The CHAPS, SIFTER, and TAPS-R as predictors of (C)AP skills and (C)APD.
In this study, the authors investigated the relationships between 3 tests used to screen for (central) auditory processing disorder ([C]APD)--the Children's Auditory Performance Scale (CHAPS; W. J. Smoski, M. A. Brunt, & J. C. Tannahill, 1998), the Screening Instrument for Targeting Educational Risk (SIFTER; K. Anderson, 1989), and the Test of Auditory Perceptual Skills--Revised (TAPS-R; M. Y. Gardner, 1997)-and 4 tests used to diagnostically assess for (C)APD: Low-Pass Filtered Speech (LPFS), Competing Sentences (CS), Two-Pair Dichotic Digits (DD), and Frequency Patterns With Linguistic Report (FP). The screening and diagnostic (C)APD tests results of 104 children (71 boys, 33 girls) aged 6.9-14.3 years were reviewed following their attendance at a university clinic in Brisbane, Australia. Pearson's product-moment correlation coefficient analysis showed weak (r = .22, p < .05) to moderate (r = .47, p < .01) correlations predominantly between the short-term and working memory test results of the TAPS-R and the DD and FP test results of the (C)AP test battery. Linear and binary logistic regression analyses showed a poor ability of the CHAPS, SIFTER, and TAPS-R test results to predict the individual LPFS, CS, DD, or FP test results or the overall risk for (C)APD. The CHAPS, SIFTER, and TAPS-R should be used to highlight concerns about a child but not to determine whether a diagnostic (C)AP assessment is particularly warranted.


Adhesion of echinoderm tube feet to rough surfaces.
Echinoderms attach strongly and temporarily to the substratum by means of specialized organs, the podia or tube feet. The latter consist of a basal extensible cylinder, the stem, which bears an apical flattened disc. The disc repeatedly attaches to and detaches from the substratum through adhesive and de-adhesive secretions. In their activities, echinoderms have to cope with substrata of varying degrees of roughness as well as with changing hydrodynamic conditions, and therefore their tube feet must adapt their attachment strength to these environmental constraints. This study is the first attempt to evaluate the influence of substratum roughness on the temporary adhesion of echinoderm tube feet and to investigate the material properties of their contact surface. It was demonstrated that tube foot discs are very soft (E-modulus of 6.0 and 8.1 kPa for sea stars and sea urchins, respectively), have viscoelastic properties and adapt their surface to the substratum profile. They also show increased adhesion on a rough substratum in comparison to its smooth counterpart, which is due mostly to an increase in the geometrical area of contact between the disc and the surface. Tenacity (force per unit area) increases with roughness [e.g. 0.18 and 0.34 MPa on smooth polymethyl-methacrylate (PMMA), 0.21 and 0.47 MPa on rough PMMA for sea stars and sea urchins, respectively] if only the projected surface area of the adhesive footprint is considered. However, if this tenacity is corrected to take into account the actual substratum 3-D profile, surface roughness no longer influences significantly the corrected adhesion strength (e.g. 0.18 and 0.34 MPa on smooth PMMA, 0.19 and 0.42 MPa on rough PMMA for sea stars and sea urchins, respectively). It can be hypothesized that, under slow self-imposed forces, disc material behaves viscously to adapt to substratum roughness while the adhesive fills out only very small surface irregularities (in the nanometer range). It is deposited as a thin film ideal for generation of strong adhesion. Under short pulses of wave-generated forces, attached discs probably behave elastically, distributing the stress along the entire contact area, in order to avoid crack generation and thus precluding disc peeling and tube foot detachment.


A proposed architecture for ambulatory systems development.
We have developed an architecture and application framework known as the Ambulatory Services Architecture (ASA) for computerized management of patient records for ambulatory care. Our primary design goals included the development of an architecture that will be readily adaptable to advances in technology needed to enhance computerized patient record systems (e.g., multimedia, human-computer interfaces such as voice-to-text, and a fully distributed objects, etc.) and a data model and database implementation capable of providing the flexibility and extensibility needed to support a broad spectrum of specialty medical practices. This report describes the data model, access control, and the client/server components of the Ambulatory Services Architecture.


