A chemical, crystallographic and magnetic characterisation of individual iron-oxide grains in Hawaiian lavas.
Our knowledge on the behaviour of the geomagnetic field through time critically depends on how information of the past state of the field is recorded by, and stored in iron-bearing minerals such as magnetite. For small, single domain grains these processes are described by classical Néel theory, but the magnetic behaviour of larger, pseudo-single domain or multidomain grains, still is enigmatic. Here we present a chemical, crystallographic and magnetic characterisation of three to six individual, large (~3-10 μm) iron-oxide grains from eleven different flows sampled on the Big Island of Hawai'i. These grains were all subjected to a Magnetic Force Microscopy study to characterise their magnetic domain structure; a Microprobe analyses to assess their chemical composition; and a Scanning Electron Microscopy study to identify phases and crystallographic orientations. This comprehensive dataset enables systematic analyses of their magnetic behaviour as function of chemistry and forms the basis for future micromagnetic modelling studies eventually contributing to the development of a fundamental theory of magnetic behaviour in large iron-oxide grains.


Cefuroxime axetil in the treatment of uncomplicated UTI: a comparison with cefaclor and augmentin.
Cefuroxime axetil (CAE) is an acetoxyethyl ester prodrug of cefuroxime. The efficacy and safety of cefuroxime axetil was studied in a randomized general practice trial in urological infections where cefuroxime axetil 250 mg b.d. was compared with amoxycillin/clavulanate (Augmentin, AUG) 375 mg t.d.s. A randomized trial was then performed in hospital outpatients, who received cefuroxime axetil 250 mg b.d. or cefaclor (CCL) 250 mg t.d.s. Of 140 clinically assessable patients, 108 were cured and 28 improved on cefuroxime axetil (97% success) compared with 75 cured and 13 improved out of 89 on Augmentin (99% success) and 31 cured and 7 improved out of 38 patients treated with cefaclor (97% success). Bacteriology was assessable in 101 patients given cefuroxime axetil (72% cleared), 61 of those given Augmentin (70% cleared) and 27 out of 28 (96%) given cefaclor. As expected, the predominant pathogen was E. coli, accounting for 61% of isolates overall. Drug-related adverse events occurred in 10% of patients given cefuroxime axetil, including diarrhoea in 4%. Eleven percent of patients given Augmentin suffered adverse events (5% diarrhoea) and 5% of those given cefaclor. Superinfections occurred in 4 cefaclor patients (2 Pseudomonas aeruginosa, 1 Candida, 1 E. coli) compared with 2 on cefuroxime axetil (1 Candida, 1 E. coli). Uncomplicated UTI accounted for 92% of cases in the G.P. trial and 82% of cases in the hospital trial. Cefuroxime axetil may be used safely and effectively to treat uncomplicated UTI at a dose of 250 mg b.d.


Disturbed reproductive function following section of the portal vein.
Integrity of the portal vein is a condition for normal function of the reproductive tract in female rats. Section of the portal vein (PVS) always abolished periodic sexual function. In a series of 23 animals, 6 developed continuous estrus and other signs of the presence of excessive amounts of estrogenic hormones; yet the ovaries of these rats were small. In 6 other rats there was growth of the prostate and additional evidence of increased activity of androgenic hormones. Many rats failed to become pregnant and nearly all pregnant rats aborted. Except for a decrease in lipid content, the composition of the liver of PVS rats resembled that of intact mates in the criteria which were applied. The rapid passage of blood through the liver is necessary to conjugate the excessive amounts of steroids which the rat ovary normally produces and an intact portal vein is an essential unit in the mechanism necessary for their partial inactivation.


Assessment of physical inactivity and locomotor dysfunction in adults with visual impairment.
To evaluate the association between vision-related quality of life (QoL), physical inactivity, and locomotor dysfunction in subjects with visual impairment.This cross-sectional study included 215 visually impaired subjects recruited from six ophthalmology departments in Japan. The physical inactivity and locomotor dysfunction associated with their visual impairment was investigated. The physical activity level was assessed using the short form of the International Physical Activity Questionnaire and classified as high, moderate, or low. Locomotor function was evaluated with the Geriatric Locomotive Function Scale. Vision-related QoL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire. Background data, including for age, sex, best-corrected visual acuity for each eye, causative eye diseases, systemic comorbidities, and body mass index, were also collected.The average patient age was 69.6 (range, 20-93 years; standard deviation, 14.5 years) and 118 patients (54.9%) were men. Multivariate analysis showed that vision-related QoL and best-corrected visual acuity in the worse eye were significantly associated with physical inactivity and that vision-related QoL, female sex, age, and presence of systemic comorbidity were significantly associated with locomotor dysfunction. Vision-related quality of life is associated with physical inactivity and locomotor dysfunction.


Obesity-induced metabolic disturbance drives oxidative stress and complement activation in the retinal environment.
Systemic increases in reactive oxygen species, and their association with inflammation, have been proposed as an underlying mechanism linking obesity and age-related macular degeneration (AMD). Studies have found increased levels of oxidative stress biomarkers and inflammatory cytokines in obese individuals; however, the correlation between obesity and retinal inflammation has yet to be assessed. We used the leptin-deficient (ob/ob) mouse to further our understanding of the contribution of obesity to retinal oxidative stress and inflammation. Retinas from ob/ob mice were compared to age-matched wild-type controls for retinal function (electroretinography) and gene expression analysis of retinal stress (Gfap), oxidative stress (Gpx3 and Hmox1), and complement activation (C3, C2, Cfb, and Cfh). Oxidative stress was further quantified using a reactive oxygen species and reactive nitrogen species (ROS and RNS) assay. Retinal microglia and macrophage migration to the outer retina and complement activation were determined using immunohistochemistry for IBA1 and C3, respectively. Retinas and sera were used for metabolomic analysis using QTRAP mass spectrometry. Retinal function was reduced in ob/ob mice, which correlated to changes in markers of retinal stress, oxidative stress, and inflammation. An increase in C3-expressing microglia and macrophages was detected in the outer retinas of the ob/ob mice, while gene expression studies showed increases in the complement activators (C2 and Cfb) and a decrease in a complement regulator (Cfh). The expression of several metabolites were altered in the ob/ob mice compared to the controls, with changes in polyunsaturated fatty acids (PUFAs) and branched-chain amino acids (BCAAs) detected. The results of this study indicate that oxidative stress, inflammation, complement activation, and lipid metabolites in the retinal environment are linked with obesity in ob/ob animals. Understanding the interplay between these components in the retina in obesity will help inform risk factor analysis for acquired retinal degenerations, including AMD.


Comment from the Editor to the Special Issue: "Periodontitis: From Dysbiotic Microbial Immune Response to Systemic Inflammation".
The human oral cavity contains a large number of different microbial habitats. When microbes from the oral indigenous flora colonize the interspace between the tooth and the connective tissue, they induce an inflammatory response. If the microbes are in sufficient numbers, and release components that cause an imbalance in the host inflammatory response, degenerative processes in the surrounding tissues are induced, ultimately resulting in periodontal disease. The disease progress depends on bacterial load, the composition of the microbial community, and host genetic factors. The two most studied periodontal pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans express virulence factors, including proteases and exotoxins. Periodontal infections are also linked to the risk pattern of several systemic diseases. We would like to shed light on the mechanisms behind periodontitis and the associations of periodontal infections with systemic inflammation. Seven articles are included in this Special Issue and cover several pathogenic processes in the periodontal infection with capacity to cause imbalance in the host response. Highlights from each of the published papers are summarized and discussed below.


Midregional proadrenomedullin predicts mortality and major adverse cardiac events in patients presenting with chest pain: results from the CHOPIN trial.
Chest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR-proADM) in prediction of mortality and major adverse cardiac events (MACE). This was a subanalysis of the CHOPIN study, a 16-center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure. MR-proADM performed similarly to troponin (cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR-proADM, history of coronary artery disease (CAD), and hypertension were predictors of short-term MACE, while history of CAD, hypertension, cTnI, and MR-proADM were predictors of long-term MACE. In patients with chest pain, MR-proADM predicts mortality and MACE in all-comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses-generating and future prospective studies to identify its utility in risk stratification should be considered.


International consensus statement on the use of disease-modifying agents in multiple sclerosis.
To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.


Amniotic membrane graft: histopathological findings in five cases.
Amniotic membrane transplantation (AMT) is an effective treatment for ocular surface reconstruction; however, the mechanisms through which amniotic membrane (AM) exerts its effects as well as its fate after transplantation have not been entirely elucidated and have been investigated only in part. We evaluate the integration of AM in the host cornea in five patients who underwent AMT as the result of Bowen's disease, band keratopathy, radio- or cryotherapy-induced keratopathy, chemical burn or post-herpetic deep corneal ulcer with descemetocele. Due to persistent opacification in four cases and a progressing tumor in one case, penetrating keratoplasty (PK) and enucleation were performed as early as 2 months and up to 20 months after AMT. The corneas were analyzed histopathologically. To evaluate AM remnants, corneas were stained with periodic acid Schiff's reaction (PAS), Alcian blue, and Gomory and Masson trichrome; immunostaining including collagens III and IV antibodies was also performed. None of the corneas showed remnants of AM. In all cases, we observed discontinuity of Bowman's membrane. In three cases, the corneal epithelium was completely restored, ranging from three to six cell layers. In the other two cases, we detected an intense inflammatory reaction with rich neovascularization; the epithelial surface of the central cornea was completely restored, while at the periphery of the cornea goblet mucus-producing cells were present. Although clinically useful in all cases, restoration of a stable corneal epithelium through AMT is limited by the extent and severity of limbal stem cell deficiency (LSCD). The lack of histologically documented AM remnants in our cases seems to explain the efficacy of AMT more through its biological properties than through its mechanical properties.


