells usually involves a broad range of dynamic variations. To an extent, the difficulty of monitoring the systemic change has been alleviated by recent developments in the high-throughput technologies. At both the genomic as well as proteomic levels, the technological advances in microarray and mass spectrometry, in conjunction with computational simulations and the construction of human interactome maps have facilitated the progress of identifying disease-associated genes. On a systems level, computational approaches developed for network analysis are becoming especially useful for providing insights into the mechanism behind tumour development and metastasis. This review emphasizes network approaches that have been developed to study cancer and provides an overview of our current knowledge of protein-protein interaction networks, and how their systemic perturbation can be analysed by two popular network simulation methods: Boolean network and ordinary differential equations.


Improving adherence for management of acute exacerbation of chronic obstructive pulmonary disease.
Clinical practice guidelines recommend 40-60 mg of prednisone equivalent for 10-14 days for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the amount of corticosteroid prescribed varies widely in clinical practice. Using the electronic health record, we implemented an evidence-based order set to standardize treatment of patients hospitalized with acute exacerbations of COPD. This is a pre- and post-intervention study on patients hospitalized between January 1, 2009 and September 30, 2012 with primary discharge diagnosis of COPD (International Classification of Diseases, 9(th) Revision code: 491.xx, 492.xx, and 496) and receipt of at least one dose of corticosteroid at our tertiary care hospital. Data on baseline demographics, dose of corticosteroid in prednisone equivalent administered during the first 48 hours and during the entire hospitalizations were collected from the electronic health record. Evidence-based guidelines were used to build and implement acute exacerbations of COPD management electronic ordersets in our electronic health record, Epic (Verona, WI). We divided the study into 2 time periods (January 1, 2009 through February 28, 2011 as pre- [n = 203] and March 1, 2011 through September 30, 2012 as post-intervention periods [n = 217]). The primary outcome measure was corticosteroid dose administered in the first 48 hours. Secondary outcome measures were corticosteroid dosage during the entire hospitalization, length of stay, hospital follow-up rates, and 30-day readmission rates. A total of 420 patients with acute exacerbations of COPD were included in the study. In the post-intervention period, the median amount of corticosteroid used in the first 48 hours was significantly reduced (306.2 mg vs 156.25 mg, P < .0001), as was that used during the entire hospitalization (352.5 mg vs 175 mg, P < .0001). There was no difference in hospital follow-up rates, length of stay, or 30-day readmission rates between the 2 periods. Evidence-based electronic ordersets improve compliance with clinical practice guidelines and reduce the total dose of corticosteroid administered in patients hospitalized with acute exacerbations of COPD.


NetVenn: an integrated network analysis web platform for gene lists.
Many lists containing biological identifiers, such as gene lists, have been generated in various genomics projects. Identifying the overlap among gene lists can enable us to understand the similarities and differences between the data sets. Here, we present an interactome network-based web application platform named NetVenn for comparing and mining the relationships among gene lists. NetVenn contains interactome network data publically available for several species and supports a user upload of customized interactome network data. It has an efficient and interactive graphic tool that provides a Venn diagram view for comparing two to four lists in the context of an interactome network. NetVenn also provides a comprehensive annotation of genes in the gene lists by using enriched terms from multiple functional databases. In addition, it allows for mapping the gene expression data, providing information of transcription status of genes in the network. The power graph analysis tool is integrated in NetVenn for simplified visualization of gene relationships in the network. NetVenn is freely available at http://probes.pw.usda.gov/NetVenn or http://wheat.pw.usda.gov/NetVenn.


Gastrointestinal Bleeding Following Heartmate 3 Left Ventricular Assist Device Implantation: The Michigan Bleeding Risk Model.
Gastrointestinal bleeding (GIB) results in frequent hospitalizations and impairs quality of life in durable left ventricular assist device (LVAD) recipients. Anticipation of these events before implantation could have important implications for patient selection and management. The study population included all adult HeartMate 3 (HM3) primary LVAD recipients enrolled in the STS-Intermacs registry from January 2017-December 2020. Using multivariable modeling methodologies, we investigated the relationships between preimplantation characteristics and postimplant bleeding, bleeding and death, and additional bleeding episodes on subsequent bleeding episodes, and created a risk score to predict the likelihood of post-LVAD GIB based solely on pre-implantation factors. Of 6425 patients who received a HM3 LVAD, 1010 (15.7%) patients experienced GIB. Thirteen pre-implantation factors were independent predictors of post-LVAD GIB. A risk score was created from these factors and calculated for each patient. By 3-years postimplant, GIB occurred in 11%, 26%,and 43% of low-, medium- and high-risk patients. Experiencing one post-LVAD GIB event was associated with an increased risk for further GIB events, with 33.9% of patients experiencing at least one recurrence. While post-LVAD GIB was associated with mortality, there was no relationship between number of GIB events and death. The Michigan Bleeding Risk Model is a simple tool which facilitates the prediction of post-LVAD GIB in HM3 recipients, by using 13 pre-implant variables. The implementation of this tool may help in the risk stratification process and may have therapeutic and clinical implications in HM3 LVAD recipients.