Improving the Identification and Coverage of Plant Transmembrane Proteins in Medicago Using Bottom-Up Proteomics.
Plant transmembrane proteins (TMPs) are essential for normal cellular homeostasis, nutrient exchange, and responses to environmental cues. Commonly used bottom-up proteomic approaches fail to identify a broad coverage of peptide fragments derived from TMPs. Here, we used mass spectrometry (MS) to compare the effectiveness of two solubilization and protein cleavage methods to identify shoot-derived TMPs from the legume Medicago. We compared a urea solubilization, trypsin Lys-C (UR-TLC) cleavage method to a formic acid solubilization, cyanogen bromide and trypsin Lys-C (FA-CTLC) cleavage method. We assessed the effectiveness of these methods by (i) comparing total protein identifications, (ii) determining how many TMPs were identified, and (iii) defining how many peptides incorporate all, or part, of transmembrane domains (TMD) sequences. The results show that the FA-CTLC method identified nine-fold more TMDs, and enriched more hydrophobic TMPs than the UR-TLC method. FA-CTLC identified more TMPs, particularly transporters, whereas UR-TLC preferentially identified TMPs with one TMD, particularly signaling proteins. The results suggest that combining plant membrane purification techniques with both the FA-CTLC and UR-TLC methods will achieve a more complete identification and coverage of TMPs.


[Verification of rotational conformation radiotherapy using megavoltage CT scanning].
Although portal imaging is a promising method of verification during static multi-port irradiation, it cannot be applied directly to dynamic irradiation such as rotational conformation with multi-leaf collimator movement. A real-time beam monitoring system based on megavoltage computed tomography scanning has been developed to establish a verification method for the rotational conformation technique. The exit beam through the patient is extracted by the same detector unit as that used for megavoltage scanning during the actual treatment. The beam edge is defined as the 50% level of the maximum dose of the detector array. Megavoltage computed tomography is done after patient setup and just prior to the actual irradiation. Detected beam pathways are overlaid on this image approximately every 1 sec. Therapists can monitor the correlation between the target and actual beam pathways on a real-time computer display. The accuracy of field edge detection has been proven to be less than 2 mm from various measurements. Field errors were identified in two of 54 sessions using this method. Although several limitations remain to be solved, the method presented is an useful tool for treatment verification of high accuracy radiation therapy, particularly rotational conformation irradiation.


Inflammation and vascular injury: basic discovery to drug development.
The invited special lecture at the 76(th) Annual Scientific Meeting of the Japanese Circulation Society focused on the central role of inflammation in vascular injury and repair. Early studies pioneered the concept that mechanical injury, such as balloon angioplasty and endovascular stent deployment, elicits an inflammatory response from the vessel wall. This hypothesis was developed and substantiated at a time when the prevailing dogma viewed restenosis following angioplasty as a primarily proliferative smooth muscle cell disease. Antibody targeting of Mac-1 reduced leukocyte accumulation and limited neointimal formation following balloon injury or stent implantation. Genetic absence of Mac-1 resulted in diminished leukocyte accumulation and neointimal thickening after carotid artery injury in mice. In the course of those studies, our laboratory made fundamental discoveries regarding the mechanism of leukocyte recruitment at sites of vascular injury and identified platelet glycoprotein (GP) Ibα, a component of the GPIb-IX-V complex, as the previously unknown platelet counter-receptor for Mac-1. Follow-on studies have focused extensively on the structure, function, and signaling of the leukocyte integrin Mac-1. The binding site for GPIbα in Mac-1 has been mapped and subsequently showed that leukocyte engagement of platelet GPIbα via Mac-1 is critical not only for the biological response to vascular injury, but also for thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis, thereby advancing the hypothesis that virtually all inflammation is platelet-dependent. Furthermore, ligand engagement of Mac-1 initiates a novel gene program that promotes inflammation by activating NFκB and downregulating the expression of the forkhead transcription factor Foxp1 that controls monocyte differentiation. Small molecule inhibitors of Mac-1 function have been pursued, including targeting of Mac-1-GPIbα binding or the downstream tyrosine kinase spleen tyrosine kinase. Drs Teruo Inoue, Koichi Node, Tatsuya Fukotomi, Masashi Sakuma, Toshifumi Morooka, and Kohsuke Nakajima, valued Japanese collaborators and post-doctoral fellows, have contributed enormously to these discoveries.


Characterization of the human p53 gene promoter.
Transcriptional deregulation of the p53 gene may play an important part in the genesis of some tumors. We report here an accurate determination of the transcriptional start sites of the human p53 gene and show that the majority of p53 mRNA molecules do not contain a postulated stem-loop structure at their 5' ends. Recombinant plasmids of the human p53 promoter-leader region fused to the bacterial chloramphenicol acetyltransferase gene (cat) were constructed. After transfection into rodent or human cells, a 350-base-pair fragment spanning the promoter region conferred 4% of the CAT activity mediated by the simian virus 40 early promoter/enhancer. We monitored the efficiency with which 15 3' and 5' promoter deletion constructs initiated transcription. Our results show that an 85-base-pair fragment, previously thought to have resided in exon 1, is all that is required for full promoter activity.