Medicinal plants and cancer chemoprevention.
Cancer is the second leading cause of death worldwide. Although great advancements have been made in the treatment and control of cancer progression, significant deficiencies and room for improvement remain. A number of undesired side effects sometimes occur during chemotherapy. Natural therapies, such as the use of plant-derived products in cancer treatment, may reduce adverse side effects. Currently, a few plant products are being used to treat cancer. However, a myriad of many plant products exist that have shown very promising anti-cancer properties in vitro, but have yet to be evaluated in humans. Further study is required to determine the efficacy of these plant products in treating cancers in humans. This review will focus on the various plant-derived chemical compounds that have, in recent years, shown promise as anticancer agents and will outline their potential mechanism of action.


Drink and Think: Impact of Alcohol on Cognitive Functions and Dementia - Evidence of Dose-Related Effects.
Regular alcohol consumption affects cognitive performance and the development of dementia. So far, findings are contradicting, which might be explained in part by dose-related effects. For this narrative review, we undertook a literature search for surveys investigating the impact of alcohol consumption on cognitive performance and the development of dementia. The majority of studies observed a U-shaped relationship between regular alcohol consumption and cognitive function: frequent heavy consumption of alcohol alters brain functions and decreases cognitive performance; regular light and moderate consumption may have protective impact. In many studies, total abstainers show an inferior cognitive performance than people with moderate or light consumption. Nevertheless, policy implications are difficult to draw for at least 2 reasons: (1) the possible risks associated with alcohol consumption and (2) the potential confounders in the group of non-consumers and heavy consumers.


DNA Methylation of the Oxytocin Receptor Across Neurodevelopmental Disorders.
Many neurodevelopmental disorders (NDDs) share common learning and behavioural impairments, as well as features such as dysregulation of the oxytocin hormone. Here, we examined DNA methylation (DNAm) in the 1st intron of the oxytocin receptor gene, OXTR, in patients with autism spectrum (ASD), attention deficit and hyperactivity (ADHD) and obsessive compulsive (OCD) disorders. DNAm of OXTR was assessed for cohorts of ASD (blood), ADHD (saliva), OCD (saliva), which uncovered sex-specific DNAm differences compared to neurotypical, tissue-matched controls. Individuals with ASD or ADHD exhibiting extreme DNAm values had lower IQ and more social problems, respectively, than those with DNAm within normative ranges. This suggests that OXTR DNAm patterns are altered across NDDs and may be correlated with common clinical outcomes.


Activation of the somatosensory cortex during Abeta-fiber mediated hyperalgesia. A MSI study.
To investigate the neural activation in the primary somatosensory cortex (SI) that is induced by capsaicin-evoked secondary Abeta-fiber-mediated hyperalgesia with magnetic source imaging (MSI) in healthy humans. Dynamic mechanical hyperalgesia, i.e. pain to innocuous light touching, is a symptom of painful neuropathies. Animal experiments suggest that alterations in central pain processing occur so that tactile stimuli conveyed in Abeta low threshold mechanoreceptive afferents become capable of activating central pain signalling neurons. A similar state of central sensitization can be experimentally produced with capsaicin. In six individuals the somatosensory evoked magnetic fields (SEFs) induced by non-painful electrical stimulation of Abeta-afferents at the forearm skin were recorded. Capsaicin was injected adjacent to the stimulation site to induce secondary dynamic Abeta-hyperalgesia. Thereafter, the SEFs induced by the identical electrical stimulus applied within the secondary hyperalgesic skin were analyzed. The electrical stimulus was subsequently perceived as painful without changing the stimulus intensity and location. Latencies, anatomical source location and amplitudes of SEFs during both conditions were compared. Non-painful electrical stimulation of Abeta-afferents induced SEFs in SI at latencies between 20 and 150 ms. Stimulation of Abeta-afferents within the capsaicin-induced secondary hyperalgesic skin induced SEFs at identical latencies and locations as compared with the stimulation of Abeta-afferents within normal skin. The amplitudes, i.e., the magnetic dipole strengths of the SEFs were higher during Abeta-hyperalgesia. Acute application of capsaicin produces an increase in the excitability of central neurons, e.g., in SI. This might be due to sensitization of central neurons so that normally innocuous stimuli activate pain signalling neurons or cortical neurons might increase their receptive fields.


Interaction between prostaglandin E2 and l-cis-diltiazem, a specific blocker of cyclic nucleotide gated channels in bovine aortic endothelial cells.
Prostaglandins are known to transduce their signals via 7 transmembrane prostanoid receptors, which typically signal through coupling to G proteins and downstream second messenger molecules and protein kinase activation. Recently we have shown that cyclic nucleotides affect prostaglandins binding to bovine aortic endothelial cells independent of protein kinases. Here we show that incubation of bovine aortic endothelial cells with permeable analogs of cAMP or cGMP leads to a rapid and reversible reduction in PGE(2) binding to the cells. Since cyclic nucleotides are known modulators of cyclic nucleotide gated channels, we examined the effect of a specific cyclic nucleotide gated channel blocker l-cis-diltiazem on prostaglandin E(2) (PGE(2)) binding to bovine aortic endothelial cells. L-cis-diltiazem is shown to displace PGE(2) binding to bovine aortic endothelial cells in a dose dependent manner. In addition the effect of PGE(2) and l-cis-diltiazem on thapsigargin induced calcium elevation in the cells was compared. Both agents reduced in bovine aortic endothelial cells the thapsigargin induced calcium elevation by about half. PGE(2) also retarded the time course of the response to thapsigargin. Simultaneous treatment of the cells with both PGE(2) and l-cis-diltiazem did not yield an inhibitory effect beyond that observed with l-cis-diltiazem alone. Together our data point at the cyclic nucleotide gated channels as a feasible candidate for association with the PGE(2) binding site in bovine aortic endothelial cells.


Swiveling-domain mechanism for enzymatic phosphotransfer between remote reaction sites.
The crystal structure of pyruvate phosphate dikinase, a histidyl multiphosphotransfer enzyme that synthesizes adenosine triphosphate, reveals a three-domain molecule in which the phosphohistidine domain is flanked by the nucleotide and the phosphoenolpyruvate/pyruvate domains, with the two substrate binding sites approximately 45 angstroms apart. The modes of substrate binding have been deduced by analogy to D-Ala-D-Ala ligase and to pyruvate kinase. Coupling between the two remote active sites is facilitated by two conformational states of the phosphohistidine domain. While the crystal structure represents the state of interaction with the nucleotide, the second state is achieved by swiveling around two flexible peptide linkers. This dramatic conformational transition brings the phosphocarrier residue in close proximity to phosphoenolpyruvate/pyruvate. The swiveling-domain paradigm provides an effective mechanism for communication in complex multidomain/multiactive site proteins.


Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator.
During hibernation, animals cycle between torpor and arousal. These cycles involve dramatic but poorly understood mechanisms of dynamic physiological regulation at the level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic arousal from torpor by generating essential heat. We applied digital transcriptome analysis to precisely timed samples to identify molecular pathways that underlie the intense activity cycles of hibernator BAT. A cohort of transcripts increased during torpor, paradoxical because transcription effectively ceases at these low temperatures. We show that this increase occurs not by elevated transcription but rather by enhanced stabilization associated with maintenance and/or extension of long poly(A) tails. Mathematical modeling further supports a temperature-sensitive mechanism to protect a subset of transcripts from ongoing bulk degradation instead of increased transcription. This subset was enriched in a C-rich motif and genes required for BAT activation, suggesting a model and mechanism to prioritize translation of key proteins for thermogenesis.


[Rat spleen cellular composition after water baths].
The aim of this study was to determine the effect of fresh water baths on rat spleen structural components (lymphoid nodules with or without germinal centers, periarterial lymphoid sheaths and splenic cords). Experiments included the submersion of the cages with outbred albino male rats into the baths containing fresh water at 36-37 degrees C. Histological analysis has shown the changes of cytoarchitectonics in all the splenic structures studied. The number of cells per unit area in the germinal centers of lymphoid nodules was decreased, while that one in the periarterial lymphoid sheaths was increased. The number of disintegrating cells in the splenic cords was found to be reduced. The major effect of fresh water baths on spleen parenchyma was the uniform increase in plasma cell content in all the structural components of the organ. These changes may indicate the activation of humoral immunity.


Rickettsia rickettsii infection of human macrovascular and microvascular endothelial cells reveals activation of both common and cell type-specific host response mechanisms.
Although inflammation and altered barrier functions of the vasculature, due predominantly to the infection of endothelial cell lining of small and medium-sized blood vessels, represent salient pathological features of human rickettsioses, the interactions between pathogenic rickettsiae and microvascular endothelial cells remain poorly understood. We have investigated the activation of nuclear transcription factor-kappa B (NF-kappaB) and p38 mitogen-activated protein (MAP) kinase, expression of heme oxygenase 1 (HO-1) and cyclooxygenase 2 (COX-2), and secretion of chemokines and prostaglandins after Rickettsia rickettsii infection of human cerebral, dermal, and pulmonary microvascular endothelial cells in comparison with pulmonary artery cells of macrovascular origin. NF-kappaB and p38 kinase activation and increased HO-1 mRNA expression were clearly evident in all cell types, along with relatively similar susceptibility to R. rickettsii infection in vitro but considerable variations in the intensities/kinetics of the aforementioned host responses. As expected, the overall activation profiles of macrovascular endothelial cells derived from human pulmonary artery and umbilical vein were nearly identical. Interestingly, cerebral endothelial cells displayed a marked refractoriness in chemokine production and secretion, while all other cell types secreted various levels of interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) in response to infection. A unique feature of all microvascular endothelial cells was the lack of induced COX-2 expression and resultant inability to secrete prostaglandin E(2) after R. rickettsii infection. Comparative evaluation thus yields the first experimental evidence for the activation of both common and unique cell type-specific host response mechanisms in macrovascular and microvascular endothelial cells infected with R. rickettsii, a prototypical species known to cause Rocky Mountain spotted fever in humans.