[Phenotype-genotype relations in growth hormone insensitivity].
Growth hormone (GH) insensitivity is associated with several different mutations of the GH receptor gene and a recently described new genetic disorder of the IFGI gene. The phenotype and biochemical characteristics were studied in 82 patients with growth hormone insensitivity, from 23 different countries, with a mean age of 8.25 years. Mean height SDS was -6.09. SDS of the IGF binding protein -3 (IGF BP3) was 7.99. Twenty three per cent of the patients were GH binding protein (GHBP) positive (> 10%). Mean height SDS score was -6.5 in the GHBP negative patients and -4.9 in the GHBP positive patients (p < 0.001). Fifteen different mutations of the GH receptor gene were identified in 27 patients. There were no relationships between the type of mutation or the involved GH receptor gene exon and height or IGFBP-3 SDS. The new phenotype due to a partial deletion of the IGFI gene was described in a 15-year-old boy who presented with a severe intrauterine growth retardation, a very poor postnatal statural growth, a neurosensorial deafness and a mild mental retardation. He had elevated GH levels, normal levels of IGFBP3, undetectable levels of IGFI, and showed no response to GH treatment. A partial deletion concerning the exons 4 and 5 of the IGFI gene was found. Thus, GH insensitivity is associated with large variations in the clinical and biochemical phenotypes.


Rimonabant--a selective CB1 antagonist.
To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of rimonabant, a new selective cannabinoid receptor antagonist. Primary literature and review articles were obtained via a MEDLINE search (1966-November 2004) using the key terms obesity, smoking cessation, cannabinoid, rimonabant, SR 141716, and SR 141716a. Additional studies and abstracts were identified from the bibliographies of reviewed literature. Studies and review articles related to rimonabant and the endocannabinoid system were reviewed. Data pertinent to this article were included. Rimonabant is a selective cannabinoid receptor antagonist. Recent data have demonstrated beneficial effects of rimonabant in obesity, smoking cessation, and metabolic syndrome. Animal studies using rimonabant have shown a positive role for reducing hunger, caloric intake, and body weight and in increasing satiety. In humans, rimonabant appears to be effective for treatment of obesity and smoking cessation. Ongoing studies will examine the effect of rimonabant on obesity, metabolic syndrome, smoking cessation, and alcohol abuse. To date, the incidence of adverse effects with rimonabant has been slightly greater than placebo, with the most common being nausea. Rimonabant appears to be a promising drug in an entirely new class called selective cannabinoid CB1 receptor antagonists. The drug may be approved for treatment of obesity and smoking cessation in 2005. Additional studies are ongoing that may provide information on other clinical uses for this medication.


Studies on the methylation of avian sarcoma proviruses in permissive and non-permissive cells.
The extent of methylation of several avian oncogenic proviruses was determined by using the restriction endonucleases HpaII and MspI. The results indicated that the transformation-defective proviruses (RAV-O or B77-td), which are exogenously introduced into avian host cells, were not methylated. However, endogenous proviruses (RAV-O) or ASV proviruses present in non-permissive host cells were found to be partly or completely methylated. The methyl-sensitive restriction endonuclease PvuI, which recognizes a unique site within the long terminal repeat in the ASV genome, failed to cleave proviruses present in several non-permissive host cells. From these results we suggest that modification of the sequence around the PvuI site results in reduced levels of transcription.


Pathological and Radiological Correlation in Prolonged Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-related Diffuse Alveolar Hemosiderosis.
A 60-year-old woman with a 20-year history of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis visited our hospital due to productive cough and a low-grade fever for several weeks. Thoracic computed tomography demonstrated scattered tiny nodules, patchy consolidation, ground glass opacities, and thickening interlobular septa. On video-assisted thoracic surgery, those abnormalities were found to correspond to the accumulation of hemosiderin-laden alveolar macrophages (AMs) in the alveolar spaces and alveolar septa due to MPO-ANCA vasculitis. The radiological findings persisted for a further two years, indicating the possibility of persistent vasculitis in the lung or evidence of incomplete clearance of hemosiderin-laden AMs.


