Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke.
This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl-2 gene expression (the activity of which improves cell survival), upregulated excision repair cross-complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.


Using experimental and computational energy equilibration to understand hierarchical self-assembly of Fmoc-dipeptide amphiphiles.
Despite progress, a fundamental understanding of the relationships between the molecular structure and self-assembly configuration of Fmoc-dipeptides is still in its infancy. In this work, we provide a combined experimental and computational approach that makes use of free energy equilibration of a number of related Fmoc-dipeptides to arrive at an atomistic model of Fmoc-threonine-phenylalanine-amide (Fmoc-TF-NH2) which forms twisted fibres. By using dynamic peptide libraries where closely related dipeptide sequences are dynamically exchanged to eventually favour the formation of the thermodynamically most stable configuration, the relative importance of C-terminus modifications (amide versus methyl ester) and contributions of aliphatic versus aromatic amino acids (phenylalanine F vs. leucine L) is determined (F > L and NH2 > OMe). The approach enables a comparative interpretation of spectroscopic data, which can then be used to aid the construction of the atomistic model of the most stable structure (Fmoc-TF-NH2). The comparison of the relative stabilities of the models using molecular dynamic simulations and the correlation with experimental data using dynamic peptide libraries and a range of spectroscopy methods (FTIR, CD, fluorescence) allow for the determination of the nanostructure with atomistic resolution. The final model obtained through this process is able to reproduce the experimentally observed formation of intertwining fibres for Fmoc-TF-NH2, providing information of the interactions involved in the hierarchical supramolecular self-assembly. The developed methodology and approach should be of general use for the characterization of supramolecular structures.


The comparative osteology of the petrotympanic complex (ear region) of extant baleen whales (Cetacea: Mysticeti).
Anatomical comparisons of the ear region of baleen whales (Mysticeti) are provided through detailed osteological descriptions and high-resolution photographs of the petrotympanic complex (tympanic bulla and petrosal bone) of all extant species of mysticete cetaceans. Salient morphological features are illustrated and identified, including overall shape of the bulla, size of the conical process of the bulla, morphology of the promontorium, and the size and shape of the anterior process of the petrosal. We place our comparative osteological observations into a phylogenetic context in order to initiate an exploration into petrotympanic evolution within Mysticeti. The morphology of the petrotympanic complex is diagnostic for individual species of baleen whale (e.g., sigmoid and conical processes positioned at midline of bulla in Balaenoptera musculus; confluence of fenestra cochleae and perilymphatic foramen in Eschrichtius robustus), and several mysticete clades are united by derived characteristics. Balaenids and neobalaenids share derived features of the bulla, such as a rhomboid shape and a reduced anterior lobe (swelling) in ventral aspect, and eschrichtiids share derived morphologies of the petrosal with balaenopterids, including loss of a medial promontory groove and dorsomedial elongation of the promontorium. Monophyly of Balaenoidea (Balaenidae and Neobalaenidae) and Balaenopteroidea (Balaenopteridae and Eschrichtiidae) was recovered in phylogenetic analyses utilizing data exclusively from the petrotympanic complex. This study fills a major gap in our knowledge of the complex structures of the mysticete petrotympanic complex, which is an important anatomical region for the interpretation of the evolutionary history of mammals. In addition, we introduce a novel body of phylogenetically informative characters from the ear region of mysticetes. Our detailed anatomical descriptions, illustrations, and comparisons provide valuable data for current and future studies on the phylogenetic relationships, evolution, and auditory physiology of mysticetes and other cetaceans throughout Earth's history.


Uptake and intracellular distribution of amrubicin, a novel 9-amino-anthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells.
Amrubicin, a 9-aminoanthracycline anti-cancer drug, and its C-13 hydroxyl metabolite amrubicinol, were examined for growth-inhibitory activity as well as cellular uptake and distribution in P388 murine leukemia cells and doxorubicin-resistant P388 cells. Also discussed are the differences in the mechanisms of action among amrubicin, amrubicinol and doxorubicin in terms of their cellular pharmacokinetic character. In P388 cells, amrubicinol was about 80 times as potent as amrubicin, and about 2 times more potent than doxorubicin in a 1-h drug exposure growth-inhibition test. A clear cross-resistance was observed to both amrubicin and amrubicinol in doxorubicin-resistant P388 cells, though the resistance index was lower for amrubicin. The intracellular concentration of amrubicinol was about 6 times and 2 times higher than those of amrubicin and doxorubicin, respectively. Compared to doxorubicin, amrubicin and amrubicinol were released rapidly after removal of the drugs from the medium. A clear correlation was found between the growth-inhibiting activity and the cellular level of amrubicin and amrubicinol in P388 cells. About 10 to 20% of amrubicin or amrubicinol taken up by the cells was detected in the cell nuclear fraction, whereas 70 to 80% of doxorubicin was localized in this fraction. These results suggest that amrubicin and amrubicinol exert cytotoxic activity via a different mechanism from that of doxorubicin.


Machine learning insight into the role of imaging and clinical variables for the prediction of obstructive coronary artery disease and revascularization: An exploratory analysis of the CONSERVE study.
Machine learning (ML) is able to extract patterns and develop algorithms to construct data-driven models. We use ML models to gain insight into the relative importance of variables to predict obstructive coronary artery disease (CAD) using the Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization (CONSERVE) study, as well as to compare prediction of obstructive CAD to the CAD consortium clinical score (CAD2). We further perform ML analysis to gain insight into the role of imaging and clinical variables for revascularization. For prediction of obstructive CAD, the entire ICA arm of the study, comprising 719 patients was used. For revascularization, 1,028 patients were randomized to invasive coronary angiography (ICA) or coronary computed tomographic angiography (CCTA). Data was randomly split into 80% training 20% test sets for building and validation. Models used extreme gradient boosting (XGBoost). Mean age was 60.6 ± 11.5 years and 64.3% were female. For the prediction of obstructive CAD, the AUC was significantly higher for ML at 0.779 (95% CI: 0.672-0.886) than for CAD2 (0.696 [95% CI: 0.594-0.798]) (P = 0.01). BMI, age, and angina severity were the most important variables. For revascularization, the model obtained an overall area under the receiver-operation curve (AUC) of 0.958 (95% CI = 0.933-0.983). Performance did not differ whether the imaging parameters used were from ICA (AUC 0.947, 95% CI = 0.903-0.990) or CCTA (AUC 0.941, 95% CI = 0.895-0.988) (P = 0.90). The ML model obtained sensitivity and specificity of 89.2% and 92.9%, respectively. Number of vessels with ≥70% stenosis, maximum segment stenosis severity (SSS) and body mass index (BMI) were the most important variables. Exclusion of imaging variables resulted in performance deterioration, with an AUC of 0.705 (95% CI 0.614-0.795) (P <0.0001). For obstructive CAD, the ML model outperformed CAD2. BMI is an important variable, although currently not included in most scores. In this ML model, imaging variables were most associated with revascularization. Imaging modality did not influence model performance. Removal of imaging variables reduced model performance.


The role of arousal in the spontaneous regulation of emotions in healthy aging: a fMRI investigation.
Despite ample support for enhanced affective well-being and emotional stability in healthy aging, the role of potentially important dimensions, such as the emotional arousal, has not been systematically investigated in neuroimaging studies. In addition, the few behavioral studies that examined effects of arousal have produced inconsistent findings. The present study manipulated the arousal of pictorial stimuli to test the hypothesis that preserved emotional functioning in aging is modulated by the level of arousal, and to identify the associated neural correlates. Young and older healthy participants were presented with negative and neutral pictures, which they rated for emotional content, while fMRI data were recorded. There were three main novel findings regarding the neural mechanisms underlying the processing of negative pictures with different levels of arousal in young and older adults. First, the common engagement of the right amygdala in young and older adults was driven by high arousing negative stimuli. Second, complementing an age-related reduction in the subjective ratings for low arousing negative pictures, there were opposing patterns of activity in the rostral/ventral anterior cingulate cortex (ACC) and the amygdala, which showed increased vs. decreased responses, respectively, to low arousing negative pictures. Third, increased spontaneous activity in the ventral ACC/ventromedial prefrontal cortex (vmPFC) in older adults was linked to reduced ratings for low arousing negative pictures. Overall, these findings advance our understanding of the neural correlates underlying processing of negative emotions with different levels of arousal in the context of enhanced emotional functioning in healthy aging. Notably, the results support the idea that older adults have emotion regulation networks chronically activated, in the absence of explicit induction of the goal to regulate emotions, and that this effect is specific to low arousing negative emotions.


Mechanism of mosaic attenuation of the lungs on computed tomography in induced bronchospasm.
The purpose of this study was to investigate whether hypoxic pulmonary vasoconstriction is the major determinant of the computed tomography (CT) pattern of mosaic attenuation in asthmatic patients with induced bronchoconstriction. Thin-section CT was performed at suspended full inspiration immediately and 30 min after methacholine bronchoprovocation in 22 asthmatic subjects, who were randomly assigned to breathe room air (group A, n = 8), oxygen via nasal prongs at 5 l/min (group B, n = 8), and oxygen via face mask at 12 l/min (group C, n = 6). CT changes were quantified in terms of global lung density and density in hypodense and hyperdense areas. Lung parenchymal density increases were greatest in group C and greater in group B than in group A, globally (P = 0.03) and in hypodense regions (P = 0.01). On bivariate analysis, the only change in cross-sectional area was related to change in global density. In hypodense regions, density change was related both to reduction in cross-sectional area (P < 0.0005) and to oxygen administration (P = 0.01). After correction for changes in global lung density, only oxygen was independently related to density increase in hypodense areas (P = 0.02). In induced bronchoconstriction, the CT appearance of mosaic attenuation can be largely ascribed to hypoxic vasoconstriction rather than to changes in lung inflation.