Instant Visual Odometry Initialization for Mobile AR.
Mobile AR applications benefit from fast initialization to display world-locked effects instantly. However, standard visual odometry or SLAM algorithms require motion parallax to initialize (see Figure 1) and, therefore, suffer from delayed initialization. In this paper, we present a 6-DoF monocular visual odometry that initializes instantly and without motion parallax. Our main contribution is a pose estimator that decouples estimating the 5-DoF relative rotation and translation direction from the 1-DoF translation magnitude. While scale is not observable in a monocular vision-only setting, it is still paramount to estimate a consistent scale over the whole trajectory (even if not physically accurate) to avoid AR effects moving erroneously along depth. In our approach, we leverage the fact that depth errors are not perceivable to the user during rotation-only motion. However, as the user starts translating the device, depth becomes perceivable and so does the capability to estimate consistent scale. Our proposed algorithm naturally transitions between these two modes. Our second contribution is a novel residual in the relative pose problem to further improve the results. The residual combines the Jacobians of the functional and the functional itself and is minimized using a Levenberg-Marquardt optimizer on the 5-DoF manifold. We perform extensive validations of our contributions with both a publicly available dataset and synthetic data. We show that the proposed pose estimator outperforms the classical approaches for 6-DoF pose estimation used in the literature in low-parallax configurations. Likewise, we show our relative pose estimator outperforms state-of-the-art approaches in an odometry pipeline configuration where we can leverage initial guesses. We release a dataset for the relative pose problem using real data to facilitate the comparison with future solutions for the relative pose problem. Our solution is either used as a full odometry or as a pre-SLAM component of any supported SLAM system (ARKit, ARCore) in world-locked AR effects on platforms such as Instagram and Facebook.


Consistent Differential Expression Pattern (CDEP) on microarray to identify genes related to metastatic behavior.
To utilize the large volume of gene expression information generated from different microarray experiments, several meta-analysis techniques have been developed. Despite these efforts, there remain significant challenges to effectively increasing the statistical power and decreasing the Type I error rate while pooling the heterogeneous datasets from public resources. The objective of this study is to develop a novel meta-analysis approach, Consistent Differential Expression Pattern (CDEP), to identify genes with common differential expression patterns across different datasets. We combined False Discovery Rate (FDR) estimation and the non-parametric RankProd approach to estimate the Type I error rate in each microarray dataset of the meta-analysis. These Type I error rates from all datasets were then used to identify genes with common differential expression patterns. Our simulation study showed that CDEP achieved higher statistical power and maintained low Type I error rate when compared with two recently proposed meta-analysis approaches. We applied CDEP to analyze microarray data from different laboratories that compared transcription profiles between metastatic and primary cancer of different types. Many genes identified as differentially expressed consistently across different cancer types are in pathways related to metastatic behavior, such as ECM-receptor interaction, focal adhesion, and blood vessel development. We also identified novel genes such as AMIGO2, Gem, and CXCL11 that have not been shown to associate with, but may play roles in, metastasis. CDEP is a flexible approach that borrows information from each dataset in a meta-analysis in order to identify genes being differentially expressed consistently. We have shown that CDEP can gain higher statistical power than other existing approaches under a variety of settings considered in the simulation study, suggesting its robustness and insensitivity to data variation commonly associated with microarray experiments. CDEP is implemented in R and freely available at: http://genomebioinfo.musc.edu/CDEP/. firstname.lastname@example.com.


Antiviral activity of the 3'-amino derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine.
3'-NH2-BV-dUrd, the 3'-amino derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, was found to be a potent and selective inhibitor of herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) replication. 3'-NH2-BV-dUrd was about 4-12 times less potent but equally selective in its anti-herpes activity as BV-dUrd. Akin to BV-dUrd, 3'-NH2-BV-dUrd was much less inhibitory to herpes simplex virus type 2 than type 1. It was totally inactive against a thymidine kinase-deficient mutant of HSV-1. The 5'-triphosphate of 3'-NH2-BV-dUrd (3'-NH2-BV-dUTP) was evaluated for its inhibitory effects on purified herpes viral and cellular DNA polymerases. Among the DNA polymerases tested, HSV-1 DNA polymerase and DNA polymerase alpha were the most sensitive to inhibition by 3'-NH2-BV-dUTP (Ki values 0.13 and 0.10 microM, respectively). The Km/Ki ratio for DNA polymerase alpha was 47, as compared with 4.6 for HSV-1 DNA polymerase. Thus, the selectivity of 3'-NH2-BV-dUrd as an anti-herpes agent cannot be ascribed to a discriminative effect of its 5'-triphosphate at the DNA polymerase level. This selectivity most probably resides at the thymidine kinase level. 3'-NH2-BV-dUrd would be phosphorylated preferentially by the HSV-1-induced thymidine kinase (Ki 1.9 microM, as compared with greater than 200 microM for the cellular thymidine kinase), and this preferential phosphorylation would confine the further action of the compound to the virus-infected cell.


Isolation of Legionella pneumophila from blood with the BACTEC system: a prospective study yielding positive results.
In a prospective study of 16 patients with Legionnaires disease confirmed by cultural isolation of Legionella pneumophila from the respiratory tract, 38% (6 of 16) had positive blood cultures. Daily subcultures were made onto buffered charcoal-yeast extract plates from 6B aerobic and 7C anaerobic BACTEC blood culture bottles (Johnston Laboratories, Inc., Towson, Md.). Isolation of L. pneumophila was achieved from both aerobic and anaerobic bottles. L. pneumophila growth indices failed to exceed the BACTEC threshold limits; thus, the organism would have been overlooked despite its presence in the blood culture bottles. Bacteremic patients had statistically significant higher quantities of L. pneumophila isolated from sputum and visualized on direct fluorescent antibody stains. Thus, the potential exists for improved diagnosis of Legionella infection by a relatively noninvasive procedure (blood culture) with an instrument already in use in many hospital laboratories.


A Promising High-Voltage Cathode Material Based on Mesoporous Na3 V2 (PO4 )3 /C for Rechargeable Magnesium Batteries.
The lack of suitable high-voltage cathode materials has hindered the development of rechargeable magnesium batteries (RMBs). Here, mesoporous Na3 V2 (PO4 )3 /C (NVP/C) spheres have been synthesized through a facile spray-drying-annealing method, and their electrochemically desodiated phase NaV2 (PO4 )3 /C (ED-NVP/C) has been investigated as an intercalation host for Mg2+ ions. The obtained ED-NVP/C exhibits an average discharge voltage of around 2.5 V (vs. Mg2+ /Mg), higher than those of most previously reported cathode materials. In addition, it can deliver an initial discharge capacity of 88.8 mA h g-1 at 20 mA g-1 , with good cycling stability. Ex situ X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) results demonstrate that the electrochemical reaction is based on an intercalation mechanism and shows good reversibility. Galvanostatic intermittent titration technique (GITT) data have revealed that the intercalation process involves a two-phase transition. The reported ED-NVP/C cathode material with high working voltage offers promising potential for application in RMBs.


Drugs to enhance athletic performance in the adolescent.
Why would any athlete expose himself to these pharmacologic agents? The most obvious answer is to improve performance. Since athletic performance is composed of so many variables, for example, attitude, diligence in training, strength, agility, and the competitive spirit, it is difficult to ascribe improvement in performance to any particular agent. It may be due to the placebo effect or to better or more efficient training, to say nothing about the effects of the normal maturational process. Certainly the peer pressure of others using these agents weighs heavily upon the adolescent's mind. Might peers have a competitive advantage? All of these points would be moot if it were not for the ready availability of many of these compounds. All are within reach of the athlete with a little knowledge of this subculture, and all are relatively inexpensive (with the exception of GH). They can be as tempting to adolescents as are brightly colored packages of household cleaners, vitamins, or flavored children's aspirin tablets to toddlers. Continuing with this analogy, one notes that most of the time children easily recover from accidental ingestions, but these instances, just as with drugs of adolescent and adult abuse, can be deadly.


Basal cell carcinoma within vulvar Paget's disease.
An 85-year-old Japanese woman had noticed erythema on her vulvar region 3 years before. The erythema gradually increased in size and followed erosion and ulceration with pigmentation on the edge of the erythema. A skin biopsy from the pigmented area showed large round cells with ample cytoplasm, which formed nests or glandular structures. In the dermis there was mass formation of basophilic cells and peripheral cells in a palisade arrangement. The tumor cells in the epidermis showed positive immunoreactivity for carcinoembryonic antigen; on the other hand, the dermal tumor was negative. We diagnosed that the tumor in the epidermis was vulvar Paget's disease, and the dermal tumor was a solid type of basal cell carcinoma. We speculate that the vulvar Paget's disease preceded and then the basal cell carcinoma developed in the area of Paget's disease. This is the first report in which basal cell carcinoma in the area of Paget's disease was documented.


SHARK FIN ECG PATTERN IN A PATIENT WITH TAKOTSUBO SYNDROME - CASE STUDY AND LITERATURE REVIEW.
Shark fin or triangular QRS-ST-T waveform ECG pattern, also known as lambda-wave ST elevation or giant R wave syndrome, is a particular ECG presentation where QRS complex, ST-segment and T-wave are fused in a unique complex. Originally described in some patients with ST-segment elevation myocardial infarction (STEMI) during the acute phase, it has been found to be associated with a high risk of ventricular fibrillation and cardiogenic shock as well as with a high in-hospital mortality. However, shark fin ECG pattern has also been reported in patients with non-acute coronary syndrome related ST-elevation (NASTEP), including stress-induced takotsubo syndrome (TTS). Fourteen such cases (all females) have been reported so far. The authors present a case of a 56-year-old male with shark fin ECG pattern associated with TTS triggered by burn injuries of head, back, upper, lower limbs and the respiratory tract. Due to respiratory insufficiency and heart failure with hemodynamic compromise, he required mechanical ventilation and catecholamines use. Echocardiography showed apical and midventricular akinesia with left ventricular ejection fraction and global longitudinal strain reduced to 30% and -6.8%, respectively and a high segmental post-systolic index. Shark fin pattern maintained within 2 days, then ST-T evolution was observed. Echocardiographic improvement followed by almost normalization were seen after 6 and 9 days, respectively. No cardiac arrhythmias were recorded as in most of the described cases with shark fin ECG and TTS.