[Immunochemical properties of the regulatory subunit of cAMP-dependent protein kinase II].
Immunochemical analysis of the cAMP-dependent protein kinase regulatory subunit type II was performed with the use of two rabbit antisera elicited to a free R-subunit from pig brain and to a RcAMP complex. Quantitative precipitation of the homogeneous antigen revealed six determinants on the R-molecule. Of these at least one is localized in the R-fragment (37 kD), the others--in the N-terminal part of the R-molecule. The antigenic determinants seem to be remoted from the cAMP-binding centers, since the attachment of the affinity purified antibody Fab-fragments to the R-subunit did not influence the cAMP-binding activity of the latter. The antibodies to RcAMP caused dissociation of the holoenzyme. The antibody Fab-fragment binding to the R-subunit prevented its association with the catalytic subunit. The results of immunochemical analysis suggest that the R-subunit adopts different conformations when bound to cAMP or to the catalytic subunit.


miRNAs and cancer: New research developments and potential clinical applications.
miRNAs are small non-protein coding transcripts that regulate gene expression post-transcriptionally by binding to the 3' UTRs (untranslated regions) of messenger RNAs (mRNAs). The number of newly discovered miRNAs and our understanding of their biological roles continue to grow. In addition to their roles in important biological processes such as development, differentiation, proliferation and cell death, deregulated expression of miRNAs has been implicated in a wide range of pathologies, especially in cancer. We now understand that miRNA expression is often deregulated in cancer cells and that a vast number of genes, including tumor suppressor genes and oncogenes, are regulated by these small RNAs. The small size of miRNAs and sequence similarity of miRNA family members pose some challenges in routine molecular detection and quantification techniques. Therefore, methods are being modified to specifically and sensitively detect miRNAs in cancer cells. Our current knowledge and the ever increasing pace of new discoveries clearly show that miRNAs are quite important in normal and in cancer cells in surprisingly diverse aspects. The better we understand how miRNAs contribute to cancer, the more likely we will be able to exploit them as tumor classifiers, biomarkers and, potentially, as unique targets for therapeutic applications.


Interactions of high hydrostatic pressure, pressurization temperature and pH on death and injury of pressure-resistant and pressure-sensitive strains of foodborne pathogens.
The objective of this study is to determine the interactions between high hydrostatic pressure, pressurization temperature, time and pH during pressurization on death and injury of pressure-resistant and pressure-sensitive strains of four foodborne pathogens: Staphylococcus aureus 485 and 765, Listeria ,monocytogenes CA and OH2, Escherichia coli O157:H7 933 and 931, Salmonella enteritidis FDA and Salmonella typhimurium E21274. Among these strains S. aureus 485, L. monocytogenes CA, E. coli O157:H7 933 and S. enteritidis FDA were reported to be more pressure-resistant than the respective strain of the same species (Alpas et al., 1999). In general, viability loss of all pathogens was enhanced significantly as the level of pressure and temperature were increased (P < 0.05). All the strains except S. aureus 485 demonstrated more than 8 log cycle reduction when pressurized at 345 MPa at 50 degrees C for 5 min. This strain seemed to be the most pressure-resistant strain within the conditions of the study. Pressurization in the presence of either citric or lactic acid increased the viability loss by an additional 1.2-3.9 log cycles at pH 4.5 for both acids at 345 MPa. This study has indicated that high hydrostatic pressure applied in conjunction with mild heat and acidity can be an effective method for inactivating pressure-resistant and pressure-sensitive strains of four foodborne pathogens in organic acid solutions. This combination treatment indicates possible pressure pasteurization applications to liquid foods that have low pH. reserved.


Exportin1 genes are essential for development and function of the gametophytes in Arabidopsis thaliana.
Gametes are produced in plants through mitotic divisions in the haploid gametophytes. We investigated the role of EXPORTIN1 (XPO1) genes during the development of both female and male gametophytes of Arabidopsis. Exportins exclude target proteins from the nucleus and are also part of a complex recruited at the kinetochores during mitosis. Here we show that double mutants in Arabidopsis XPO1A and XPO1B are gametophytic defective. In homozygous-heterozygous plants, 50% of the ovules were arrested at different stages according to the parental genotype. Double-mutant female gametophytes of xpo1a-3/+; xpo1b-1/xpo1b-1 plants failed to undergo all the mitotic divisions or failed to complete embryo sac maturation. Double-mutant female gametophytes of xpo1a-3/xpo1a-3; xpo1b-1/+ plants had normal mitotic divisions and fertilization occurred; in most of these embryo sacs the endosperm started to divide but an embryo failed to develop. Distortions in male transmission correlated with the occurrence of smaller pollen grains, poor pollen germination, and shorter pollen tubes. Our results show that mitotic divisions are possible without XPO1 during the haploid phase, but that XPO1 is crucial for the maternal-to-embryonic transition.