N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity.
Based on the isosterism concept, we have designed and synthesized homologous N-alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides (from C1 to C18) as potential antimicrobial agents and enzyme inhibitors. They were obtained from 4-(trifluoromethyl)benzohydrazide by three synthetic approaches and characterized by spectral methods. The derivatives were screened for their inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) via Ellman's method. All the hydrazinecarboxamides revealed a moderate inhibition of both AChE and BuChE, with IC50 values of 27.04-106.75 µM and 58.01-277.48 µM, respectively. Some compounds exhibited lower IC50 for AChE than the clinically used drug rivastigmine. N-Tridecyl/pentadecyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides were identified as the most potent and selective inhibitors of AChE. For inhibition of BuChE, alkyl chain lengths from C5 to C7 are optimal substituents. Based on molecular docking study, the compounds may work as non-covalent inhibitors that are placed in a close proximity to the active site triad. The compounds were evaluated against Mycobacterium tuberculosis H37Rv and nontuberculous mycobacteria (M. avium, M. kansasii). Reflecting these results, we prepared additional analogues of the most active carboxamide (n-hexyl derivative 2f). N-Hexyl-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-amine (4) exhibited the lowest minimum inhibitory concentrations within this study (MIC ≥ 62.5 µM), however, this activity is mild. All the compounds avoided cytostatic properties on two eukaryotic cell lines (HepG2, MonoMac6).


The conundrum between immunological memory to adenovirus and their use as vectors in clinical gene therapy.
In the context of clinical gene transfer using viral vectors, the risk of memory antivector immunity is often poorly appreciated. The immunological past of the patient, the site of injection, and the vector dose will play intertwined and decisive roles in the safety and efficacy of treatment. To circumvent the drawbacks due to the ubiquitous human adenovirus (HAd) memory immunity, we believe that vectors derived from canine adenovirus type 2 (CAV-2) will be more clinically useful than those derived from HAds based, in part, on the potential lack of immunological memory. CAV-2 is not a human pathogen in spite of the approx 100,000 yr of cohabitation of humans with dogs. During the last 8 yr, we found that CAV-2 vectors preferentially transduced neurons in the central nervous system (CNS) of several species, and had a surprisingly efficient level of axoplasmic transport. CAV-2 vectors also lead to greater than 1 yr transgene expression in the immunocompetent rat CNS-without immunosuppression. However, more immediate harm can be caused to a patient via an acute and/or chronic vector-induced cellular infiltration in the CNS than by the normal progression of most neurodegenerative disorders. In this context, we continue to assess the clinical potential of CAV-2. This mini-review addresses our analysis of the interaction of CAV-2 vectors with human memory immunity and monocyte-derived dendritic cells.


A new fluorescence-based method for characterizing in vitro aerosol exposure systems.
Knowledge of how an in vitro aerosol exposure system delivers a test aerosols to the biological test system is among the most crucial prerequisites for the interpretation of exposure experiments and relies on detailed exposure system characterization. Although various methods for this purpose exist, many of them are time consuming, require extensive instrumentation, or offer only limited ability to assess the performance of the system under experimental settings. We present the development and evaluation of a new, highly robust and sensitive fluorometry-based method for assessing the particle size specific delivery of liquid aerosols. Glycerol aerosols of different mean particle sizes and narrow size distributions, carrying the fluorophore disodium fluorescein, were generated in a condensation monodisperse aerosol generator. Their detailed characterization confirmed their stability and the robustness and reproducibility of their generation. Test exposures under relevant experimental settings in the Vitrocell® 24/48 aerosol exposure system further confirmed their feasibility for simulating exposures and the high sensitivity of the method. Potential applications of the presented method range from the experimental confirmation of computationally simulated particle dynamics, over the characterization of in vitro aerosol exposure systems, to the detailed description of aerosol delivery in test systems of high complexity.


Radiation exposure in the young level 1 trauma patient: a retrospective review.
Computed tomography (CT) has become an increasingly popular and powerful tool for clinicians managing trauma patients with life-threatening injuries, but the ramifications of increasing radiation burden on individual patients are not insignificant. This study examines a continuous series of 337 patients less than 40 years old admitted to a level 1 trauma center during a 4-month period. Primary outcome measures included number of scans; effective dose of radiation from radiographs and CT scans, respectively; and total effective dose from both sources over patients' hospital stays. Several variables, including hospital length of stay, initial Glasgow Coma Scale score, and Injury Severity Score, correlated with greater radiation exposure. Blunt trauma victims were more prone to higher doses than those with penetrating or combined penetrating and blunt trauma. Location and mechanism of injury were also found to correlate with radiation exposure. Trauma patients as a group are exposed to high levels of radiation from X-rays and CT scans, and CT scans contribute a very high proportion (91.3% ± 11.7%) of that radiation. Certain subgroups of patients are at a particularly high risk of exposure, and greater attention to cumulative radiation dose should be paid to patients with the above mentioned risk factors.


Seasonal prevalence and determinants of food insecurity in Iqaluit, Nunavut.
Food insecurity is an ongoing problem in the Canadian Arctic. Although most studies have focused on smaller communities, little is known about food insecurity in larger centres. This study aimed to estimate the prevalence of food insecurity during 2 different seasons in Iqaluit, the territorial capital of Nunavut, as well as identify associated risk factors. A modified United States Department of Agriculture Food Security Survey was applied to 532 randomly selected households in September 2012 and 523 in May 2013. Chi-square tests and multivariable logistic regression were used to examine potential associations between food security and 9 risk factors identified in the literature. In September 2012, 28.7% of surveyed households in Iqaluit were food insecure, a rate 3 times higher than the national average, but lower than smaller Inuit communities in Nunavut. Prevalence of food insecurity in September 2012 was not significantly different in May 2013 (27.2%). When aggregating results from Inuit households from both seasons (May and September), food insecurity was associated with poor quality housing and reliance on income support (p<0.01). Unemployment and younger age of the person in charge of food preparation were also significantly associated with food insecurity. In contrast to previous research among Arctic communities, gender and consumption of country food were not positively associated with food security. These results are consistent with research describing high food insecurity across the Canadian Arctic. The factors associated with food insecurity in Iqaluit differed from those identified in smaller communities, suggesting that experiences with, and processes of, food insecurity may differ between small communities and larger commercial centres. These results suggest that country food consumption, traditional knowledge and sharing networks may play a less important role in larger Inuit communities.


Scanning orientation and polarization effects for XRQA radiochromic film.
Gafchromic XRQA radiochromic film, is an effective tool for quality assurance and dose assessment in kilovoltage radiotherapy and diagnostic applications. Like other Gafchromic film products, XRQA film exhibits a variation in dose to reflected optical density response with angle of rotation when analysed with a light source that is partially or fully polarised such as a desktop scanner. Although warnings are not given on manufacturers specifications, this can affect dosimetry accuracy and we recommend that it is essential to scan all XRQA films in the same orientation. The effect is not as pronounced as EBT Gafchromic film. The magnitude of this variation has been measured and shown to be up to 16 ± 2% (1SD) using a fully linear polarised light source was seen with a 90° angle rotation. This would be the maximum variation seen on a desktop scanner with a fully polarised light source. For our standard desktop scanner (Epson v700) a mean variation of 2 ± 1% from 0 cGy to 20 cGy applied dose was measured as compared to 8 ± 2% for EBT Gafchromic. We recommend that to decrease uncertainty in dose measurement, accurate alignment of the calibration films to experimental films be performed on a regular basis. This is especially important if your desktop scanner has a high degree of polarization of its light source.


Neural dynamics of motion integration and segmentation within and across apertures.
A neural model is developed of how motion integration and segmentation processes, both within and across apertures, compute global motion percepts. Figure-ground properties, such as occlusion, influence which motion signals determine the percept. For visible apertures, a line's terminators do not specify true line motion. For invisible apertures, a line's intrinsic terminators create veridical feature-tracking signals. Sparse feature-tracking signals can be amplified before they propagate across position and are integrated with ambiguous motion signals within line interiors. This integration process determines the global percept. It is the result of several processing stages: directional transient cells respond to image transients and input to a directional short-range filter that selectively boosts feature-tracking signals with the help of competitive signals. Then, a long-range filter inputs to directional cells that pool signals over multiple orientations, opposite contrast polarities, and depths. This all happens no later than cortical area MT. The directional cells activate a directional grouping network, proposed to occur within cortical area MST, within which directions compete to determine a local winner. Enhanced feature-tracking signals typically win over ambiguous motion signals. Model MST cells that encode the winning direction feed back to model MT cells, where they boost directionally consistent cell activities and suppress inconsistent activities over the spatial region to which they project. This feedback accomplishes directional and depthful motion capture within that region. Model simulations include the barberpole illusion, motion capture, the spotted barberpole, the triple barberpole, the occluded translating square illusion, motion transparency and the chopsticks illusion. Qualitative explanations of illusory contours from translating terminators and plaid adaptation are also given.