Microarray analysis identifies a common set of cellular genes modulated by different HCV replicon clones.
Hepatitis C virus (HCV) RNA synthesis and protein expression affect cell homeostasis by modulation of gene expression. The impact of HCV replication on global cell transcription has not been fully evaluated. Thus, we analysed the expression profiles of different clones of human hepatoma-derived Huh-7 cells carrying a self-replicating HCV RNA which express all viral proteins (HCV replicon system). First, we compared the expression profile of HCV replicon clone 21-5 with both the Huh-7 parental cells and the 21-5 cured (21-5c) cells. In these latter, the HCV RNA has been eliminated by IFN-alpha treatment. To confirm data, we also analyzed microarray results from both the 21-5 and two other HCV replicon clones, 22-6 and 21-7, compared to the Huh-7 cells. The study was carried out by using the Applied Biosystems (AB) Human Genome Survey Microarray v1.0 which provides 31,700 probes that correspond to 27,868 human genes. Microarray analysis revealed a specific transcriptional program induced by HCV in replicon cells respect to both IFN-alpha-cured and Huh-7 cells. From the original datasets of differentially expressed genes, we selected by Venn diagrams a final list of 38 genes modulated by HCV in all clones. Most of the 38 genes have never been described before and showed high fold-change associated with significant p-value, strongly supporting data reliability. Classification of the 38 genes by Panther System identified functional categories that were significantly enriched in this gene set, such as histones and ribosomal proteins as well as extracellular matrix and intracellular protein traffic. The dataset also included new genes involved in lipid metabolism, extracellular matrix and cytoskeletal network, which may be critical for HCV replication and pathogenesis. Our data provide a comprehensive analysis of alterations in gene expression induced by HCV replication and reveal modulation of new genes potentially useful for selection of antiviral targets.


Adsorption of Carbonyl Sulfide on Propylamine Tethered to Porous Silica.
Carbonyl sulfide (COS) reacts slowly with amines in the aqueous solutions used to absorb CO2 from natural gas and flue gas and can also deactivate certain aqueous amines. The effects of COS on amines tethered to porous silica, however, have not been investigated before. Hence, the adsorption of COS on aminopropyl groups tethered to porous silica was studied using in situ IR spectroscopy. COS chemisorbed mainly and reversibly as propylammonium propylthiocarbamate ion pairs [R-NH(C═O)S-+H3N-R] under dry conditions. In addition, a small amount of another chemisorbed species formed slowly and irreversibly. Nevertheless, the CO2 capacities of the adsorbents were fully retained after COS was desorbed.


Familial occurrence of preeclampsia.
We conducted a cohort study on whether preeclampsia during the pregnancy of a mother is a risk factor for preeclampsia during the pregnancy of her daughter. Data from the Medical Birth Registry were combined with data from a local registry of births from 1955 to 1990. We could identify the births of 22,768 elder daughters and 2,959 younger daughters. These daughters had also experienced at least one delivery. If the mother had preeclampsia during her pregnancy with an elder daughter, then the elder daughter had an increased risk for preeclampsia in her first pregnancy (relative risk (RR) = 1.7; 95% confidence interval (CI) = 1.3-2.2). This increased risk persisted into the elder daughter's second pregnancy (RR = 1.7; 95% CI = 1.1-2.6). The risks for the daughters were also increased to a similar level if the mother had experienced preeclampsia in any other pregnancy. Furthermore, the risks were similarly elevated if only mothers with firstborn children were included in the analyses. Hence, preeclampsia during the pregnancy of a mother was a risk factor for development of preeclampsia during the pregnancy of her daughters; however, owing to a relatively small population attributable proportion, genetic predisposition explained only a minor part of the occurrence of preeclampsia in this population.


Effect of directly compressible excipient and treated agar on drug release of clopidogrel oral disintegrating tablets.
In the present investigation, oral dissolving/dispersible/disintegrating tablets (ODTs) of clopidogrel were designed with a view to enhance the bioavailability and patient compliance by two different methods, namely, direct compression and effervescent methods using directly compressible excipient and treated agar (TAG). In the direct compression method, TAG was used as a disintegrant and another method used a mixture of sodium bicarbonate and tartaric acid along with TAG as disintegrants. Among the directly compressed tablets, treated agar formulation 3 and among the effervescent tablets, treated agar and effervescent formulation 4 was found to be promising. Treated agar formulation 3 prepared by direct compression method emerged as an overall best formulation based on the in vitro drug release characteristics.


Measurement of the thermal inertia of the skin using successive thermograms taken at a stepwise change in ambient radiation temperature.
Skin thermal properties are difficult to measure in vivo in the steady state because there is a constant temperature gradient across the skin surface. However, measurement of skin thermal properties is postulated in quantitative evaluation for thermographic observation. In this study, imaging of the thermal inertia of the skin was attempted by thermographic measurements at a stepwise change in ambient radiation temperature achieved by quickly switching two hoods maintained at different temperatures. Using this technique, a total of 65 thermograms were sequentially recorded at intervals of 0.5 s beginning 2 s before the stepwise change. The image of skin thermal inertia was estimated by applying statistical curve fitting at each pixel of the thermograms. In addition, the emissivity and true temperature of the skin were also determined, together with thermal inertia, in a single measurement. Measurements were made at different sites on 10 subjects. The average values of thermal inertia of normal skin were scattered throughout a range from 1.4 x 10(3) to 2.1 x 10(3) W s1/2 m-2 K-1. Investigations of the relationship between skin blood flow and thermal inertia were also made by imaging thermal inertia when skin blood flow was changed by applying a vasodilator or vasoconstrictor on the skin surface. In a comparison with the data measured by laser Doppler flowmetry, the average slope of skin blood flow versus thermal inertia was 2.88 x 10(-4) V per W s1/2 m-2 K-1, and the thermal inertia of the skin with no blood flow was 1.03 x 10(3) W s1/2 m-2 K-1. The results also show an almost linear correlation between skin blood flow and thermal inertia in each individual, but inter-individual differences were also observed. The results suggest that skin blood flow distribution can be estimated by non-contact imaging of thermal inertia.


Size effects on atomic collapse in the dice lattice.
We study the role of size effects on atomic collapse of charged impurity in the flat band system. The tight-binding simulations are made for the dice lattice with circular quantum dot shapes. It is shown that the mixing of in-gap edge states with bound states in impurity potential leads to increasing the critical charge value. This effect, together with enhancement of gap due to spatial quantization, makes it more difficult to observe the dive-into-continuum phenomenon in small quantum dots. At the same time, we show that if in-gap states are filled, the resonant tunneling to bound state in the impurity potential might occur at much smaller charge, which demonstrates non-monotonous dependence with the size of sample lattice. In addition, we study the possibility of creating supercritical localized potential well on different sublattices, and show that it is possible only on rim sites, but not on hub site. The predicted effects are expected to naturally occur in artificial flat band lattices.


Baseline Lower Urinary Tract Symptoms in Patients Enrolled in LURN: A Prospective, Observational Cohort Study.
We described and compared the frequency and type of lower urinary tract symptoms reported by men and women at the time that they were recruited from urology and urogynecology clinics into the Symptoms of Lower Urinary Tract Dysfunction Research Network multicenter, prospective, observational cohort study. At 6 research sites treatment seeking men and women were enrolled who reported any lower urinary tract symptoms at a frequency more than rarely during the last month on the LUTS (Lower Urinary Tract Symptoms) Tool. At baseline the study participants underwent a standardized clinical evaluation and completed validated questionnaires. Urological tests were performed, including pelvic/rectal examination, post-void residual urine measurement and urinalysis. A total of 545 women and 519 men were enrolled in the study. Mean ± SD age was 58.8 ± 14.1 years. At baseline nocturia, frequency and a sensation of incomplete emptying were similar in men and women but men experienced more voiding symptoms (90% vs 85%, p = 0.007) and women reported more urgency (85% vs 66%, p <0.001). Women also reported more of any type of urinary incontinence than men (82% vs 51% p <0.001), which was mixed incontinence in 57%. Only 1% of men reported stress incontinence but they had other urinary incontinence, including post-void dribbling in 44% and urgency incontinence in 46%. Older participants had higher odds of reporting symptoms of nocturia and urgency. In this large, treatment seeking cohort of men and women lower urinary tract symptoms varied widely by gender and age. Men reported more voiding symptoms and nonstress or urgency urinary incontinence while women reported more incontinence overall and urgency. Older participants had greater odds of urgency and nocturia.


Long-term 238Pu and 239Pu retention and organ distribution in mice at low doses.
The 238Pu and 239Pu distribution in femur, liver, kidneys and testes and the retention function in the skeleton and liver have been studied in about 50 (C57 BL X C3H) F1 male mice. Groups of about 5-10 male mice were sacrificed from 10 to 800 days postinjection to cover their entire life span. All animals were injected intravenously with monomeric solutions of plutonium (1% trisodium citrate at pH 6.5) at doses of the order 7-15 kBq/kg body weight. The low levels of plutonium have been measured by direct counting in the entire animals and by radiochemical methods in the various tissues and organs. Significant differences between 238Pu and 239Pu were not observed at the injected doses used. The following proportions of the injected doses are retained in mice at the end of their life span: 12% in the skeleton, 0.7% in the liver, 0.1% in kidneys and 0.06% in gonads. Furthermore, the data have shown that (1) the long-term component of the plutonium skeleton retention in mice has a biological half-time that is much longer than their average life span; and (2) the long-term component of the plutonium liver retention in mice has a biological half-time of about 350 days.