The electric double layer at a rutile TiO₂ water interface modelled using density functional theory based molecular dynamics simulation.
A fully atomistic model of a compact electric double layer at the rutile TiO2(1 1 0)-water interface is constructed by adding protons to bridging oxygens or removing them from H2O molecules adsorbed on terminal metal cation sites. The surface charge is compensated by F(-) or Na(+) counter ions in outer as well as inner sphere coordination. For each of the protonation states the energy of the TiO2 conduction band minimum is determined relative to the standard hydrogen electrode by computing the free energy for the combined insertion of an electron in the solid and a proton in solution away from the double layer using density functional theory based molecular dynamics methods. Interpreted as electrode potentials, this gives an estimate of the capacitance which is compared to the capacitance obtained from the difference in the average electrostatic potentials in the solid and aqueous phase. When aligned at the point of zero charge these two methods lead to almost identical potential-charge profiles. We find that inner sphere complexes have a slightly larger capacitance (0.4 F m(-2)) compared to outer sphere complexes (0.3 F m(-2)).


Characterization of the activity and folding of the glutathione transferase from Escherichia coli and the roles of residues Cys(10) and His(106).
GSTs (glutathione transferases) are an important class of enzymes involved in cellular detoxification. GSTs are found in all classes of organisms and are implicated in resistance towards drugs, pesticides, herbicides and antibiotics. The activity, structure and folding, particularly of eukaryotic GSTs, have therefore been widely studied. The crystal structure of EGST (GST from Escherichia coli) was reported around 10 years ago and it suggested Cys(10) and His(106) as potential catalytic residues. However, the role of these residues in catalysis has not been further investigated, nor have the folding properties of the protein been described. In the present study we investigated the contributions of residues Cys(10) and His(106) to the activity and stability of EGST. We found that EGST shows a complex equilibrium unfolding profile, involving a population of at least two partially folded intermediates, one of which is dimeric. Mutation of residues Cys(10) and His(106) leads to stabilization of the protein and affects the apparent steady-state kinetic parameters for enzyme catalysis. The results suggest that the imidazole ring of His(106) plays an important role in the catalytic mechanism of the enzyme, whereas Cys(10) is involved in binding of the substrate, glutathione. Engineering of the Cys(10) site can be used to increase both the stability and GST activity of EGST. However, in addition to GST activity, we discovered that EGST also possesses thiol:disulfide oxidoreductase activity, for which the residue Cys(10) plays an essential role. Further, tryptophan quenching experiments indicate that a mixed disulfide is formed between the free thiol group of Cys(10) and the substrate, glutathione.


Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS.
The application of inspiratory occlusion stimuli produces cortical responses called respiratory-related evoked potentials (RREPs). During wakefulness the RREP waveform consists of early P1 and Nf components, an N1 and a P300. During non-REM sleep the predominant component is an N550, best seen in the averages of elicited K-complexes. Obstructive sleep apnea syndrome (OSAS) patients have been previously shown to have a normal wake RREP but to have a reduced amplitude N550 and a smaller proportion of elicited K-complexes than controls. The present study tested the hypothesis that this reflects a sleep-specific dampening peculiar to inspiratory effort-related stimuli, by assessing both respiratory and auditory evoked potentials (AEPs) during wakefulness and non-REM sleep in OSAS patients and controls. Auditory tones were presented in an oddball sequence during wakefulness and as a monotonous series during stage 2 sleep. Inspiratory occlusions, delivered for 500 msec via an nCPAP mask were also presented during wakefulness and stage 2 sleep, every three to five breaths. Data were collected from ten OSAS patients and ten controls. There were no significant differences in the amplitudes of the auditory N1 and P3 or the respiratory P1, Nf, N1 or P3 components during wakefulness. The amplitude of the auditory N550 and the proportion of elicited K-complexes did not differ between groups for auditory stimuli presented during stage 2 sleep. The respiratory N550 and K-complex elicitation rate were both significantly reduced in the OSAS group, despite there being no differences in the mask occlusion pressure response to the occlusion. The results confirm a blunted cortical response to inspiratory occlusions that is specific to sleep. The absence of significant group differences in the responses to auditory stimuli highlight that the sleep-related differences seen in OSAS patients are specific to the processing of inspiratory effort related stimuli.