A Pilot Study of the Effects of Mindfulness-Based Cognitive Therapy on Positive Affect and Social Anxiety Symptoms.
Randomized controlled trials have demonstrated that mindfulness-based cognitive therapy (MBCT) is efficacious in reducing residual depressive symptoms and preventing future depressive episodes (Kuyken et al., 2016). One potential treatment effect of MBCT may be improvement of positive affect (PA), due to improved awareness of daily positive events (Geschwind et al., 2011). Considering social anxiety disorder (SAD) is characterized by diminished PA (Brown et al., 1998; Kashdan, 2007), we sought to determine whether MBCT would reduce social anxiety symptoms, and whether this reduction would be associated with improvement of PA deficits. Adults (N = 22) who met criteria for varied anxiety disorders participated in a small, open-label trial of an 8-week manualized MBCT intervention. Most participants presented with either a diagnosis (primary, secondary, or tertiary) of generalized anxiety disorder (GAD) (N = 15) and/or SAD (N = 14) prior to treatment, with eight individuals meeting diagnostic criteria for both GAD and SAD. We hypothesized participants would demonstrate improvements in social anxiety symptoms, which would be predicted by improvements in PA, not reductions in negative affect (NA). Results of several hierarchical linear regression analyses (completed in both full and disorder-specific samples) indicated that improvements in PA but not reductions in NA predicted social anxiety improvement. This effect was not observed for symptoms of worry, which were instead predicted by decreased NA for individuals diagnosed with GAD and both decreased NA and increased PA in the entire sample. Results suggest that MBCT may be efficacious in mitigating social anxiety symptoms, and this therapeutic effect may be linked to improvements in PA. However, further work is necessary considering the small, heterogeneous sample, uncontrolled study design, and exploratory nature of the study.


High-yield production of "difficult-to-express" proteins in a continuous exchange cell-free system based on CHO cell lysates.
Cell-free protein synthesis (CFPS) represents a promising technology for efficient protein production targeting especially so called "difficult-to-express" proteins whose synthesis is challenging in conventional in vivo protein production platforms. Chinese hamster ovary (CHO) cells are one of the most prominent and safety approved cell lines for industrial protein production. In this study we demonstrated the ability to produce high yields of various protein types including membrane proteins and single chain variable fragments (scFv) in a continuous exchange cell-free (CECF) system based on CHO cell lysate that contains endogenous microsomal structures. We showed significant improvement of protein yield compared to batch formatted reactions and proved biological activity of synthesized proteins using various analysis technologies. Optimized CECF reaction conditions led to membrane protein yields up to 980 µg/ml, which is the highest protein yield reached in a microsome containing eukaryotic cell-free system presented so far.


Costs, needs, and integration efforts shape helping behavior toward refugees.
Recent political instabilities and conflicts around the world have drastically increased the number of people seeking refuge. The challenges associated with the large number of arriving refugees have revealed a deep divide among the citizens of host countries: one group welcomes refugees, whereas another rejects them. Our research aim is to identify factors that help us understand host citizens' (un)willingness to help refugees. We devise an economic game that captures the basic structural properties of the refugee situation. We use it to investigate both economic and psychological determinants of citizens' prosocial behavior toward refugees. In three controlled laboratory studies, we find that helping refugees becomes less likely when it is individually costly to the citizens. At the same time, helping becomes more likely with the refugees' neediness: helping increases when it prevents a loss rather than generates a gain for the refugees. Moreover, particularly citizens with higher degrees of prosocial orientation are willing to provide help at a personal cost. When refugees have to exert a minimum level of effort to be eligible for support by the citizens, these mandatory "integration efforts" further increase prosocial citizens' willingness to help. Our results underscore that economic factors play a key role in shaping individual refugee helping behavior but also show that psychological factors modulate how individuals respond to them. Moreover, our economic game is a useful complement to correlational survey measures and can be used for pretesting policy measures aimed at promoting prosocial behavior toward refugees.


Data-driven modeling based on volterra series for multidimensional blast furnace system.
The multidimensional blast furnace system is one of the most complex industrial systems and, as such, there are still many unsolved theoretical and experimental difficulties, such as silicon prediction and blast furnace automation. For this reason, this paper is concerned with developing data-driven models based on the Volterra series for this complex system. Three kinds of different low-order Volterra filters are designed to predict the hot metal silicon content collected from a pint-sized blast furnace, in which a sliding window technique is used to update the filter kernels timely. The predictive results indicate that the linear Volterra predictor can describe the evolvement of the studied silicon sequence effectively with the high percentage of hitting the target, very low root mean square error and satisfactory confidence level about the reliability of the future prediction. These advantages and the low computational complexity reveal that the sliding-window linear Volterra filter is full of potential for multidimensional blast furnace system. Also, the lack of the constructed Volterra models is analyzed and the possible direction of future investigation is pointed out.


Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL.
We performed sensitive polymerase chain reaction-based minimal residual disease (MRD) analyses on bone marrow samples at 9 follow-up time points in 71 children with T-lineage acute lymphoblastic leukemia (T-ALL) and compared the results with the precursor B-lineage ALL (B-ALL) results (n = 210) of our previous study. At the first 5 follow-up time points, the frequency of MRD-positive patients and the MRD levels were higher in T-ALL than in precursor-B-ALL, reflecting the more frequent occurrence of resistant disease in T-ALL. Subsequently, patients were classified according to their MRD level at time point 1 (TP1), taken at the end of induction treatment (5 weeks), and at TP2 just before the start of consolidation treatment (3 months). Patients were considered at low risk if TP1 and TP2 were MRD negative and at high risk if MRD levels at TP1 and TP2 were 10(-3) or higher; remaining patients were considered at intermediate risk. The relative distribution of patients with T-ALL (n = 43) over the MRD-based risk groups differed significantly from that of precursor B-ALL (n = 109). Twenty-three percent of patients with T-ALL and 46% of patients with precursor B-ALL were classified in the low-risk group (P =.01) and had a 5-year relapse-free survival (RFS) rate of 98% or greater. In contrast, 28% of patients with T-ALL were classified in the MRD-based high-risk group compared to only 11% of patients with precursor B-ALL (P =.02), and the RFS rates were 0% and 25%, respectively (P =.03). Not only was the distribution of patients with T-ALL different over the MRD-based risk groups, the prognostic value of MRD levels at TP1 and TP2 was higher in T-ALL (larger RFS gradient), and consistently higher RFS rates were found for MRD-negative T-ALL patients at the first 5 follow-up time points.


Evolution of Helicobacter: Acquisition by Gastric Species of Two Histidine-Rich Proteins Essential for Colonization.
Metal acquisition and intracellular trafficking are crucial for all cells and metal ions have been recognized as virulence determinants in bacterial pathogens. Virulence of the human gastric pathogen Helicobacter pylori is dependent on nickel, cofactor of two enzymes essential for in vivo colonization, urease and [NiFe] hydrogenase. We found that two small paralogous nickel-binding proteins with high content in Histidine (Hpn and Hpn-2) play a central role in maintaining non-toxic intracellular nickel content and in controlling its intracellular trafficking. Measurements of metal resistance, intracellular nickel contents, urease activities and interactomic analysis were performed. We observed that Hpn acts as a nickel-sequestration protein, while Hpn-2 is not. In vivo, Hpn and Hpn-2 form homo-multimers, interact with each other, Hpn interacts with the UreA urease subunit while Hpn and Hpn-2 interact with the HypAB hydrogenase maturation proteins. In addition, Hpn-2 is directly or indirectly restricting urease activity while Hpn is required for full urease activation. Based on these data, we present a model where Hpn and Hpn-2 participate in a common pathway of controlled nickel transfer to urease. Using bioinformatics and top-down proteomics to identify the predicted proteins, we established that Hpn-2 is only expressed by H. pylori and its closely related species Helicobacter acinonychis. Hpn was detected in every gastric Helicobacter species tested and is absent from the enterohepatic Helicobacter species. Our phylogenomic analysis revealed that Hpn acquisition was concomitant with the specialization of Helicobacter to colonization of the gastric environment and the duplication at the origin of hpn-2 occurred in the common ancestor of H. pylori and H. acinonychis. Finally, Hpn and Hpn-2 were found to be required for colonization of the mouse model by H. pylori. Our data show that during evolution of the Helicobacter genus, acquisition of Hpn and Hpn-2 by gastric Helicobacter species constituted a decisive evolutionary event to allow Helicobacter to colonize the hostile gastric environment, in which no other bacteria persistently thrives. This acquisition was key for the emergence of one of the most successful bacterial pathogens, H. pylori.


Sponge larval settlement cues: the role of microbial biofilms in a warming ocean.
Microbial biofilms play important roles in initiating settlement of marine invertebrate larvae. Given the importance of habitat selection by the motile larval phase, understanding settlement choices is critical if we are to successfully predict the population dynamics of sessile adults. Marine microbial biofilms show remarkable variability in community composition, often mediated by environmental conditions and biofilm age. To determine if biofilm communities were influenced by the time allowed to establish (age) and/or seawater temperature, we manipulated experimental surfaces to firstly determine biofilm community composition and secondly test larval settlement responses for the abundant coral reef sponge Rhopaloeides odorabile. Microbial profiling of biofilms revealed different communities according to both age and temperature. Biofilm community composition, as a result of both elevated seawater temperature and biofilm age, contributed to settlement for sponge larvae with markedly higher numbers of larvae settling to biofilms developed over longer periods (10 d) and at temperatures 2-6°C above ambient.