Polygenic effects of schizophrenia on hippocampal grey matter volume and hippocampus-medial prefrontal cortex functional connectivity.
Schizophrenia is a complex mental disorder with high heritability and polygenic inheritance. Multimodal neuroimaging studies have also indicated that abnormalities of brain structure and function are a plausible neurobiological characterisation of schizophrenia. However, the polygenic effects of schizophrenia on these imaging endophenotypes have not yet been fully elucidated. To investigate the effects of polygenic risk for schizophrenia on the brain grey matter volume and functional connectivity, which are disrupted in schizophrenia. Genomic and neuroimaging data from a large sample of Han Chinese patients with schizophrenia (N = 509) and healthy controls (N = 502) were included in this study. We examined grey matter volume and functional connectivity via structural and functional magnetic resonance imaging, respectively. Using the data from a recent meta-analysis of a genome-wide association study that comprised a large number of Chinese people, we calculated a polygenic risk score (PGRS) for each participant. The imaging genetic analysis revealed that the individual PGRS showed a significantly negative correlation with the hippocampal grey matter volume and hippocampus-medial prefrontal cortex functional connectivity, both of which were lower in the people with schizophrenia than in the controls. We also found that the observed neuroimaging measures showed weak but similar changes in unaffected first-degree relatives of patients with schizophrenia. These findings suggested that genetically influenced brain grey matter volume and functional connectivity may provide important clues for understanding the pathological mechanisms of schizophrenia and for the early diagnosis of schizophrenia.


A System Architecture for Efficient Transmission of Massive DNA Sequencing Data.
The DNA sequencing data analysis pipelines require significant computational resources. In that sense, cloud computing infrastructures appear as a natural choice for this processing. However, the first practical difficulty in reaching the cloud computing services is the transmission of the massive DNA sequencing data from where they are produced to where they will be processed. The daily practice here begins with compressing the data in FASTQ file format, and then sending these data via fast data transmission protocols. In this study, we address the weaknesses in that daily practice and present a new system architecture that incorporates the computational resources available on the client side while dynamically adapting itself to the available bandwidth. Our proposal considers the real-life scenarios, where the bandwidth of the connection between the parties may fluctuate, and also the computing power on the client side may be of any size ranging from moderate personal computers to powerful workstations. The proposed architecture aims at utilizing both the communication bandwidth and the computing resources for satisfying the ultimate goal of reaching the results as early as possible. We present a prototype implementation of the proposed architecture, and analyze several real-life cases, which provide useful insights for the sequencing centers, especially on deciding when to use a cloud service and in what conditions.


Anterior knee pain after intramedullary nailing of fractures of the tibial shaft. A prospective, randomized study comparing two different nail-insertion techniques.
Anterior knee pain is the most common complication after intramedullary nailing of the tibia. Dissection of the patellar tendon and its sheath during nailing is thought to be a contributing cause of chronic anterior knee pain. The purpose of this prospective, randomized study was to assess whether the prevalence or the intensity of anterior knee pain following intramedullary nailing of a tibial shaft fracture is reduced by the use of a paratendinous incision for the nail entry portal. Fifty patients with a tibial shaft fracture requiring intramedullary nailing were randomized equally to treatment with paratendinous or transtendinous nailing. Twenty-one patients from both study groups were followed for an average of three years after nailing. After fracture union, all but two patients had elective nail removal through the same surgical approach as was used for the nailing. At the follow-up evaluation, the patients used visual analog scales to report their level of anterior knee pain and the impairment caused by that pain. The scales described by Lysholm and Gillquist and by Tegner et al., the Iowa knee scoring system, and simple functional tests were used to quantitate the functional results. Isokinetic thigh-muscle strength was also measured. Fourteen (67%) of the twenty-one patients treated with transtendinous nailing reported anterior knee pain at the final evaluation. Of these fourteen patients, thirteen were mildly to severely impaired by the pain. Fifteen (71%) of the twenty-one patients treated with paratendinous nailing reported anterior knee pain, and ten of the fifteen were impaired by the pain. The Lysholm, Tegner, and Iowa knee scoring systems; muscle-strength measurements; and functional tests showed no significant differences between the two groups. Compared with a transpatellar tendon approach, a paratendinous approach for nail insertion does not reduce the prevalence of chronic anterior knee pain or functional impairment by a clinically relevant amount after intramedullary nailing of a tibial shaft fracture.


The McDonaldization of appraisal? Doctors' views of the early impacts of medical revalidation in the United Kingdom.
Medical regulation is rapidly changing with claims that systems such as revalidation/relicensing will reassure the public. Yet the impact of such initiatives is unknown. Using the principles of efficiency, calculability, predictability and control through technology, identified by Ritzer, and exampled by the McDonalds business model, we analyzed interviews with doctors between May 2012-Dec 2013 which focused on doctor experiences of appraisal and revalidation in SW England. The research found significant changes in appraisals since the launch of revalidation in December 2012. Appraisal has been standardized with a list of supporting information that must be collected by doctors. The success of implementation is measured in the numbers of appraisals completed but less is known about the quality of the appraisal itself. Such efficiencies have been supported by IT systems that themselves might be at risk of driving the process. There are potential advantages to McDonaldization including appraisals available to all, not just for doctors working in the NHS, and a potentially more appetizing recipe for their completion. As yet a state of McAppraisal has not been reached; with a complete transfer of trust in the doctor to trust in the appraisal process within revalidation. However policymakers will need to continue to ensure that regulatory initiatives, such as revalidation, are not just a process for their own sake.


Chk1 versus Cdc25: chking one's levels of cellular proliferation.
This review summarizes recent studies which have provided new insight into the mechanisms by which the DNA damage response kinase, Chk1 inhibits the dual specificity phosphatase, Cdc25, and thereby regulates cell cycle progression. Recently, Chk1 has been shown to not only regulate Cdc25A degradation but also its ability to interact with various Cdk complexes through phosphorylation of the carboxy-terminus of the phosphatase. Surprisingly, these effects appear to be specific for Chk1, but not Chk2, which may explain the recently reported in vivo haploinsufficiency phenotype observed in the mammary gland using a Chk1 conditional mouse model.


Relational use of an electronic quality of life and practice support system in hospital palliative consult care: A pilot study.
This study is part of an overarching research initiative on the development and integration of an electronic Quality of Life and Practice Support System (QPSS) that uses patient-reported outcome and experience measures in clinical practice. The current study focused on palliative nurse consultants trialing the QPSS with older hospitalized adults receiving acute care. The primary aim of the study was to better understand consultants' and patients' experiences and perspectives of use. The project involved two nurse specialists within a larger palliative outreach consult team (POCT) and consenting older adult patients (age 55+) in a large tertiary acute care hospital in western Canada. User-centered design of the QPSS was informed by three focus groups with the entire POCT team, and implementation was evaluated by direct observation as well as interviews with the POCT nurses and three patients. Thematic analysis of interviews and field notes was informed by theoretical perspectives from social sciences. Over 9 weeks, the POCT nurses used the QPSS at least once with 20 patients, for a total of 47 administrations. The nurses most often assisted patients in using the QPSS. Participants referenced three primary benefits of relational use: enhanced communication, strengthened therapeutic relations, and cocreation of new insights about quality of life and care experiences. The nurses also reported increased visibility of quality of life concerns and positive development as relational care providers. Participants expressed that QPSS use positively influenced relations of care and enhanced practices consistent with person-centered care. Results also indicate that electronic assessment systems may, in some instances, function as actor-objects enabling new knowledge and relations of care rather than merely as a neutral technological platform. This is the first study to examine hospital palliative consult clinicians' use of a tablet-based system for routine collection of patient-reported outcome and experience measures.


Self-ratiometric fluorescence approach based on plant extract-assisted synthesized silver nanoparticles for the determination of vanillin.
The current study designed and applied a novel self-ratiometric fluorescent nanosensor composed of green-synthesized silver nanoparticles (Ag-NPs) to determine vanillin in adult and infant foods and human plasma. A straightforward microwave-assisted approach is proposed for synthesizing Ag-NPs in less than 1 min using a reducing agent, tailed pepper seed extract. The synthesized Ag-NPs had a strong fluorescence with an intense emission band at 360 nm and a shoulder peak at 430 nm when excited at 265 nm. Upon interaction with vanillin, the fluorescence peak of Ag-NPs at 360 nm decreases in a concentration-dependent manner while being shifted to a longer wavelength, 385 nm. Meanwhile, the shoulder fluorescence peak at 430 nm is only slightly affected by vanillin addition. Thus, a new Ag-NP self-ratiometric probe was designed and validated for vanillin determination using the peak at 385 nm and the shoulder peak at 430 as two built-in reference peaks. The optimized system accurately measured vanillin with a detection limit of 9.0 ng/mL and a linear range of 0.05-8.0 μg/mL without needing pre-derivatization or high-cost instrumentation. The method successfully measured vanillin in adult and infant milk formula, biscuits, and human plasma samples with high percentage recoveries (95.3-104.6%) and excellent precision (relative SD; ≤3.85%).


The German VR Simulation Realism Scale--psychometric construction for virtual reality applications with virtual humans.
Virtual training applications with high levels of immersion or fidelity (for example for social phobia treatment) produce high levels of presence and therefore belong to the most successful Virtual Reality developments. Whereas display and interaction fidelity (as sub-dimensions of immersion) and their influence on presence are well researched, realism of the displayed simulation depends on the specific application and is therefore difficult to measure. We propose to measure simulation realism by using a self-report questionnaire. The German VR Simulation Realism Scale for VR training applications was developed based on a translation of scene realism items from the Witmer-Singer-Presence Questionnaire. Items for realism of virtual humans (for example for social phobia training applications) were supplemented. A sample of N = 151 students rated simulation realism of a Fear of Public Speaking application. Four factors were derived by item- and principle component analysis (Varimax rotation), representing Scene Realism, Audience Behavior, Audience Appearance and Sound Realism. The scale developed can be used as a starting point for future research and measurement of simulation realism for applications including virtual humans.