The dynamics of neurological disease: integrating computational, experimental and clinical neuroscience.
There is a vast (and rapidly growing) amount of experimental and clinical data of the nervous system at very diverse spatial scales of activity (e.g. from sub-cellular through to whole organ), with many neurological disorders characterized by oscillations in neural activity across these disparate scales. Computer modelling and the development of associated mathematical theories provide us with a unique opportunity to integrate information from across these diverse scales of activity; leading to explanations of the potential mechanisms underlying the time-evolving dynamics and, more importantly, allowing the development of new hypotheses regarding neural function that may be tested experimentally and ultimately translated into the clinic. The purpose of this special issue is to present an overview of current integrative research in the areas of epilepsy, Parkinson's disease and schizophrenia, where multidisciplinary relationships involving theory, experimental and clinical research are becoming increasingly established.


Autotransplantation of splenic fragments: lymphocyte subsets in blood, lymph nodes and splenic tissue.
Abnormal ratios of T helper-type to T suppressor-type lymphocytes in the blood of patients with replanted autologous splenic tissue led to the present study in rats. Lymphocyte subsets were studied in the blood, mesenteric lymph nodes and spleen after autotransplantation and compared to splenectomized and control rats. In the blood of transplanted rats the percentage of T and T helper-type lymphocytes was lower, in the spleen B lymphocytes higher and T lymphocytes and their subsets lower. Comparable changes were seen in the lymph nodes. The data of the mesenteric lymph nodes in autotransplanted rats did not differ from splenectomized animals. Even after 37 weeks the regenerated splenic tissue only reached 13% of the weight of control rats and the absolute lymphocyte number was only 2.5% of a normal spleen. Splenic autotransplantation results in a small hypocellular mass of splenic tissue with a different composition of lymphocyte subsets and does not correct the obvious effect of splenectomy on lymphocyte subpopulations in lymph nodes.


CXCR2 receptor antagonists: a medicinal chemistry perspective.
Dysregulated leukocyte recruitment is believed to be a key contributor to various acute and chronic inflammatory disorders which can lead to serious pathological consequences. Chemokines are small molecular weight proteins that have been shown to be imperative in the direction of leukocytes to the sites of inflammation. In humans, several of these chemokines (CXCL8 and CXCL1) are elevated in inflammatory disorders such as asthma, arthritis, and chronic obstructive pulmonary disease (COPD). These chemokines modulate their downstream effects thru G-protein coupled receptors, such as CXCR2, making the identification of small-molecule antagonists of this receptor attractive towards developing novel therapies to treat inflammatory conditions. Since the first report of a CXCR2 receptor antagonist in 1998, there has been a considerable effort conducted mainly in the pharmaceutical industry to identify novel classes of CXCR2 receptor antagonists. Over a dozen distinct classes of CXCR2 receptor antagonists have been reported in the literature to date with a number of these compounds having reached mid-stage clinical trials. This review will provide a broad overview the medicinal chemistry efforts over the past 15 years towards the identification of CXCR2 receptor antagonists. The discussion will focus upon the early preclinical space covering the structure activity relationships (SAR), pharmacology, as well in preclinical in vivo evaluation for the different series of CXCR2 receptor antagonists. In addition, the available clinical data for the most advanced compounds in the clinic will be discussed and along with a perspective of the area moving forward.


A hydrogel derived from decellularized dermal extracellular matrix.
The ECM of mammalian tissues has been used as a scaffold to facilitate the repair and reconstruction of numerous tissues. Such scaffolds are prepared in many forms including sheets, powders, and hydrogels. ECM hydrogels provide advantages such as injectability, the ability to fill an irregularly shaped space, and the inherent bioactivity of native matrix. However, material properties of ECM hydrogels and the effect of these properties upon cell behavior are neither well understood nor controlled. The objective of this study was to prepare and determine the structure, mechanics, and the cell response in vitro and in vivo of ECM hydrogels prepared from decellularized porcine dermis and urinary bladder tissues. Dermal ECM hydrogels were characterized by a more dense fiber architecture and greater mechanical integrity than urinary bladder ECM hydrogels, and showed a dose dependent increase in mechanical properties with ECM concentration. In vitro, dermal ECM hydrogels supported greater C2C12 myoblast fusion, and less fibroblast infiltration and less fibroblast mediated hydrogel contraction than urinary bladder ECM hydrogels. Both hydrogels were rapidly infiltrated by host cells, primarily macrophages, when implanted in a rat abdominal wall defect. Both ECM hydrogels degraded by 35 days in vivo, but UBM hydrogels degraded more quickly, and with greater amounts of myogenesis than dermal ECM. These results show that ECM hydrogel properties can be varied and partially controlled by the scaffold tissue source, and that these properties can markedly affect cell behavior.


Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer.
Optimal adjuvant treatment for early-stage clear cell and serous endometrial cancer remains unclear. We report outcomes for women with surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I clear cell, serous, and mixed endometrial cancers following adjuvant vaginal cuff brachytherapy with or without chemotherapy. From April 1998 to January 2020, women with FIGO stage IA-IB clear cell, serous, and mixed endometrial cancer underwent surgery and adjuvant vaginal cuff brachytherapy. Seventy-six patients received chemotherapy. High-dose rate vaginal cuff brachytherapy was planned to a total dose of 21 gray in three fractions using a multichannel vaginal cylinder. The primary objective was to determine the effectiveness of adjuvant vaginal cuff brachytherapy and to identify surgicopathological risk factors that could portend towards worse oncological outcomes. A total of 182 patients were included in the analysis. Median follow-up was 5.3 years (2.3-12.2). Ten-year survival was 73.3%. Five-year cumulative incidence (CI) of vaginal, pelvic, and para-aortic relapse was 1.4%, 2.1%, and 0.9%, respectively. Five-year locoregional failure, any recurrence, peritoneal relapse, and other distant recurrence was 4.4%, 11.6%, 5.3%, and 6.7%, respectively. On univariate analysis, locoregional failure was worse for larger tumors (per 1 cm) (HR 1.9, 95% CI 1.2 to 3.0, p≤0.01). Any recurrence was worse for tumors of at least 3.5 cm (HR 3.8, 95% CI 1.3 to 11.7, p=0.02) and patients with positive/suspicious cytology (HR 4.4, 95% CI 1.5 to 12.4, p≤0.01). Ten-year survival for tumors of at least 3.5 cm was 56.9% versus 86.6% for those with smaller tumors (HR 2.9, 95% CI 1.4 to 5.8, p≤0.01). Ten-year survival for positive/suspicious cytology was 50.9% versus 77.4% (HR 2.2, 95% CI 0.9 to 5.4, p=0.09). Multivariate modeling demonstrated worse locoregional failure, any recurrence, and survival with larger tumors, as well as any recurrence with positive/suspicious cytology. Subgroup analysis demonstrated improved outcomes with the use of adjuvant chemotherapy in patients with large tumors or positive/suspicious cytology. Adjuvant vaginal cuff brachytherapy alone without chemotherapy is an appropriate treatment for women with negative peritoneal cytology and small, early-stage clear cell, serous, and mixed endometrial cancer. Larger tumors or positive/suspicious cytology are at increased risk for relapse and worse survival, and should be considered for additional upfront adjuvant treatments, such as platinum-based chemotherapy.


Combined effect of individual and neighborhood socioeconomic status on mortality in patients with newly diagnosed dyslipidemia: A nationwide Korean cohort study from 2002 to 2013.
The study aims to determine whether dyslipidemia patients living in less affluent neighborhood are at a higher risk of mortality compared to those living in more affluent neighborhoods. A population-based cohort study was conducted using a stratified representative sampling from the National Health Insurance claim data from 2002 to 2013. The target subjects comprise patients newly diagnosed with dyslipidemia receiving medication. We performed a survival analysis using the Cox proportional hazard model. Of 11,946 patients with dyslipidemia, 1053 (8.8%) subjects died during the follow-up period. Of the dyslipidemia patients earning a middle-class income, the adjusted HR in less affluent neighborhoods was higher than that in the more affluent neighborhoods compared to the reference category of high individual SES in more affluent neighborhoods (less affluent; hazard ratio (HR) = 1.64, 95% confidence interval (CI): 1.35-1.99 vs. more affluent; HR = 1.48, 95% CI: 1.20-1.81, respectively). We obtained consistent results in patients with lower income, wherein the adjusted HR in less affluent neighborhoods was higher than that in more affluent neighborhoods (less affluent; HR = 1.52, 95% CI: 1.16-1.97 vs. more affluent; HR = 1.41, 95% CI: 1.04-1.92, respectively). Living in a less affluent neighborhood contributes to higher mortality among dyslipidemia patients. The individual- and neighborhood-level variables cumulatively affect individuals such that the most at-risk individuals include those having both individual- and neighborhood-level risk factors. These findings raise important clinical and public health concerns and indicate that neighborhood SES approaches should be essentially considered in health-care policies similar to individual SES.