Digital morphology analyzers in hematology: ICSH review and recommendations.
Morphological assessment of the blood smear has been performed by conventional manual microscopy for many decades. Recently, rapid progress in digital imaging and information technology has led to the development of automated methods of digital morphological analysis of blood smears. A panel of experts in laboratory hematology reviewed the literature on the use of digital imaging and other strategies for the morphological analysis of blood smears. The strengths and weaknesses of digital imaging were determined, and recommendations on improvement were proposed. By preclassifying cells using artificial intelligence algorithms, digital image analysis automates the blood smear review process and enables faster slide reviews. Digital image analyzers also allow remote networked laboratories to transfer images rapidly to a central laboratory for review, and facilitate a variety of essential work functions in laboratory hematology such as consultations, digital image archival, libraries, quality assurance, competency assessment, education, and training. Different instruments from several manufacturers are available, but there is a lack of standardization of staining methods, optical magnifications, color and display characteristics, hardware, software, and file formats. In order to realize the full potential of Digital Morphology Hematology Analyzers, pre-analytic, analytic, and postanalytic parameters should be standardized. Manufacturers of new instruments should focus on improving the accuracy of cell preclassifications, and the automated recognition and classification of pathological cell types. Cutoffs for grading morphological abnormalities should depend on clinical significance. With all current devices, a skilled morphologist remains essential for cell reclassification and diagnostic interpretation of the blood smear.


Improving nutrition in pregnant adolescents: recommendations for clinical practitioners.
Pregnancy represents an ideal time for health promotion activities. Many women, including adolescents, are interested and willing to change health behaviors to improve the chance that they will deliver a healthy infant. This paper focuses on improving nutrition in pregnant adolescents. Seven recommendations are presented to help achieve this goal: 1) Focus on foods, not nutrients; 2) individualize and work within the pregnant adolescent's current eating habits; 3) consider the context of family and peer groups; 4) reward efforts; 5) make it easy; 6) focus on weight gain patterns for optimal birth outcomes; and 7) refer to a dietician, as needed. Use of these recommendations comprehensively addresses adolescent developmental needs to improve nutrition during pregnancy. These recommendations are not meant to be all-inclusive; rather, they are meant to serve as a guide for clinical management of nutrition for pregnant adolescents.


Interfering with RAS-effector protein interactions prevent RAS-dependent tumour initiation and causes stop-start control of cancer growth.
RAS mutations are the most common gain-of-function change in human cancer and promise to be a critical therapy target. As a new approach, we have used a surrogate to drug the 'undruggable' (that is, RAS-effector protein-protein interactions inside cancer cells) in pre-clinical mouse models of RAS-dependent cancers. Using this novel reagent, we have specifically targeted RAS signalling in a transgenic mouse model of lung cancer by directly blockading RAS-effector interactions with an antibody fragment that binds to activated RAS, and show that the interaction of RAS and effectors, such as phosphoinositide 3-kinase and RAF, is necessary for tumour initiation. Further, interference with oncogenic RAS-effector interactions result in control of tumour growth in human cancer cells but, crucially, does not necessarily cause tumour regression. These findings support the concept that ablating RAS-dependent signalling in cancer will have chemo-preventive effects that confer a chronic state in cancer and suggest that mutant RAS-targeted therapies may require conjoint targeting of other molecules and/or current cancer therapeutic strategies (for example, radiotherapy and chemotherapy) to be curative. In this context, our findings suggest that the oncogene addiction model is not universally correct in its central thesis that cancer cell death is inevitable after loss of oncogenic protein function.


A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.
Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.


Public perception of predictive cancer genetic testing and research in Oregon.
The potential for using widespread genetic testing to inform health care has become a viable option, particularly for heritable cancers. Yet, little is known about how to effectively communicate the benefits and risks of both personal genetic testing and participation in biorepositories that aid scientific advancements. Nationwide efforts are engaging communities in large genetic studies to better estimate the population-wide prevalence of heritable cancers but have been met with hesitance or declination to participate in some communities. To successfully engage an Oregon population in longitudinal research that includes predictive genetic testing for pathogenic or likely pathogenic variants associated with an increased risk for cancer, researchers conducted 35 focus groups (two of which were held in Spanish) in 24 of Oregon's 36 counties to better understand knowledge and attitudes related to genetic testing and willingness to participate in longitudinal genetic research. A total of 203 adults (mean = 45.6 years; range 18-88), representing a range of education levels and prior knowledge of genetic research, participated in the focus groups. The majority (85%) of participants reported personal or family diagnoses of cancer (e.g., self, family, friends). A majority (87%) also reported a strong interest in cancer genetic testing and receiving genetic information about themselves. Nearly all focus groups (94%, 33 of 35 sites) included participant discussion citing their families (e.g., children, close relatives, and extended family members) as key motivators for participation in genetic research. For example, participants reported interest in increasing personal knowledge about their own and their families' cancer risks in order to respond proactively, if a pathogenic variant was found. While most focus groups (94%, 33 of 35 sites) included participant discussion describing barriers to predictive genetic, testing such as concerns about outcomes, the desire to learn about health risks in oneself mitigated or outweighed those fears for many participants. Other commonly reported concerns were related to potential mistrust of insurance companies, researchers, or institutions, or lack of knowledge about genetics, genetic testing, or genetic research. Participants, particularly in rural areas, highlighted critical factors for research recruitment, such as trust, personal interaction, public education about genetic research, and clear communication about study goals and processes. Our statewide findings reflect that public interest in predictive cancer genetic testing and cancer genetic research can surpass lack of knowledge of the complex topics, particularly when benefits for self and family are emphasized and when study considerations are well articulated.


Weekend nightlife recreational habits: prominent intrapersonal "risk factors" for drug use?
Data were collected using a questionnaire from a sample of 2670 European youngsters representing the most popular recreational areas of 9 cities (Athens, Berlin, Coimbra, Manchester, Modena, Nice, Palma de Mallorca, Utrecht, and Vienna) from February to May 1998 in order to estimate the relevance of weekend nightlife recreational habits that influence the use of drugs in comparison with other more established "risk factors." Areas investigated included: drug use, the relationship with the recreational context, and many other posited "risk" and "protective factors" (such as student performance, family supervision, sensation seeking, onset of drug use, etc). Three patterns of drug use were considered: nonusers (9.8%), legal users (35.6%) and illegal users (54.6%). Data analysis used parametric, nonparametric tests and multinomial logistic regression tests. The variables related to recreational life style were better predictors for establishing the pattern of drug use, than the study's other variables. The study's limited generalizability is due to the lack of representativeness of the sample and its limited description.


When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations.
To determine the benefits and risks of hepatic resection versus non-resectional liver-directed treatments in patients with potentially resectable neuroendocrine liver metastases. A systematic review identified 1594 reports which alluded to a possible liver resection for neuroendocrine tumour metastases, of which 38 reports (all retrospective), comprising 3425 patients, were relevant. Thirty studies reported resection alone, and 16 studies reported overall survival (OS). Only two studies addressed quality-of-life (QoL) issues. Five-year overall survival was reported at 41-100%, whereas 5-year progression-free survival (PFS) was 5-54%. We identified no robust evidence that a liver resection was superior to any other liver-directed therapies in improving OS or PFS. There was no evidence to support the use of a R2 resection (debulking), with or without tumour ablation, to improve either OS or QoL. There was little evidence to guide sequencing of surgery for patients presenting in Stage IV with resectable disease, and none to support a resection of asymptomatic primary tumours in the presence of non-resectable liver metastases. Low-level recommendations are offered to assist in the management of patients with neuroendocrine liver metastases, along with recommendations for future studies.


Random and independent sampling of endogenous tryptic peptides from normal human EDTA plasma by liquid chromatography micro electrospray ionization and tandem mass spectrometry.
Normal human EDTA plasma samples were collected on ice, processed ice cold, and stored in a freezer at - 80 °C prior to experiments. Plasma test samples from the - 80 °C freezer were thawed on ice or intentionally warmed to room temperature. Protein content was measured by CBBR binding and the release of alcohol soluble amines by the Cd ninhydrin assay. Plasma peptides released over time were collected over C18 for random and independent sampling by liquid chromatography micro electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) and correlated with X!TANDEM. Fully tryptic peptides by X!TANDEM returned a similar set of proteins, but was more computationally efficient, than "no enzyme" correlations. Plasma samples maintained on ice, or ice with a cocktail of protease inhibitors, showed lower background amounts of plasma peptides compared to samples incubated at room temperature. Regression analysis indicated that warming plasma to room temperature, versus ice cold, resulted in a ~ twofold increase in the frequency of peptide identification over hours-days of incubation at room temperature. The type I error rate of the protein identification from the X!TANDEM algorithm combined was estimated to be low compared to a null model of computer generated random MS/MS spectra. The peptides of human plasma were identified and quantified with low error rates by random and independent sampling that revealed 1000s of peptides from hundreds of human plasma proteins from endogenous tryptic peptides.


Role of CCL11 in eosinophilic lung disease during respiratory syncytial virus infection.
Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.