Transcranial direct current stimulation induces long-term potentiation-like plasticity in the human visual cortex.
Transcranial direct current stimulation (tDCS) is increasingly used as a form of noninvasive brain stimulation to treat psychiatric disorders; however, its mechanism of action remains unclear. Prolonged visual stimulation (PVS) can enhance evoked EEG potentials (visually evoked potentials, VEPs) and has been proposed as a tool to examine long-term potentiation (LTP) in humans. The objective of the current study was to induce and analyze VEP plasticity and examine whether tDCS could either modulate or mimic plasticity changes induced by PVS. Thirty-eight healthy participants received tDCS, PVS, either treatment combined or neither treatment, with stimulation sessions being separated by one week. One session consisted of a baseline VEP measurement, one stimulation block, and six test VEP measurements. For PVS, a checkerboard reversal pattern was presented, and for tDCS, a constant current of 1 mA was applied via each bioccipital anodal target electrode for 10 min (Fig. S1). Both stimulation types decreased amplitudes of C1 compared to no stimulation (F = 10.1; p = 0.002) and led to a significantly smaller increase (PVS) or even decrease (tDCS) in N1 compared to no stimulation (F = 4.7; p = 0.034). While all stimulation types increased P1 amplitudes, the linear mixed effects model did not detect a significant difference between active stimulation and no stimulation. Combined stimulation induced sustained plastic modulation of C1 and N1 but with a smaller effect size than what would be expected for an additive effect. The results demonstrate that tDCS can directly induce LTP-like plasticity in the human cortex and suggest a mechanism of action of tDCS relying on the restoration of dysregulated synaptic plasticity in psychiatric disorders such as depression and schizophrenia.


Adenovirus E1A coding sequences that enable ras and pmt oncogenes to transform cultured primary cells.
Plasmids expressing partial adenovirus early region 1A (E1A) coding sequences were tested for activities which facilitate in vitro establishment (immortalization) of primary baby rat kidney cells and which enable the T24 Harvey ras-related oncogene and the polyomavirus middle T antigen (pmt) gene to transform primary baby rat kidney cells. E1A cDNAs expressing the 289- and 243-amino acid proteins expressed both E1A transforming functions. Mutant hrA, which encodes a 140-amino acid protein derived from the amino-terminal domain shared by the 289- and 243-amino acid proteins, enabled ras (but not pmt) to transform and facilitated in vitro establishment to a low, but detectable, extent. These studies suggest that E1A functions which collaborate with ras oncogenes and those which facilitate establishment are linked. Furthermore, E1A transforming functions are not associated with activities of the 289-amino acid E1A proteins required for efficient transcriptional activation of viral early region promoters.


[The classification of streptococci and human streptococcal diseases].
The modern nomenclature, phenotypic, medical, ecological and phylogenetic classification of streptococci and different classification of streptococcal human diseases are presented. All phylogenetic groups of streptococci have been shown to contain species causing diseases in man. The most medically significant groups are the phylogenetic groups Pyogenes and Mitis. Directions of the improvement of the classification of streptococci and streptococcal human diseases on the basis of modern concepts on the taxonomy of streptococci, the biological properties and ecology of the infective agents, as well as the genesis and clinical picture of diseases induced by them, have been determined.


Popliteal vein aneurysm causing pulmonary embolus.
A case of pulmonary embolus arising from a popliteal vein aneurysm is reviewed. These aneurysms are believed to be developmental in origin; with the exception of embolic phenomenon, these venous anomalies are generally asymptomatic. To our knowledge, only six cases have been previously reported. Physical examination was not helpful, and noninvasive studies were of no value in detecting the aneurysm. Venography was the only reliable diagnostic test. Because popliteal vein aneurysms are a potential source of emboli, surgical intervention is recommended. Venous aneurysmorrhaphy or excision of the aneurysm with a venous bypass are the surgical procedures most often carried out. Aneurysmorrhaphy appears to be associated with an unacceptably high rate of thrombosis; excision with placement of a vein graft may be a more satisfactory alternative.


The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question.
Choosing Wisely® is a medical stewardship and quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States. The ASH is an active participant in the Choosing Wisely® project. Using an iterative process and an evidence-based method, ASH has identified 5 tests and treatments that in some circumstances are not well supported by evidence and which in certain cases involve a risk of adverse events and financial costs with low likelihood of benefit. The ASH Choosing Wisely® recommendations focus on avoiding liberal RBC transfusion, avoiding thrombophilia testing in adults in the setting of transient major thrombosis risk factors, avoiding inferior vena cava filter usage except in specified circumstances, avoiding the use of plasma or prothrombin complex concentrate in the nonemergent reversal of vitamin K antagonists, and limiting routine computed tomography surveillance after curative-intent treatment of non-Hodgkin lymphoma. We recommend that clinicians carefully consider anticipated benefits of the identified tests and treatments before performing them.


Genome-wide analysis of the citrus B3 superfamily and their association with somatic embryogenesis.
In citrus, genetic improvement via biotechnology is hindered by the obstacle of in vitro regeneration via somatic embryogenesis (SE). Although a few B3 transcription factors are reported to regulate embryogenesis, little is known about the B3 superfamily in citrus, and which members might be involved in SE. Genome-wide sequence analysis identified 72 (CsB3) and 69 (CgB3) putative B3 superfamily members in the genomes of sweet orange (Citrus sinensis, polyembryonic) and pummelo (C. grandis, monoembryonic), respectively. Genome duplication analysis indicated that segmental and tandem duplication events contributed to the expansion of the B3 superfamily in citrus, and that the B3 superfamily evolved under the effect of purifying selection. Phylogenetic relationships were well supported by conserved gene structure and motifs outside the B3 domain, which allowed possible functions to be inferred by comparison with homologous genes from Arabidopsis. Expression analysis identified 23 B3 superfamily members that were expressed during SE in citrus and 17 that may play functional roles at late SE stages. Eight B3 genes were identified that were specific to the genome of polyembryonic sweet orange compared to monoembryonic pummelo. Of these eight B3 genes, CsARF19 was found to be specifically expressed at higher levels in embryogenic callus (EC), implying its possible involvement in EC initiation. This study provides a genome-wide analysis of the citrus B3 superfamily, including its genome organization, evolutionary features and expression profiles, and identifies specific family members that may be associated with SE.


Multicenter clinical trial of the NexStent coiled sheet stent in the treatment of extracranial carotid artery stenosis: immediate results and late clinical outcomes.
Carotid angioplasty with stent placement has been proposed as an alternative method for revascularization of carotid artery (CA) stenosis. A novel stent with a coiled sheet design (NexStent; EndoTex Interventional Systems, Inc., Cupertino, CA) has been introduced because it provides improved flexibility over conventional tubular designs during navigation through tortuous arterial segments. The authors report the results of a multicenter study in which they evaluated the safety, feasibility, and effectiveness of this stent in the treatment of CA stenosis. Enrollment was limited to patients with 70% or more symptomatic or asymptomatic stenosis of the internal CA. The primary end point was a technically successful implantation procedure (delivery of the stent to the target siteand retrieval of the delivery device) resulting in less than 30% residual stenosis on angiograms obtained immediately postprocedure and no death or ipsilateral stroke immediately after or within 30 days following the procedure. The secondary effectiveness end point was prevention of an ipsilateral stroke within 31 days to 1 year postprocedure. The tertiary effectiveness end point was less than 70% residual stenosis demonstrated on CA Doppler ultrasonography performed at 6 and 12 months. Forty-four patients (mean age 71 years, range 51-89 years; 30 patients were men and 18 [41%] had symptomatic stenotic lesions) were treated using 45 NexStents (two stents were placed in one patient). Residual stenosis on postprocedure angiograms was less than 30% in all patients. The 1-month primary end point was achieved in 41 patients (93%). The three major adverse events that occurred within 30 days were one death related to congestive heart failure and two ipsilateral strokes, one of which resulted in death. No ipsilateral stroke occurred between 1 and 12 months postprocedure among 35 patients who completed the follow-up evaluation. Asymptomatic recurrent stenosis was identified in one patient at 6 months postprocedure, requiring the performance of repeated angioplasty. Placement of the NexStent was feasible and resulted in the effective treatment of patients with CA stenosis, with promising long-term results.


Ten-year follow-up of cluster-based asthma phenotypes in adults. A pooled analysis of three cohorts.
The temporal stability of adult asthma phenotypes identified using clustering methods has never been addressed. Longitudinal cluster-based methods may provide novel insights in the study of the natural history of asthma. To compare the stability of cluster-based asthma phenotype structures a decade apart in adults and to address the individuals' phenotypic transition across these asthma phenotypes. The latent transition analysis was applied on longitudinal data (twice, 10 yr apart) from 3,320 adults with asthma who took part in the European Community Respiratory Health Survey, the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, or the Epidemiological Study on Genetics and Environment of Asthma. Nine variables covering personal and phenotypic characteristics measured twice, 10 years apart, were simultaneously considered. Latent transition analysis identifies seven asthma phenotypes (prevalence range, 8.4-20.8%), mainly characterized by the level of asthma symptoms (low, moderate, high), the allergic status, and pulmonary function. Phenotypes observed 10 years apart showed strong similarities. The probability of membership in the same asthma phenotype at both times varied across phenotypes from 54 to 88%. Different transition patterns were observed across phenotypes. Transitions toward increased asthma symptoms were more frequently observed among nonallergic phenotypes as compared with allergic phenotypes. Results showed a strong stability of the allergic status over time. Adult asthma phenotypes identified by a clustering approach, 10 years apart, were highly consistent. This study is the first to model the probabilities of transitioning over time between comprehensive asthma phenotypes.


[Synthesis and binding characteristics of an artificial receptor for biogenic amines].
The synthesis of a ditopic linear receptor 3 consisting of an azacrown ether moiety for binding prim. ammonium functions and a macrotricyclic tetrahedral moiety for binding hydrophobic guest species is described. The covalent interconnection of these subunits was supposed to constitute a receptor with enhanced specificity towards dopamine-type biogenic amines. Host-guest complexation was studied in a competition method with potassium ion using ion selective electrodes. The binding features of 3 with a series of biogenic amines reveal that neither the absolute binding strength nor the selectivity is enhanced in relation to the monotopic receptor 4. It is concluded that 3 does not simultaneously utilize both receptor subunits in binding the biogenic amine substrates.