Time-related changes of the intestinal morphology of Atlantic salmon, Salmo salar L., at two different soybean meal inclusion levels.
Abstract Soybean meal (SBM) induces enteritis in the distal intestine of Atlantic salmon. The present study assesses the effects of SBM concentrations on the kinetics of the enteritis process. Fish of 300 g, kept at 12 degrees C, were fed diets with different SBM inclusions: 0%, 10% and 20% SBM for 57 days. Samples of the distal intestine of five fish per treatment were taken for histological and electron microscopical analysis. A semi-quantitative scoring system was used to assess the degree of the morphological changes induced by SBM feeding in the distal intestinal epithelium. The first signs of enteritis appeared earlier in the salmon fed the 20SBM diet than in those fed the 10SBM diet. Thereafter, the condition increased steadily, displaying no signs of recovery. Furthermore, at the lower concentration, the process marking the onset of enteritis began more gradually than at the higher concentration and it displayed a tendency to stabilize after 13-20 days of continuous feeding. Electron microscopy indicated that the endocytosis process was hampered at day 3 of 20SBM and at 7 days of 10SBM. Furthermore, a strong reduction of microvilli was already evident after 7 days of 20SBM feeding, thus indicating a decreased uptake capacity of the distal enterocytes. In addition, transformation and migration of eosinophilic granulocytes was observed, which, in combination with the lysozyme C immunoreactivity supports their protective role during the inflammatory process in the distal gut of Atlantic salmon. It can be concluded that the severity of enteritis and its kinetics are concentration-dependent, showing no signs of recovery during feeding with diets containing SBM.


Dopamine Receptor Dop1R2 Stabilizes Appetitive Olfactory Memory through the Raf/MAPK Pathway in Drosophila.
In Drosophila, dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative training increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of Dop1R2, Raf, or MAPK expression in KCs selectively impairs LTM, but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of Dop1R2 can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory.SIGNIFICANCE STATEMENT Dopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in Drosophila This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long-term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization.


Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment.
Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug-target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches.


Tracheal Rupture: A Rare Complication of Endotracheal Intubation.
Clinicians can encounter various complications after endotracheal intubation as a result of patient anatomy, difficult intubation, and time and number of interventions performed. A life-threatening complication of intubation is iatrogenic tracheal rupture that leads to pulmonary air leak syndromes. In this case report, we present a 10-month-old patient who presented to the healthcare center with cyanosis and cough after foreign body aspiration and underwent endotracheal intubation for hypoxia. In our report, we aim to draw attention to tracheal rupture, a complication that was identified in bronchoscopy and found to be associated with repeated interventions and stylet use.


The deforestation of Easter Island.
Easter Island deforestation has traditionally been viewed as an abrupt island-wide event caused by the prehistoric Rapanui civilization, which precipitated its own cultural collapse. This view emerges from early palaeoecological analyses of lake sediments, which showed a sudden and total replacement of palm pollen by grass pollen shortly after Polynesian settlement (800-1200 CE). However, further palaeoecological research has challenged this view, showing that the apparent abruptness and island-wide synchronicity of forest removal was an artefact due to the occurrence of a sedimentary gap of several millennia that prevented a detailed record of the replacement of palm-dominated forests by grass meadows. During the last decade, several continuous (gap-free) and chronologically coherent sediment cores encompassing the last millennia have been retrieved and analysed, providing a new picture of forest removal on Easter Island. According to these analyses, deforestation was not abrupt but gradual and occurred at different times and rates, depending on the site. Regarding the causes, humans were not the only factors responsible for forest clearing, as climatic droughts as well as climate-human-landscape feedbacks and synergies also played a role. In summary, the deforestation of Easter Island was a complex process that was spatially and temporally heterogeneous and took place under the actions and interactions of both natural and anthropogenic drivers. In addition, archaeological evidence shows that the Rapanui civilization was resilient to deforestation and remained healthy until European contact, which contradicts the occurrence of a cultural collapse. Further research should aim to obtain new continuous cores and make use of recently developed biomarker analyses to advance towards a holistic view of the patterns, causes and consequences of Easter Island deforestation.