In vitro inhibition of angiogenesis by hydroalcoholic extract of oak (Quercus infectoria) acorn shell via suppressing VEGF, MMP-2, and MMP-9 secretion.
Angiogenesis is an essential factor for cancer progression. Although more attention is paid in angiogenesis on its role in cancer biology, many other non-neoplastic diseases are also angiogenic-dependent. Recently, there is motivation to control cancer via inhibition of angiogenesis. Quercus infectoria Olivier var (Fagaceae) (oak) is a plant whose different parts, such as its fruit shell, have been used extensively as a traditional drug in the west part of Iran. Although some biological properties of oak are determined, its effects on angiogenesis are unclear. So, we investigated the antiangiogenic effects of oak acorn shell. Fresh oak acorns were collected, and after authentication; hydroalcoholic extract of acorn shells (5, 10, 20, 30, 40, 60, 80, and 100 μg/ml) was used for evaluation of its cytotoxicity, antiproliferative, and antiangiogenic effects in vitro. Also, effects of the extract on vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and MMP-9 secretion were assayed using enzyme-linked immunosorbent assay (ELISA) and gelatin zymography. Treatment with hydroalcoholic extract in eight doses resulted in a significant decrease of endothelial cell proliferation and angiogenesis with an IC₅₀ value of ~20 μg/ml, without any toxic effect. At 40 μg/ml, the extract inhibited MMP-9 activity; however, a dose-dependent reduction (60-80 µg/ml) in MMP-2 activity was seen. VEGF secretion was decreased with increase in the concentration of the extract from 5 to 100 μg/ml. This study indicated that hydroalcoholic extract of oak acorn shell acts as a potent antiangiogenic agent which exerts its inhibitory effect mainly through downregulation of essential mediators such as VEGF and MMPs.


Ion channels and transporters in cancer. 4. Remodeling of Ca(2+) signaling in tumorigenesis: role of Ca(2+) transport.
The Ca(2+) signal has major roles in cellular processes important in tumorigenesis, including migration, invasion, proliferation, and apoptotic sensitivity. New evidence has revealed that, aside from altered expression and effects on global cytosolic free Ca(2+) levels via direct transport of Ca(2+), some Ca(2+) pumps and channels are able to contribute to tumorigenesis via mechanisms that are independent of their ability to transport Ca(2+) or effect global Ca(2+) homeostasis in the cytoplasm. Here, we review some of the most recent studies that present evidence of altered Ca(2+) channel or pump expression in tumorigenesis and discuss the importance and complexity of localized Ca(2+) signaling in events critical for tumor formation.


Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125.
The primary objective of this study was to determine the safety and maximum tolerated dose (MTD) of the antimesothelin immunotoxin SS1(dsFv)PE38 (SS1P) (a recombinant antimesothelin immunotoxin consisting of a murine antimesothelin variable antibody fragment [Fv] linked to PE38, a truncated portion of Pseudomonas exotoxin A) in combination with pemetrexed and cisplatin in chemotherapy-naive patients with advanced malignant pleural mesothelioma (MPM). Secondary objectives included tumor response, SS1P pharmacokinetics, and serum biomarkers of response. Chemotherapy-naive patients with stage III or IV, unresectable, epithelial or biphasic MPM and normal organ functions were eligible. Pemetrexed (500 mg/m(2) on day 1) and cisplatin (75 mg/m(2) on day 1) were administered every 3 weeks for up to 6 cycles with escalating doses of SS1P administered intravenously on days 1, 3, and 5 during cycles 1 and 2. Tumor response was evaluated every 6 weeks. Twenty-four patients received SS1P at 4 dose levels from 25 to 55 mcg/kg. Grade 3 fatigue was dose-limiting in 1 patient at 55 mcg/kg. The MTD of SS1P was established as 45 mcg/kg. Other grade 3 toxicities associated with SS1P included hypoalbuminemia (21%), back pain (13%), and hypotension (8%). Of 20 evaluable patients, 12 (60%) had a partial response, 3 had stable disease, and 5 had progressive disease. Of 13 patients who received the MTD, 10 (77%) had a partial response, 1 had stable disease, and 2 had progressive disease. Objective radiologic responses were associated with significant decreases in serum mesothelin (P=.0030), megakaryocyte potentiating factor (P=.0005), and cancer antigen 125 (P < .0001). SS1P given with pemetrexed and cisplatin is safe and well tolerated and exhibits significant antitumor activity in patients with unresectable, advanced pleural mesothelioma. Serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125 levels correlated with objective tumor responses.


A self-contained fully-enclosed microfluidic cartridge for lab on a chip.
We describe a self-contained fully-enclosed cartridge for lab-on-a-chip applications where sample and reagents can be applied sequentially as is performed in a heterogeneous immunoassay, or nucleic acid extraction. Both the self-contained and fully-enclosed features of the cartridge are sought to ensure its safe use in the field by unskilled staff. Simplicity in cartridge design and operation is obtained via adopting a valveless concept whereby reagents are stored and used in the form of liquid plugs isolated by air spacers around a fluidic loop. Functional components integrated in the loop include a microfluidic chip specific to the target application, a novel peristaltic pump to displace the liquid plugs, and a pair of removable tubing segments where one is used to introduce biological sample and while the other is to collect eluant. The novel pump is fabricated through soft-lithography technique and works by pinching a planar channel under stainless-steel ball bearings that have been magnetically loaded. The utility of the cartridge is demonstrated for automated extraction and purification of nucleic acids (DNA) from a cell lysate on a battery-operated portable system. The cartridge shown here can be further extended to sample-in-answer-out diagnostic tests.


Effect of paralytic type on time to post-intubation sedative use in the emergency department.
To determine the difference between rocuronium and succinylcholine with regard to post-intubation sedative initiation in the emergency department. This was a retrospective cohort study conducted in a tertiary care emergency department (ED) in the USA. Consecutive adult patients intubated in the ED using succinylcholine or rocuronium for paralysis were included. Data collected included patient demographics, vital signs, medications used post-intubation and times of drug administration. Patients were divided into two groups based on the type of paralytic used for rapid sequence intubation: (1) rocuronium or (2) succinylcholine. All patients received etomidate for induction of sedation. Time between intubation and post-intubation sedative use was compared between the two groups using an unpaired Student's t test. A total of 200 patients were included in the final analyses (100 patients in each group). There were no significant differences between the groups with regard to patient demographics, vital signs or other baseline characteristics. After intubation, 77.5% (n=155) of patients were initiated on a sedative infusion of propofol (n=148) or midazolam (n=7). The remaining patients received sedation as bolus doses only. Mean time between intubation and post-intubation sedative use was significantly greater in the rocuronium group compared with the succinylcholine group (27 min vs 15 min, respectively; p<0.001). Patients intubated with rocuronium had greater delays in post-intubation sedative initiation compared with succinylcholine.


KRAS-dependent sorting of miRNA to exosomes.
Mutant KRAS colorectal cancer (CRC) cells release protein-laden exosomes that can alter the tumor microenvironment. To test whether exosomal RNAs also contribute to changes in gene expression in recipient cells, and whether mutant KRAS might regulate the composition of secreted microRNAs (miRNAs), we compared small RNAs of cells and matched exosomes from isogenic CRC cell lines differing only in KRAS status. We show that exosomal profiles are distinct from cellular profiles, and mutant exosomes cluster separately from wild-type KRAS exosomes. miR-10b was selectively increased in wild-type exosomes, while miR-100 was increased in mutant exosomes. Neutral sphingomyelinase inhibition caused accumulation of miR-100 only in mutant cells, suggesting KRAS-dependent miRNA export. In Transwell co-culture experiments, mutant donor cells conferred miR-100-mediated target repression in wild-type-recipient cells. These findings suggest that extracellular miRNAs can function in target cells and uncover a potential new mode of action for mutant KRAS in CRC.


Early results of comparison of polypropylene mesh and 75% resorbable mesh (monofilament polypropylene and poly-L-lactic acid (PLLA) mesh) for laparoscopic total extraperitoneal (TEP) inguinal hernia repair.
Laparoscopic totally extraperitoneal (TEP) hernia repair has become increasingly widespread. Faster recovery than conventional open methods shortens the return to work. Polypropylene (PP) mesh is still in use in hernia surgery because it is an inexpensive and easily accessible patch. The post-operative chronic pain and foreign body sensation are the disadvantages of these PP patches. Poly-L-lactic acid and polypropylene (PLLA) were used in this study because of the good biocompatibility and low tissue inflammation response. We compared the early clinical outcomes of PP patch and PLLA patches. Between January 2013 and April, 2018,469 patients with inguinal hernia underwent TEP procedure. Patients were divided into two groups. PP mesh (n=211) in group 1, PLLA mesh (n=258) in group 2. Patients were compared regarding age, gender, hernia side, ASA scores, the duration of operation, pain, time to return to work, the sensation of foreign body, seroma and hematoma. A total of 469 patients were analyzed retrospectively (426 male, 43 female). The mean age was 52.23±13.66 years. The operative times of the patients were 40.92±8.9 minutes in group 1, and 38.82±8.5 minutes in group 2 (p<0.05). The time to return to work was 10.2±1.47 days in Group 1 and 8.4±1.0 days in Group 2 (p<0.05). Visual Analog Scale (VAS) in group 2 was lower than in group 1 (p<0.005). In group 2, the feeling of the organic body decreased in the early and late period (p<0.005). Seroma and hematoma were less in Group 2 than in Group 1 (p<0.005). The mean follow-up period of the patients was 18 (3-63) months, two patients in Group 1, two patients in Group 2 recurred. The PLLA patch used in the TEP method is thought to be a herniated patch that can be safely used because of its ease of application and less postoperative complication rates and more rapid return to work.


Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination.
Brassinosteroids are plant steroid hormones that control many aspects of plant growth and development, and are perceived at the cell surface by the plasma membrane-localized receptor kinase BRI1. Here we show that BRI1 is post-translationally modified by K63 polyubiquitin chains in vivo. Using both artificial ubiquitination of BRI1 and generation of an ubiquitination-defective BRI1 mutant form, we demonstrate that ubiquitination promotes BRI1 internalization from the cell surface and is essential for its recognition at the trans-Golgi network/early endosomes (TGN/EE) for vacuolar targeting. Finally, we demonstrate that the control of BRI1 protein dynamics by ubiquitination is an important control mechanism for brassinosteroid responses in plants. Altogether, our results identify ubiquitination and K63-linked polyubiquitin chain formation as a dual targeting signal for BRI1 internalization and sorting along the endocytic pathway, and highlight its role in hormonally controlled plant development.


Multi-Pig Part Detection and Association with a Fully-Convolutional Network.
Computer vision systems have the potential to provide automated, non-invasive monitoring of livestock animals, however, the lack of public datasets with well-defined targets and evaluation metrics presents a significant challenge for researchers. Consequently, existing solutions often focus on achieving task-specific objectives using relatively small, private datasets. This work introduces a new dataset and method for instance-level detection of multiple pigs in group-housed environments. The method uses a single fully-convolutional neural network to detect the location and orientation of each animal, where both body part locations and pairwise associations are represented in the image space. Accompanying this method is a new dataset containing 2000 annotated images with 24,842 individually annotated pigs from 17 different locations. The proposed method achieves over 99% precision and over 96% recall when detecting pigs in environments previously seen by the network during training. To evaluate the robustness of the trained network, it is also tested on environments and lighting conditions unseen in the training set, where it achieves 91% precision and 67% recall. The dataset is publicly available for download.


Inverted critical adsorption of polyelectrolytes in confinement.
What are the fundamental laws for the adsorption of charged polymers onto oppositely charged surfaces, for convex, planar, and concave geometries? This question is at the heart of surface coating applications, various complex formation phenomena, as well as in the context of cellular and viral biophysics. It has been a long-standing challenge in theoretical polymer physics; for realistic systems the quantitative understanding is however often achievable only by computer simulations. In this study, we present the findings of such extensive Monte-Carlo in silico experiments for polymer-surface adsorption in confined domains. We study the inverted critical adsorption of finite-length polyelectrolytes in three fundamental geometries: planar slit, cylindrical pore, and spherical cavity. The scaling relations extracted from simulations for the critical surface charge density σc-defining the adsorption-desorption transition-are in excellent agreement with our analytical calculations based on the ground-state analysis of the Edwards equation. In particular, we confirm the magnitude and scaling of σc for the concave interfaces versus the Debye screening length 1/κ and the extent of confinement a for these three interfaces for small κa values. For large κa the critical adsorption condition approaches the known planar limit. The transition between the two regimes takes place when the radius of surface curvature or half of the slit thickness a is of the order of 1/κ. We also rationalize how σc(κ) dependence gets modified for semi-flexible versus flexible chains under external confinement. We examine the implications of the chain length for critical adsorption-the effect often hard to tackle theoretically-putting an emphasis on polymers inside attractive spherical cavities. The applications of our findings to some biological systems are discussed, for instance the adsorption of nucleic acids onto the inner surfaces of cylindrical and spherical viral capsids.


Extraneous lipid contamination in single-volume proton MR spectroscopy: phantom and human studies.
To determine the degree of extraneous lipid contamination in defined volumes of interest studied with single-volume proton MR spectroscopy. Single-volume proton MR spectroscopy was performed on a fat/water phantom and in three volunteers using the stimulated-echo acquisition mode (STEAM) and point-resolved spectroscopy (PRESS) localization methods. Three different volumes of interest (8, 27, and 64 cm3) were examined at echo times of 20, 135, and 270 for the STEAM sequences and 135 and 270 for the PRESS acquisitions in both the phantom and the volunteers (volumes of interest were placed adjacent to but not encompassing fat-containing structures, such as the scalp and retroorbital fat). The degree of lipid contamination was then correlated with measurements of the section profiles. The PRESS method resulted in less extraneous lipid contamination in both phantom and volunteer studies. The STEAM method had the highest level of lipid contamination signal in phantom and human studies. In the volunteers, volumes of interest abutting fat-containing structures obtained with PRESS or STEAM sequences showed no lipid contamination. However, the STEAM sequences showed lipid signal in the volume of interest adjacent to orbital fat whereas the PRESS sequences did not. These observations are supported by the section profile studies, which showed that the actual volume excited by the STEAM sequence was 7% to 32% larger than that originally selected, while with PRESS the actual excited volume was 12% to 16% smaller than that originally selected. In our MR unit, short-echo-time STEAM sequences (< or = 135 milliseconds) resulted in extraneous lipid contamination in phantom and human studies adjacent to the orbits. PRESS sequences showed no lipid contamination in volumes abutting fat structures in phantoms or humans. These results correlated closely with the configuration of the section profiles. Although these findings might be dependent on the MR unit used, our study could help determine extraneous lipid contamination for other MR units.


Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity.
Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer. Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis. Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15). Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.


HEAR4Health: a blueprint for making computer audition a staple of modern healthcare.
Recent years have seen a rapid increase in digital medicine research in an attempt to transform traditional healthcare systems to their modern, intelligent, and versatile equivalents that are adequately equipped to tackle contemporary challenges. This has led to a wave of applications that utilise AI technologies; first and foremost in the fields of medical imaging, but also in the use of wearables and other intelligent sensors. In comparison, computer audition can be seen to be lagging behind, at least in terms of commercial interest. Yet, audition has long been a staple assistant for medical practitioners, with the stethoscope being the quintessential sign of doctors around the world. Transforming this traditional technology with the use of AI entails a set of unique challenges. We categorise the advances needed in four key pillars: Hear, corresponding to the cornerstone technologies needed to analyse auditory signals in real-life conditions; Earlier, for the advances needed in computational and data efficiency; Attentively, for accounting to individual differences and handling the longitudinal nature of medical data; and, finally, Responsibly, for ensuring compliance to the ethical standards accorded to the field of medicine. Thus, we provide an overview and perspective of HEAR4Health: the sketch of a modern, ubiquitous sensing system that can bring computer audition on par with other AI technologies in the strive for improved healthcare systems.


Surgical Treatment of Degenerative Disk Disease in Three Scandinavian Countries: An International Register Study Based on Three Merged National Spine Registers.
Observational study of prospectively collected data. Patients with chronic low back pain resistant to nonoperative treatment often face a poor prognosis for recovery. The aim of the current study was to compare the variation and outcome of surgical treatment of degenerative disc disease in the Scandinavian countries based on The International Consortium for Health Outcomes Measurement core spine data sets. Anonymized individual level data from 3 national registers were pooled into 1 database. At the time of surgery, the patient reports data on demographics, lifestyle topics, comorbidity, and data on health-related quality of life such as Oswestry Disability Index, Euro-Qol-5D, and back and leg pain scores. The surgeon records diagnosis, type of surgery performed, and complications. One-year follow-ups are obtained with questionnaires. Baseline and 1-year follow-up data were analyzed to expose any differences between the countries. A total of 1893 patients were included. At 1-year follow-up, 1315 (72%) patients responded. There were statistically significant baseline differences in age, smoking, comorbidity, frequency of previous surgery and intensity of back and leg pain. Isolated fusion was the primary procedure in all the countries ranging from 84% in Denmark to 76% in Sweden. There was clinically relevant improvement in all outcome measures except leg pain. In homogenous populations with similar health care systems the treatment traditions can vary considerably. Despite variations in preoperative variables, patient reported outcomes improve significantly and clinically relevant with surgical treatment.


Guidance of callosal axons by radial glia in the developing cerebral cortex.
During development, columns of the mammalian cerebral cortex are formed by migration of neurons along fascicles of radial glia. Subsequently, axons of the corpus callosum connect reciprocal regions of each cerebral hemisphere. To determine whether the radial growth of callosal afferents through the developing cortex may be guided by particular cellular elements, we examined the ultrastructural relationship between callosal afferents and radial fibers in the early postnatal hamster sensorimotor cortex. Developing callosal axons and their growth cones were labeled with HRP injected into the cortex at 3 d postnatal when the growth cones have extended across the callosum and are just entering the contralateral cortex. An EM analysis of 30 HRP-labeled axons and their growth cones revealed that they extended upon fascicles of radial processes associated with migrating neurons. Reconstruction of seven of these growth cones, serially sectioned in their entirety, showed that growth cones were associated with the same radial fascicle as their axon. Growth cones also touched other cellular elements such as axons. However, the finding that callosal afferents, from the point at which they enter the cortex to their growth cones, were apposed to a continuous fascicle of radial fibers suggests that callosal axons are tracking along radial processes. We conclude that the majority of the radial processes within fascicles are likely to be glial, based on their relatively large diameters, electron-lucent cytoplasm with a regular array of microtubules, the presence of glycogen granules, occasional cytoplasmic protrusions lacking microtubules, and their consistent association with migrating neurons. We propose therefore that radial glia may serve a guidance function for growing callosal axons in their radial trajectory through the developing cerebral cortex.