Self-rated oral health and oral health-related factors: the role of social inequality.
The reasons why social inequality is associated with oral health outcomes is poorly understood. This study investigated whether stratification by different measures of socio-economic status (SES) helped elucidate these associations. Cross-sectional survey data were used from Australia's 2004-06 National Survey of Adult Oral Health. The outcome variable was poor self-rated oral health. Explanatory variables comprised five domains: demographic, economic, general health behaviour, oral health-related quality of life and perceived need for dental care. These explanatory variables were each stratified by three measures of SES: education, income and occupation. The overall proportion of adults reporting fair or poor oral health was 17.0% (95% CI 16.1, 18.0). Of these, a higher proportion were older, Indigenous, non-Australian born, poorly educated, annual income <$20 000, unemployed, eligible for public dental care, smoked tobacco, avoided food in the last 12 months, experienced discomfort with their dental appearance, experienced toothache or reported a need for dental care. In stratified analyses, a greater number of differences persisted in the oral health impairment and perceived need for dental care domains. Irrespective of the SES measure used, more associations between self-rated oral health and dental-specific factors were observed than associations between self-rated oral health and general factors.


8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients.
The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000.


Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes.
Mutations that disrupt developmental patterning in Drosophila have provided considerable information about growth factor signaling mechanisms. Three genes recently demonstrated to affect signaling by members of the Wnt, transforming growth factor-beta, Hedgehog, and fibroblast growth factor families in Drosophila encode proteins with homology to vertebrate enzymes involved in glycosaminoglycan synthesis. We report here the biochemical characterization of glycosaminoglycans in Drosophila bearing mutations in sugarless, sulfateless, and tout-velu. We find that mutations in sugarless, which encodes a protein with homology to UDP-glucose dehydrogenase, compromise the synthesis of both chondroitin and heparan sulfate, as would be predicted from a defect in UDP-glucuronate production. Defects in sulfateless, a gene encoding a protein with similarity to vertebrate N-deacetylase/N-sulfotransferases, do not affect chondroitin sulfate levels or composition but dramatically alter the composition of heparin lyase-released disaccharides. N-, 6-O-, and 2-O-sulfated disaccharides are absent and replaced entirely with an unsulfated disaccharide. A mutation in tout-velu, a gene related to the vertebrate Exostoses 1 heparan sulfate co-polymerase, likewise does not affect chondroitin sulfate synthesis but reduces all forms of heparan sulfate to below the limit of detection. These findings show that sugarless, sulfateless, and tout-velu affect glycosaminoglycan biosynthesis and demonstrate the utility of Drosophila as a model organism for studying the function and biosynthesis of glycosaminoglycans in vivo.


QTc prolongation during erythromycin used as prokinetic agent in ICU patients.
High-dose erythromycin used as antibiotic prolongs QTc interval. Low-dose erythromycin is frequently used as a prokinetic agent, especially in patients in the intensive care unit (ICU). It is unknown whether low-dose erythromycin affects cardiac repolarisation and puts patients at risk for torsades de pointes. In this prospective study, we included ICU patients treated with erythromycin as prokinetic in a dose of 200 mg twice a day. An ECG was performed before, 15 min and 24 hours after the start of erythromycin. Cardiac repolarisation was assessed by rate-corrected analysis of the QT interval (QTc) on the ECG by two independent investigators. Starting or stopping other possibly QTc prolonging drugs during the study period was an exclusion criterion. Wilcoxon signed-rank test and Friedman's test were used for statistical analysis to assess prolongation of QTc. Primary outcome was defined by the prolongation of QTc after 15 min and 24 hours. 51 patients were eligible for this study. In these patients, QTc increased significantly from 430 ms at baseline to 439 ms (p=0.03) after 15 min and 444 ms (p=0.01) after 24 hours. After 15 min and 24 hours, the upper limit of 95% CI for prolongation of QTc was well above 10 ms. No QTc-related arrhythmias were seen. During treatment with erythromycin in a dose of 200 mg twice a day. QTc prolonged mildly but significantly. Sequential ECG registration should be performed when low-dose erythromycin is prescribed, especially in the presence of other risk factor for QTc prolongation.


The impact of functionalization on the stability, work function, and photoluminescence of reduced graphene oxide.
Reduced graphene oxide (rGO) is a promising material for a variety of thin-film optoelectronic applications. Two main barriers to its widespread use are the lack of (1) fabrication protocols leading to tailored functionalization of the graphene sheet with oxygen-containing chemical groups, and (2) understanding of the impact of such functional groups on the stability and on the optical and electronic properties of rGO. We carry out classical molecular dynamics and density functional theory calculations on a large set of realistic rGO structures to decompose the effects of different functional groups on the stability, work function, and photoluminescence. Our calculations indicate the metastable nature of carbonyl-rich rGO and its favorable transformation to hydroxyl-rich rGO at room temperature via carbonyl-to-hydroxyl conversion reactions near carbon vacancies and holes. We demonstrate a significant tunability in the work function of rGO up to 2.5 eV by altering the composition of oxygen-containing functional groups for a fixed oxygen concentration, and of the photoluminescence emission by modulating the fraction of epoxy and carbonyl groups. Taken together, our results guide the application of tailored rGO structures in devices for optoelectronics and renewable energy.