Molecular and genetic organization of bands and interbands in the dot chromosome of Drosophila melanogaster.
The fourth chromosome smallest in the genome of Drosophila melanogaster differs from other chromosomes in many ways. It has high repeat density in conditions of a large number of active genes. Gray bands represent a significant part of this polytene chromosome. Specific proteins including HP1a, POF, and dSETDB1 establish the epigenetic state of this unique chromatin domain. In order to compare maps of localization of genes, bands, and chromatin types of the fourth chromosome, we performed FISH analysis of 38 probes chosen according to the model of four chromatin types. It allowed clarifying the dot chromosome cytological map consisting of 16 loose gray bands, 11 dense black bands, and 26 interbands. We described the relation between chromatin states and bands. Open aquamarine chromatin mostly corresponds to interbands and it contains 5'UTRs of housekeeping genes. Their coding parts are embedded in gray bands substantially composed of lazurite chromatin of intermediate compaction. Polygenic black bands contain most of dense ruby chromatin, and also some malachite and lazurite. Having an accurate map of the fourth chromosome bands and its correspondence to physical map, we found that DNase I hypersensitivity sites, ORC2 protein, and P-elements are mainly located in open aquamarine chromatin, while element 1360, characteristic of the fourth chromosome, occupies band chromatin types. POF and HP1a proteins providing special organization of this chromosome are mostly located in aquamarine and lazurite chromatin. In general, band organization of the fourth chromosome shares the features of the whole Drosophila genome.


Comparison of Metaraminol, Phenylephrine, and Norepinephrine Infusion for Prevention of Hypotension During Combined Spinal-Epidural Anaesthesia for Elective Caesarean Section: A Three-Arm, Randomized, Double-Blind, Non-Inferiority Trial.
A direct comparison of phenylephrine, metaraminol, and norepinephrine in preventing hypotension during spinal anaesthesia for elective caesarean section has never been made. Seventy-five parturients scheduled for elective caesarean section were randomly assigned into the three groups. After spinal anaesthesia induction, patients received a bonus dose of vasopressor (norepinephrine 4ug, phenylephrine 50ug, or metaraminol 250ug) combined with continuous infusion (norepinephrine 8ug/mL, phenylephrine 100ug/mL, or metaraminol 500ug/mL) at a rate of 30 mL/h to prevent hypotension. The primary outcome was umbilical arterial (UA) pH and other intraoperative data were also recorded. The UA pH was 7.32±0.03 for metaraminol, 7.31±0.03 for phenylephrine, and 7.31±0.03 for norepinephrine. The 95% CI of MD was -0.011 to 0.026 comparing metaraminol with norepinephrine and 0.0181 to 0.0182 comparing phenylephrine with norepinephrine. Both lower bounds of the 95% CI of MD were above the predetermined lower boundary of clinical non-inferiority of -0.03, indicating both metaraminol and phenylephrine were non-inferior to norepinephrine. Moreover, the incidence of hypotension was lower in metaraminol compared with norepinephrine (P = 0.01). However, the incidence of hypertension was significantly lower in both phenylephrine and metaraminol compared with norepinephrine. Both metaraminol and phenylephrine were non-inferior to norepinephrine with respect to neonatal UA pH when used as a bolus and continuous infusion to prevent hypotension during combined spinal-epidural anaesthesia for elective caesarean section.


Self-reported characteristics of women and men with intimate body piercings.
The purpose of this paper is to report the findings of a study exploring factors associated with female and male intimate body piercing, with particular emphasis on health issues. Nipple and genital piercings (intimate piercings) have become common types of body art. Scant medical and nursing literature is available, leading to little understanding of these body modifications by health care providers. A convenience sample of intimately pierced individuals (63 women and 83 men) from 29 states in the United States of America was surveyed via an author-developed questionnaire. Questions focused on demographic characteristics, decision factors and health problems related to intimate piercings. Self-reported characteristics were compared between female and male participants, and participants were compared demographically to United States general population. Participants reported wearing nipple piercings (43%), genital piercings (25%) and both types (32%). Respondents were significantly younger, less ethnically diverse, better educated, less likely to be married, more often homosexual or bisexual and they initiated sexual activity at a younger age than the US population. Deliberate, individual decisions for procurement of the intimate piercings were made. Average purchase consideration was at age 25 (nipple) and 27 (genital); average age to obtain the piercing was 27 (nipple) and 28 (genital) years. Purposes for obtaining the piercings included uniqueness, self-expression and sexual expression. Most participants still liked their piercing (73-90%). Health concerns related to intimate piercings were described by both those with nipple piercings (66%) and with genital piercings (52%) and included site sensitivity, skin irritation, infection and change in urinary flow (male genital). Few STDs (3%) were reported and no HIV or hepatitis. Usually non-medical advice was sought for problems -- often from the body piercer. Understanding client rationale is not a necessary prerequisite for providing quality patient care; however, awareness of purposes and decision-making in intimate piercing can help nurses to be sensitive to client needs and plan appropriate health education.