Measures of maturation in early fossil hominins: events at the first transition from australopiths to early Homo.
An important question in palaeoanthropology is whether, among the australopiths and the first fossil hominins attributed to early Homo, there was a shift towards a more prolonged period of growth that can be distinguished from that of the living great apes and whether between the end of weaning and the beginning of puberty there was a slow period of growth as there is in modern humans. Evidence for the pace of growth in early fossil hominins comes from preserved tooth microstructure. A record of incremental growth in enamel and dentine persists, which allows us to reconstruct tooth growth and compare key measures of dental maturation with modern humans and living great apes. Despite their diverse diets and way of life, it is currently difficult to identify any clear differences in the timing of dental development among living great apes, australopiths and the earliest hominins attributed to the genus Homo There is, however, limited evidence that some early hominins may have attained a greater proportion of their body mass and stature relatively earlier in the growth period than is typical of modern humans today.This article is part of the themed issue 'Major transitions in human evolution'.


Brown adipose tissue uncoupling protein content in human infants, children and adults.
A solid-phase radioimmunoassay is described for the estimation of the uncoupling protein content of human brown adipose tissue mitochondria, as an index of thermogenic capacity. The concentration of inner mitochondrial membrane uncoupling protein was measured in brown adipose tissue samples from 48 individuals who died suddenly. The uncoupling protein content of axillary adipose tissue was greater than that of perirenal adipose tissue. Variations in brown adipose tissue uncoupling protein content, which would be consistent with changing thermogenic requirements and capacity, were observed in different groups of subjects. Significantly lower concentrations were found in adults and in pre-term and stillborn infants than in older infants and children.


Indirect Energy Flows in Niche Model Food Webs: Effects of Size and Connectance.
Indirect interactions between species have long been of interest to ecologists. One such interaction type takes place when energy or materials flow via one or more intermediate species between two species with a direct predator-prey relationship. Previous work has shown that, although each such flow is small, their great number makes them important in ecosystems. A new network analysis method, dynamic environ approximation, was used to quantify the fraction of energy flowing from prey to predator over paths of length greater than 1 (flow indirectness or FI) in a commonly studied food web model. Web structure was created using the niche model and dynamics followed the Yodzis-Innes model. The effect of food web size (10 to 40 species) and connectance (0.1 to 0.48) on FI was examined. For each of 250 model realizations run for each pair of size and connectance values, the FI of every predator-prey interaction in the model was computed and then averaged over the whole network. A classification and regression tree (CART) analysis was then used to find the best predictors of FI. The mean FI of the model food webs is 0.092, with a standard deviation of 0.0279. It tends to increase with system size but peaks at intermediate connectance levels. Of 27 potential predictor variables, only five (mean path length, dominant eigenvalue of the adjacency matrix, connectance, mean trophic level and fraction of species belonging to intermediate trophic levels) were selected by the CART algorithm as best accounting for variation in the data; mean path length and the dominant eigenvalue of the adjacency matrix were dominant.


Adapting Open Dialogue for Early-Onset Psychosis Into the U.S. Health Care Environment: A Feasibility Study.
Open Dialogue (OD) is a Finnish approach to crisis intervention and ongoing care for young people experiencing psychosis and other psychiatric crises. OD engages the individual and family (or other supports) in meetings, with open discussions of all aspects of the clinical situation, and in decision making. Although psychiatric assessment and treatment occur, the initial emphasis is on engagement, crisis intervention, and promoting dialogue. Finnish studies are encouraging, with excellent clinical and functional outcomes after five years. The authors conducted a one-year study of the feasibility of implementing an outpatient program based on OD principles, serving 16 young people ages 14-35 experiencing psychosis-the first study of OD in the United States. Qualitative and quantitative findings suggest that this model can be successfully implemented in the United States and can achieve good clinical outcomes, high satisfaction, and shared decision making.


Effects of hemoglobin vesicles on resting and agonist-stimulated human platelets in vitro.
Hemoglobin vesicles (HbV) are artificial oxygen carriers that encapsulate a concentrated hemoglobin (Hb) solution with a phospholipid bilayer membrane. The oxygen transporting ability of HbV in vivo has been demonstrated by the transfusion of HbV into hemorrhagic shock rodent models. However, the compatibility of HbV with human blood cells must be evaluated. Preincubation of platelets with concentrations of 20% or 40% HbV had no effect on the binding of PAC-1, a monoclonal antibody that detects activation-dependent conformational changes in alphaIIbbeta3 on platelets, or the surface expression of CD62P in whole blood. ADP-induced increases in PAC-1 binding were significantly enhanced by exposing the platelets to concentrations of either 20% or 40% HbV, whereas the ADP-induced increases in CD62P expression were not affected by HbV treatment at either concentration. Preincubation of platelet-rich plasma (PRP) with HbV minimally reduced the spontaneous release of TXB2 and RANTES, but did not significantly affect the formation of TXB2 or the release of RANTES and beta-TG in platelets stimulated with ADP. Similarly, preincubation of PRP with HbV minimally reduced the spontaneous release of RANTES but did not significantly affect the formation of TXB2 or the release of RANTES and beta-TG in platelets stimulated with collagen, although collagen-induced serotonin release tended to decrease with HbV pretreatment. These data suggest that the exposure of human platelets to high concentrations of HbV (up to 40%) in vitro did not cause platelet activation and did not adversely affect the formation and secretion of prothrombotic substances or proinflammatory substances triggered by platelet agonists, although one of the earliest events in ADP-induced platelet activation was slightly potentiated by HbV pretreatment at the doses tested. Taken together, these results imply that HbV, at concentrations of up to 40%, do not have any aberrant interactions with either unstimulated or agonist-induced platelets.


Unified Model for Photophysical and Electro-Optical Properties of Green Fluorescent Proteins.
Green fluorescent proteins (GFPs) have become indispensable imaging and optogenetic tools. Their absorption and emission properties can be optimized for specific applications. Currently, no unified framework exists to comprehensively describe these photophysical properties, namely the absorption maxima, emission maxima, Stokes shifts, vibronic progressions, extinction coefficients, Stark tuning rates, and spontaneous emission rates, especially one that includes the effects of the protein environment. In this work, we study the correlations among these properties from systematically tuned GFP environmental mutants and chromophore variants. Correlation plots reveal monotonic trends, suggesting that all these properties are governed by one underlying factor dependent on the chromophore's environment. By treating the anionic GFP chromophore as a mixed-valence compound existing as a superposition of two resonance forms, we argue that this underlying factor is defined as the difference in energy between the two forms, or the driving force, which is tuned by the environment. We then introduce a Marcus-Hush model with the bond length alternation vibrational mode, treating the GFP absorption band as an intervalence charge transfer band. This model explains all of the observed strong correlations among photophysical properties; related subtopics are extensively discussed in the Supporting Information. Finally, we demonstrate the model's predictive power by utilizing the additivity of the driving force. The model described here elucidates the role of the protein environment in modulating the photophysical properties of the chromophore, providing insights and limitations for designing new GFPs with desired phenotypes. We argue that this model should also be generally applicable to both biological and nonbiological polymethine dyes.


Reduction of oxidative stress does not affect recovery of myocardial function: warm continuous versus cold intermittent blood cardioplegia.
To compare oxidative stress after cardiac surgery in patients treated with two different methods of myocardial protection: warm continuous versus cold intermittent blood cardioplegia. To correlate oxidative stress with postoperative myocardial dysfunction. Prospective, randomised, double blind, trial. Institutional centre of cardiovascular surgery. 20 patients were selected for coronary artery bypass surgery (CABG) on the following basis: stable angina, ejection fraction > 50%, double or triple vessel disease, no previous CABG or associated disease. Patients were randomised to two groups of 10 patients each. Patients underwent CABG with one of two different methods of myocardial protection and cardiopulmonary bypass. CBC group: intermittent cold blood antegrade-retrograde cardioplegia with moderate hypothermic cardiopulmonary bypass; WBC group: continuous warm blood antegrade-retrograde cardioplegia with mild hypothermic cardiopulmonary bypass. The index of oxidative stress used was the alteration of whole blood and plasma glutathione redox status. Samples were collected from the coronary sinus and peripheral vein before anaesthesia (T1), before aortic unclamping (T2), 15 minutes (T3), and 30 minutes (T4) after unclamping. Haemodynamic parameters were measured with thermodilution techniques. Oxidised glutathione and glutathione-cysteine mixed disulphide significantly increased in the coronary sinus plasma in the CBC group, and the overall redox balance of glutathione was decreased (P < 0.01) at T2-T4 versus T1, and compared with the WBC group. Comparable results were obtained for coronary sinus blood. There was no correlation between postoperative haemodynamic measurements and oxidative stress markers. Oxidative stress was significant in patients undergoing CABG using cold blood cardioplegia, while the warm technique minimised the effects of ischaemia. However, oxidative stress was not correlated with myocardial dysfunction following CABG.