The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages.
To investigate the sonoactivity of hypericin (HY), together with its sonodynamic effect on THP-1 macrophages and the underlying mechanism. CCK-8 was used to examine cell viability. Confocal laser scanning microscopy was performed to assess the localization of HY in cells, reactive oxygen species (ROS) generation, and opening of the mitochondrial permeability transition pore (mPTP) after different treatments. Apoptosis was analyzed using Hoechst-propidium iodide and transmission electron microscopy. Mitochondrial membrane potential (ΔΨm) collapse was detected via fluorescence microscopy. Lipoprotein oxidation was determined in malondialdehyde (MDA) assays. Western blotting was conducted to determine the translocation of BAX and cytochrome C and the expression of apoptosis-related proteins. HY was sublocalized among the nuclei and the mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome in the cytosol of THP-1 macrophages. Under low-intensity ultrasound irradiation, HY significantly decreased cell viability and induced apoptosis. Furthermore, greater ROS generation, higher MDA levels, and greater ΔΨm loss were observed in the sonodynamic therapy (SDT) group. Both ROS generation and MDA levels were significantly reduced by the ROS scavenger N-acetyl cysteine (NAC) and the singlet oxygen scavenger sodium azide. Most of the loss of ΔΨm was inhibited by pretreatment with NAC, sodium azide, and the mPTP inhibitor cyclosporin A (CsA). mPTP opening was induced upon SDT but was reduced by pretreatment with bongkrekic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium, CsA, and NAC. Western blot analyses revealed translocation of BAX and cytochrome C, downregulated expression of Bcl-2, and upregulated expression of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase in the SDT group, which were reversed by NAC. HY mediated SDT-induced apoptosis in THP-1 macrophages via ROS generation. Then, the proapoptotic factor BAX translocated from the cytosol to the mitochondria, increasing the ratio of BAX/Bcl-2, and the mPTP opened to release cytochrome C. This study demonstrated the great potential of HY-mediated SDT for treating atherosclerosis.


Artificial Intelligence for Diabetes Management and Decision Support: Literature Review.
Artificial intelligence methods in combination with the latest technologies, including medical devices, mobile computing, and sensor technologies, have the potential to enable the creation and delivery of better management services to deal with chronic diseases. One of the most lethal and prevalent chronic diseases is diabetes mellitus, which is characterized by dysfunction of glucose homeostasis. The objective of this paper is to review recent efforts to use artificial intelligence techniques to assist in the management of diabetes, along with the associated challenges. A review of the literature was conducted using PubMed and related bibliographic resources. Analyses of the literature from 2010 to 2018 yielded 1849 pertinent articles, of which we selected 141 for detailed review. We propose a functional taxonomy for diabetes management and artificial intelligence. Additionally, a detailed analysis of each subject category was performed using related key outcomes. This approach revealed that the experiments and studies reviewed yielded encouraging results. We obtained evidence of an acceleration of research activity aimed at developing artificial intelligence-powered tools for prediction and prevention of complications associated with diabetes. Our results indicate that artificial intelligence methods are being progressively established as suitable for use in clinical daily practice, as well as for the self-management of diabetes. Consequently, these methods provide powerful tools for improving patients' quality of life.


Ligand-based Pharmacophore Model for Generation of Active Antidepressant- like Agents from Substituted 1,3,5 Triazine Class.
Although the transition of a lead candidate into a drug is currently structured by well-defined milestone, it is still most challenging and offers no guarantee in success to the end. In fact, ligand-based pharmacophore modeling has become a key motive force for retrieving potential leads across several therapeutic areas. An urgent need towards the development of novel antidepressant agents led us to generate a pharmacophore model from an existing 44 compounds dataset. The best model with one hydrophobic, two ring aromatic, and one positive ionization features was chosen on behalf of the correlation coefficient, sensitivity, specificity, yield of actives and accuracy measures using HypoGen module of Discovery Studio. In house library consisting of 10,000 substituted 1,3,5 triazine derivatives were shortlisted to select four insilico hits. All shortlisted compounds were synthesized and characterized by FTIR, 1H-& 13C-NMR spectroscopy and finally tested for antidepressant-like activity using behavioral models on rats viz. Forced Swim Test (FST) and Elevated Plus Maze (EPM). Two shortlisted compounds with optimal fit values showed a significant decrease in the duration of immobility as compared to standard drug Imipramine in FST while time spent in open arm in enhanced in case of EPM.


[Total obstruction of the anterior interventricular artery without myocardial infarction].
Complete proximal occlusion of the the anterior interventricular artery was associated with the presence (group A: 31 cases) or the absence (group B: 31 cases) of transmural myocardial necrosis in the corresponding territory. The aim of this study was to define the factors which determine the development of permanent myocardial necrosis, on the basis of clinical, electrocardiographic, haemodynamic and angiographic criteria. Group B was characterised by the following features: almost all of the patients (30 out of 31) had unstable angina, for less than 2 months in half of the cases; 67% of cases presented an abnormality of ventricular repolarisation on the resting ECG, usually (54 per cent of cases) in leads V3 to V5, suggestive of isolated sub-pericardial ischaemia in half of these cases; 24 cases presented moderate regional hypokinesia in the anteroapical territory of the LV; the distal AIV artery was more clearly visualised (17 cases had a well perfused AIV artery compared with 6 in group A) and a greater number of patients obtained homocoronary interseptal re-perfusion (8 versus 2) and heterocoronary re-perfusion by distal anastomosis of the AIV artery and the PIV artery by the apex (13 versus 3) (p less than 0.05) than in group A. However, the possibility of surgery was considered to be limited (39%) on the basis of the angiographic criteria. Thus, in group B, a "phantom AIV artery syndrome" can not be distinguished from unstable angina on the basis of the clinical and electrocardiographic profile.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of the influence of bacteriophage titer on the treatment of colibacillosis in broiler chickens.
Two studies were conducted to determine the efficacy of bacteriophage SPR02 and DAF6 at varying titers to treat colibacillosis in chickens. In Study 1, the treatments consisted of a control, i.m. injection of bacteriophage SPR02 or DAF6, Escherichia coli airsac challenge, and E. coli challenge followed by treatment at different titers with bacteriophage SPR02 or DAF6. The E. coli- challenged birds were injected with 6 x 10(4) cfu into the left thoracic airsac at 7 d of age. Immediately after the birds were challenged with E. coli, they were treated by administration of bacteriophage SPR02 or DAF6 by i.m. injection into the left thigh with 4 x 10(8), 10(6), 10(4), or 10(2) pfu. Study 2 was identical to Study 1, with the exception that the E. coli challenge was increased to 9 x 10(4) cfu, and the titers of SPR02 and DAF6 were slightly less at 3 x 10(8), 10(6), 10(4), and 10(2) pfu. Both studies were concluded when the birds were 3 wk of age. Mortality in the birds challenged with E. coli in Studies 1 and 2 was 48 and 47%, respectively. The only consistently effective bacteriophage treatment was the highest titer (10(8) pfu) of bacteriophage SPR02, which significantly reduced mortality from 48 and 47% in the birds only challenged with E. coli (positive control) to 7% in both studies, which was not significantly different from the unchallenged negative control treatments. These studies indicate that an effective multiplicity of infection for i.m. treatment with SPR02 was 10(4) in this experimental model of colibacillosis. Bacteriophage administered at sufficient titers can be effective therapeutic agents and provide an alternative to antibiotics in the treatment of bacterial diseases.


Super Gas Barrier of a Polyelectrolyte/Clay Coacervate Thin Film.
Transparent polymeric thin films with high oxygen barrier are important for extending the shelf life of food and protecting flexible organic electronic devices. Polyelectrolyte/clay multilayer nanocoatings are shown to exhibit super gas barrier performance, but the layer-by-layer assembly process requires numerous deposition steps. In an effort to more quickly fabricate this type of barrier, a polyelectrolyte/clay coacervate composed of branched polyethyleneimine (PEI), poly(acrylic acid) (PAA), and kaolinite (KAO) clay is prepared and deposited in a single step, followed by humidity and thermal post-treatments. When deposited onto a 179 µm poly(ethylene terephthalate) (PET) film, a 4 µm coacervate coating reduces the oxygen transmission rate (OTR) by more than three orders of magnitude, while maintaining high transparency. This single-step deposition process uses only low-cost, water-based components and ambient conditions, which can be used to for sensitive food and electronics packaging.


Pulsatile Load Components, Resistive Load and Incident Heart Failure: The Multi-Ethnic Study of Atherosclerosis (MESA).
Left ventricular (LV) afterload is composed of systemic vascular resistance (SVR) and components of pulsatile load, including total arterial compliance (TAC), and reflection magnitude (RM). RM, which affects the LV systolic loading sequence, has been shown to strongly predict HF. Effective arterial elastance (Ea) is a commonly used parameter initially proposed to be a lumped index of resistive and pulsatile afterload. We sought to assess how various LV afterload parameters predict heart failure (HF) risk and whether RM predicts HF independently from subclinical atherosclerosis. We studied 4345 MESA participants who underwent radial arterial tonometry and cardiac output (CO) measurements with the use of cardiac MRI. RM was computed as the ratio of the backward (Pb) to forward (Pf) waves. TAC was approximated as the ratio of stroke volume (SV) to central pulse pressure. SVR was computed as mean pressure/CO. Ea was computed as central end-systolic pressure/SV. During 10.3 years of follow-up, 91 definite HF events occurred. SVR (P = .74), TAC (P = .81), and Ea (P = .81) were not predictive of HF risk. RM was associated with increased HF risk, even after adjustment for other parameters of arterial load, various confounders, and markers of subclinical atherosclerosis (standardized hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.18-1.88; P = .001). Pb was also associated with an increased risk of HF after adjustment for Pf (standardized HR 1.43, 95% CI 1.17-1.75; P = .001). RM is an important independent predictor of HF risk, whereas TAC, SVR, and Ea are not. Our findings support the importance of the systolic LV loading sequence on HF risk, independently from subclinical atherosclerosis.