What is the impact of shift work on the psychological functioning and resilience of nurses? An integrative review.
To synthesize existing research to determine if nurses who work shifts have poorer psychological functioning and resilience than nurses who do not work shifts. Research exploring the impact of shift work on the psychological functioning and resilience of nurses is limited compared with research investigating the impact of shifts on physical outcomes. Integrative literature review. Relevant databases were searched from January 1995-August 2016 using the combination of keywords: nurse, shift work; rotating roster; night shift; resilient; hardiness; coping; well-being; burnout; mental health; occupational stress; compassion fatigue; compassion satisfaction; stress; anxiety; depression. Two authors independently performed the integrative review processes proposed by Whittemore and Knafl and a quality assessment using the mixed-methods appraisal tool by Pluye et al. A total of 37 articles were included in the review (32 quantitative, 4 qualitative and 1 mixed-methods). Approximately half of the studies directly compared nurse shift workers with non-shift workers. Findings were grouped according to the following main outcomes: (1) general psychological well-being/quality of life; (2) Job satisfaction/burnout; (3) Depression, anxiety and stress; and (4) Resilience/coping. We did not find definitive evidence that shift work is associated with poorer psychological functioning in nurses. Overall, the findings suggest that the impact of shift work on nurse psychological functioning is dependent on several contextual and individual factors. More studies are required which directly compare the psychological outcomes and resilience of nurse shift workers with non-shift workers.


The generalized uniqueness wavelet descriptor for planar closed curves.
In the problem of specifying a well-defined wavelet description of a planar closed curve, defining a unique start point on the curve is crucial for wavelet representation. In this paper, a generalized uniqueness property inherent in the one-dimensional (1-D) discrete periodized wavelet transformation (DPWT) is derived. The uniqueness property facilitates a quantitative analysis of the one-to-one mapping between the variation of 1-D DPWT coefficients and the starting point shift of the originally sampled curve data. By employing the uniqueness property, a new shape descriptor called the uniqueness wavelet descriptor (UWD) by which the starting point is fixed entirely within the context of the wavelet representation is proposed. The robustness of the UWD against input noise is analyzed. On the basis of local shape characteristic enhancement, several experiments were conducted to illustrate the adaptability property of the UWD for desirable starting point determination. Our experiments of pattern recognition show that the UWD can provide a supervised pattern classifier with optimal features to obtain the best matching performance in the presence of heavy noise. In addition, the generalized uniqueness property can be used for the shape regularity measurement. The UWD does not have local support and therefore it can not be applied to contour segments.


A global health partnership's use of time-limited support to catalyze health practice change: the case of GAVI's Injection Safety Support.
This paper presents the findings of a study to assess the effectiveness and sustainability of a GAVI (Global Alliance of Vaccines and Immunization) sponsored, time-limited Injection Safety (INS) support. The support came in two forms: 1) in-kind, in the form of AD syringes and safety boxes, and 2) in cash, for those countries that already had a secure, multi-year source of AD syringes and safety boxes, but proposed to use INS support to strengthen their injection safety activities. In total, GAVI gave INS support for a three-year period to 58 countries: 46 with commodities and 12 with cash support. To identify variables that might be associated with financial sustainability, frequencies and cross-tabulations were run against various programmatic and socio-economic variables in the 58 countries. All but two of the 46 commodity-recipient countries were able to replace and sustain the use of AD syringes and safety boxes after the end of their GAVI INS support despite the fact that standard disposable syringes are less costly than ADs (10-15 percent differential). In addition, all 12 cash-recipient countries continued to use AD syringes and safety boxes in their immunization programs in the years following GAVI INS assistance. At the same time, countries were often not prepared for the increased waste management requirements associated with the use of the syringes, suggesting the importance of anticipating challenges with the introduction of new technologies. The sustained use of AD syringes in countries receiving injection safety support from GAVI, in a majority of cases through government financing, following the completion of three years of time-limited support, represents an early indication of how GHPs can contribute to improved health outcomes in immunization safety in the world's poorest countries in a sustainable way.


Tumor location and IDH1 mutation may predict intraoperative seizures during awake craniotomy.
Intraoperative seizures during awake craniotomy may interfere with patients' ability to cooperate throughout the procedure, and it may affect their outcome. The authors have assessed the occurrence of intraoperative seizures during awake craniotomy in regard to tumor location and the isocitrate dehydrogenase 1 (IDH1) status of the tumor. Data were collected in 137 consecutive patients who underwent awake craniotomy for removal of a brain tumor. The authors performed a retrospective analysis of the incidence of seizures based on the tumor location and its IDH1 mutation status, and then compared the groups for clinical variables and surgical outcome parameters. Tumor location was strongly associated with the occurrence of intraoperative seizures. Eleven patients (73%) with tumor located in the supplementary motor area (SMA) experienced intraoperative seizures, compared with 17 (13.9%) with tumors in the other three non-SMA brain regions (p < 0.0001). Interestingly, there was no significant association between history of seizures and tumor location (p = 0.44). Most of the patients (63.6%) with tumor in the SMA region harbored an IDH1 mutation compared with those who had tumors in non-SMA regions. Thirty-one of 52 patients (60%) with a preoperative history of seizures had an IDH1 mutation (p = 0.02), and 15 of 22 patients (68.2%) who experienced intraoperative seizures had an IDH1 mutation (p = 0.03). In a multivariate analysis, tumor location was found as a significant predictor of intraoperative seizures (p = 0.002), and a trend toward IDH1 mutation as such a predictor was found as well (p = 0.06). Intraoperative seizures were not associated with worse outcome. Patients with tumors located in the SMA are more prone to develop intraoperative seizures during awake craniotomy compared with patients who have a tumor in non-SMA frontal areas and other brain regions. The IDH1 mutation was more common in SMA region tumors compared with other brain regions, and may be an additional risk factor for the occurrence of intraoperative seizures.


Flow disturbances in stent-related coronary evaginations: a computational fluid-dynamic simulation study.
Angiographic ectasias and aneurysms in stented segments have been associated with late stent thrombosis. Using optical coherence tomography (OCT), some stented segments show coronary evaginations reminiscent of ectasias. The purpose of this study was to explore, using computational fluid-dynamic (CFD) simulations, whether OCT-detected coronary evaginations can induce local changes in blood flow. OCT-detected evaginations are defined as outward bulges in the luminal vessel contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evaginations can be characterised cross-sectionally by depth and along the stented segment by total length. Assuming an ellipsoid shape, we modelled 3-D evaginations with different sizes by varying the depth from 0.2-1.0 mm, and the length from 1-9 mm. For the flow simulation we used average flow velocity data from non-diseased coronary arteries. The change in flow with varying evagination sizes was assessed using a particle tracing test where the particle transit time within the segment with evagination was compared with that of a control vessel. The presence of the evagination caused a delayed particle transit time which increased with the evagination size. The change in flow consisted locally of recirculation within the evagination, as well as flow deceleration due to a larger lumen - seen as a deflection of flow towards the evagination. CFD simulation of 3-D evaginations and blood flow suggests that evaginations affect flow locally, with a flow disturbance that increases with increasing evagination size.


Acute wound healing in the human central corneal epithelium appears to be independent of limbal stem cell influence.
In the adult cornea, epithelial cells are maintained by limbal stem cells (LSCs) that cycle slowly and give rise to transient amplifying (TA) cells. These migrate centripetally, differentiate outward to the surface, and are then lost by desquamation. This study was conducted to analyze the contribution of human central corneal epithelial cells toward corneal epithelial regeneration. A human corneal organotypic culture model was used to assess corneal healing in vitro in 12 matched cornea pairs. Two types of ablation were studied: (1) A ring-shaped, transepithelial, excimer laser (193 nm) ablation, of 7 mm outer diameter and 3 mm inner diameter, to a depth of 80 mum-sparing the central and peripheral corneal epithelium; and (2) an ablation pattern identical to that in (1) with ablation of the limbal epithelium in addition. Corneal healing was followed using time-lapse dark-field microscopy for up to 12 hours, and the corneas were analyzed by using immunohistochemical markers for cell proliferation and stem cells. In the donut model, corneal epithelial repair originated from both the limbus and the central corneal epithelium with the average rate of epithelial recovery from the center being similar to the rate from the periphery (0.06 +/- 0.01 mm/h vs. 0.07 +/- 0.03 mm/h, P = 0.44). When the area of recovery was calculated relative to original edge circumferences, the central epithelial rate tended to be faster than the peripheral (0.06 +/- 0.02 mm(2)/mm/h vs. 0.04 +/- 0.01 mm(2)/mm/h, P = 0.04). Similar rates in epithelial recovery were identified in centripetal and centrifugal directions in both the donut and donut+limbus ablation models. Central epithelial cell density increased 36% over the control cornea within 12 hours after surgery, but there was no change at the periphery. Cell proliferation, assessed using Ki67 and BrdU labeling, was observed across the entire cornea. Expression of the putative stem cell markers p63 and ABCG2 was clearly evident in the basal layer of the limbus. However, weaker labeling was also observed in the central epithelium. Connexin 43 (Cx43), a differentiation marker, was mainly absent in the normal untreated limbal basal cells, but more Cx43-positive cells were labeled in the basal layer of the limbus after wounding. After wounding, the capacity for epithelial cell proliferative and migration appears to be as active in the central cornea as in the periphery/limbus. Central and peripheral epithelial recovery remains equal even after ablation of the limbus. Central human corneal epithelial cells are therefore capable of corneal epithelial regeneration, at least in the first 12 hours after wounding.