Molecular aspects of gene transfer and foreign DNA acquisition in prokaryotes with regard to safety issues.
Horizontal gene transfer (HGT) is part of prokaryotic life style and a major factor in evolution. In principle, any combinations of genetic information can be explored via HGT for effects on prokaryotic fitness. HGT mechanisms including transformation, conjugation, transduction, and variations of these plus the role of mobile genetic elements are summarized with emphasis on their potential to translocate foreign DNA. Complementarily, we discuss how foreign DNA can be integrated in recipient cells through homologous recombination (HR), illegitimate recombination (IR), and combinations of both, site-specific recombination, and the reconstitution of plasmids. Integration of foreign DNA by IR is very low, and combinations of IR with HR provide intermediate levels compared to the high frequency of homologous integration. A survey of studies on potential HGT from various transgenic plants indicates very rare transfer of foreign DNA. At the same time, in prokaryotic habitats, genes introduced into transgenic plants are abundant, and natural HGT frequencies are relatively high providing a greater chance for direct transfer instead of via transgenic plants. It is concluded that potential HGT from transgenic plants to prokaryotes is not expected to influence prokaryotic evolution and to have negative effects on human or animal health and the environment.


Characterization of the ion transport responses to ADH in the MDCK-C7 cell line.
The Madin-Darby canine kidney (MDCK) cell line expresses many characteristics of the renal collecting duct. The MDCK-C7 subclone forms a high-resistance, hormone-responsive model of the principal cells, which are found in distal sections of the renal tubule. The electrophysiological technique of short-circuit current measurement was used to examine the response to antidiuretic hormone (ADH) in the MDCK-C7 clone. Three discrete electrogenic ion transport phenomena can be distinguished temporally and by the use of inhibitors and effectors. Initially the cells exhibit anion secretion through the cystic fibrosis transmembrane conductance regulator (CFTR). The presence of CFTR was confirmed by immunoprecipitation followed by Western blotting. The CFTR-mediated anion secretion is transient and is followed, in time, by a verapamil- and Ba(+)-sensitive anion secretion or cation absorption and, finally, by Na+ reabsorption via epithelial Na+ channels (ENaC). In contrast to other studies of MDCK cells, we see no indication that the presence of CFTR functionally inhibits ENaC. The characterization of the various ion transport phenomena substantiates this cell line as a model renal epithelium that can be used to study the hormonal and metabolic regulation of ion transport.


Novel resuscitation strategy for pulmonary contusion after severe chest trauma.
Adenosine A2a receptor stimulation can increase coronary perfusion and also reduce leukocyte-mediated inflammatory responses in some conditions. Hextend is a novel colloid solution that may have antioxidant properties. All these actions might be beneficial after severe chest trauma, but have never been investigated. To fill these gaps, this study evaluated the therapeutic potential of a novel adenosine A2a agonist during fluid resuscitation from severe chest trauma with either standard-of-care crystalloid or Hextend. Anesthetized, ventilated swine received unilateral, blunt trauma to the right chest via captive bolt gun, followed by a 10- to 12-mL/kg arterial hemorrhage. After 25 minutes of shock, ATL-146e was started (10 ng/kg/min intravenously for 180 minutes). After an additional 5 minutes, the minimum amount of either colloid (Hextend, 5% hetastarch in lactate-buffered, balanced electrolyte solution) or crystalloid (lactated Ringer's [LR] solution) was administered to maintain mean arterial pressure > 70 mm Hg and heart rate < 100 beats/min and to correct lactate for 180 minutes postinjury. Cardiopulmonary function was monitored and serial bronchoalveolar lavage samples were analyzed for protein, leukocyte infiltration, and expression of cyclooxygenase (COX)-1 and COX-2 isozymes as markers of the inflammatory cascade. Fluid requirements were reduced by half with Hextend compared with LR (p < 0.05). ATL-146e in either Hextend or LR transiently increased cardiac output, cardiac contractility, and systemic oxygen delivery (all p < 0.05). Pao(2)/Fio(2) ratio was 50 to 100 higher and bronchoalveolar lavage leukocytes were reduced by half with Hextend versus LR (both p < 0.05), but there was no added effect of ATL-146e. COX-1 expression was induced in macrophages (Mphis), whereas COX-2 was induced in neutrophils. Neither Hextend nor ATL-146e reduced COX expression. Hextend reduced the volume for initial resuscitation, which may offer logistical advantages in prehospital field conditions or whenever there is limited medical resources or prolonged transport times; ATL-146e improved early cardiac performance without causing hypotension or bradycardia; when administered 25 to 30 minutes after injury, neither Hextend nor ATL-146e altered inflammatory changes in pulmonary Mphis or infiltrating PMNs; and further studies are needed to determine whether these short-term benefits correlate with long-term outcome.


Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry.
To determine the effectiveness of vagus nerve stimulation (VNS) therapy among patients with persistent or recurrent seizures after lobar resection, callosotomy, and other cranial operations for intractable epilepsy. Data were obtained from the VNS therapy patient outcome registry, which was established after United States Food and Drug Administration approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. Two nonconsecutive cohorts were compared: patients tracked in the registry who had previously undergone cranial surgery for epilepsy (CS group, n=921) and those who had not (non-CS group, n = 3822). For the CS group, the median reduction in seizure frequency was 42.5% after 3 months of VNS therapy, 42.9% at 6 months, 45.7% at 12 months, 52.0% at 18 months, and 50.5% at 24 months. For the non-CS group, analogous rates were 47.0%, 52.9%, 60.0%, 62.7%, and 66.7%, respectively. In the CS group, seizures were reduced by at least 50% in 55.1% of patients, at least 75% in 31.4% of patients, at least 90% in 17.3% of patients, and 100% in 5.1% of patients after 24 months of VNS therapy. Response rates were more pronounced in the non-CS group: at least 50% in 62.2% of patients, at least 75% in 43.7% of patients, at least 90% in 26.8% of patients, and 100% in 8.3% of patients. Patients in both groups experienced marked improvements in quality of life parameters. The effectiveness of VNS is maintained during prolonged stimulation, and overall seizure control continues to improve with time. Patients in whom prior cranial surgery had failed did not respond as favorably as all other patients receiving VNS therapy. Nonetheless, many of the former group improved substantially. Thus, on the basis of these open-label data, VNS therapy represents a potentially palliative treatment option for patients with refractory seizures after failed cranial surgery.


"Many wasted months": Stakeholders' perspectives about waiting for speech-language pathology services.
Purpose: High demand for speech-language pathology services is reflected in long waiting lists. Waiting can be active or passive and has implications for stakeholders, including consumers, professionals, and organisations. The present study explored experiences and perspectives regarding waiting for speech-language pathology services through analysis of stakeholders' written submissions to an Australian Government Senate Inquiry.Method: Written submissions (n = 337) were screened for terms related to waiting. Included submissions (n = 133) were written by organisations (36.8%), speech-language pathologists (29.3%), parents (27.8%), individuals with communication and/or swallowing difficulties (5.3%), and others.Result: Inductive thematic analysis identified three themes. (1) Duration. Consistently described as long. (2) Consequences. Consumers' consequences included: burden on physical health, finances, time, emotional wellbeing, and relationships, reduced continuity of care, and increased intervention needs. Professional consequences included: stress and burnout impacting job satisfaction, and reduced effectiveness. Societal consequences included: social and ethical burden, and a drain on health and legal systems. (3) Actions. Consumers advocated and sought alternatives (e.g. threats to harm their child, relocation to a capital city), professionals implemented service delivery and policy actions, and organisations lacked effective system-wide strategies.Conclusion: Existing services did not appear to meet stakeholders' needs. Action is needed to improve speech-language pathology waiting lists and access to services, and minimise possible consequences for stakeholders.


Familial external angular dermoid: evidence for a genetic link?
Congenital craniofacial dermoid cysts are hamartomas of ectodermal and mesodermal origin, made up of keratinizing epithelium lining a cavity containing dermal skin appendages. They usually present as an asymptomatic, firm, round mass, usually noticed at birth or in the first year. They are thought to occur as a result of ectodermal sequestration at lines of fusion during embryological development. Although nasal and epibulbar dermoid cysts have occurred in families and have been associated with inheritable gene defects, there has previously been no evidence for a similar etiology in external angular cases. We present the first description of external angular dermoids occurring in siblings suggesting that this subgroup may, in some instances, also have a genetic origin.


Chronic granulomatous disease. Expression of the metabolic defect by in vitro culture of bone marrow progenitors.
Chronic granulomatous disease (CGD), an often fatal syndrome of recurrent infections results from the inability of patients' peripheral blood phagocytic leukocytes to generate superoxide despite otherwise normal phagocytic functions such as ingestion and degranulation. Circulating granulocytes and monocytes are the progeny of bone marrow progenitor cells, colony-forming units in culture. We compared the function of cells grown in two different in vitro cuture systems from the bone marrow of a CGD patient with those from normal subjects. The cells of normal colony-forming unit in culture colonies grown in semisolid medium reduced nitroblue tetrazolium dye when stimulated by phorbol myristate acetate; none of the cells from colonies derived from CGD marrow did so. Cells grown in liquid suspension culture from normal marrow generated superoxide nearly as well as normal peripheral blood granulocytes; those from CGD marrow produced no superoxide, similarly cultured cells from both normal and CGD marrow ingested opsonized bacteria at rates equal to peripheral blood granulocytes. CGD marrow-derived cells showed increased exocytic degranulation relative to both normal marrow-derived cells and normal peripheral blood granulocytes. These studies demonstrate that the basic functional characteristics of CGD are embedded in the genetic program of granulocyte progenitors.