Leukocyte Count versus C-Reactive Protein Levels in Obese Portuguese Patients Aged 6-12 Years Old.
to evaluate whether total and differential WBC counts are altered in young obese patients (aged 6-12 years) and if a relationship exists between WBC counts and the severity of obesity as well as with CRP level. a group of 77 obese patients [32 males and 45 females] and 19 controls [7 males and 12 females] were studied. Total WBC count was performed by using an automatic blood cell counter. Blood cell morphology and WBC differential count were evaluated in Wright stained blood films. The plasma levels of CRP were evaluated by immunoturbidimetry. obese participants presented with a statistically significant higher neutrophil percentage and CRP levels when compared to controls; the median CRP value was about 5 times higher than that observed in controls. Absolute neutrophil count and neutrophil/lymphocyte ratio were also higher in patients, though without statistical significance. The parameters that were statistically significant related with adiposity markers were neutrophil count and CRP levels. The neutrophil count was positively and statistically correlated with body mass index (BMI), BMI z-score, waist circumference and waist/height ratio, and also with CRP levels. In multiple regression analysis, the only variable that remained statistically associated with neutrophil count was CRP (neutrophil count = 2.612 + 0.439lnCRP; standardised coefficient/beta: 0.384, P=0.001). When performing multiple regression without CRP, the only variable that remained statistically associated with neutrophil count was BMI. our results demonstrated in obese patients aged 6-12 years, a significant change in the differential leukocyte count towards neutrophilia, together with a significant higher CRP concentration, and that absolute neutrophil count correlates with obesity markers and with CRP levels. Our data also indicate that neutrophil count, a current clinically used low-cost parameter, may be used as an obesity-related inflammatory marker in young obese patients.


Testosterone prohormone supplements.
Testosterone prohormones such as androstenedione, androstenediol, and dehydroepiandrosterone (DHEA) have been heavily marketed as testosterone-enhancing and muscle-building nutritional supplements for the past decade. Concerns over the safety of prohormone supplement use prompted the United States Food and Drug Administration to call for a ban on androstenedione sales, and Congress passed the Anabolic Steroid Control Act of 2004, which classifies androstenedione and 17 other steroids as controlled substances. As of January 2005, these substances cannot be sold without prescription. Here, we summarize the current scientific knowledge regarding the efficacy and safety of prohormone supplementation in humans. We focus primarily on androstenedione, but we also discuss DHEA, androstenediol, 19-nor androstenedione, and 19-nor androstenediol supplements. Contrary to marketing claims, research to date indicates that the use of prohormone nutritional supplements (DHEA, androstenedione, androstenediol, and other steroid hormone supplements) does not produce either anabolic or ergogenic effects in men. Moreover, the use of prohormone nutritional supplements may raise the risk for negative health consequences.


Assessment of prehospital care in canine trauma patients presented to Veterinary Trauma Centers: A VetCOT registry study.
To analyze the epidemiology of veterinary care in canine trauma patients prior to presentation to a Veterinary Trauma Center (VTC). Retrospective observational cross-sectional study. Retrospective descriptive analysis from 22,998 canine case records from the Veterinary Trauma Registry from September 2013 through April 2018. Analysis was focused on the type of injury, care provider, and care provided prior presentation to a VTC (pre-VTC care). A log-likelihood ratio test was used to test for association of outcome and pre-VTC care. Mann-Whitney U tests were used to compare modified Glasgow Coma Scale and Animal Trauma Triage (ATT) scores between pre-VTC and non-pre-VTC care groups. Pre-VTC care was provided in 5636 out of 22,998 dogs (24.5%) by veterinarians (81%), owners (19.6%), and first responders (0.03%). The most common nonveterinary interventions included wound care and bandaging in 42% and 39% of the patients, respectively. Mortality was higher in the pre-VTC care group (8.7% vs 7.5%); dogs receiving pre-VTC care were 1.5 times (95% confidence interval [CI], 1.15-1.88) more likely to die and 1.2 times (95% CI, 1.07-1.37) more likely to be euthanized. The ATT scores were significantly higher in dogs receiving pre-VTC care (mean = 2.53 vs 1.78; p < 0.0001). Our data demonstrate that the majority of more severely injured dogs receiving pre-VTC care obtained care by a veterinarian. Dogs receiving pre-VTC care possessed a greater mortality rate but also a greater ATT score; therefore, mortality rate is more likely related to severity of trauma rather than reception of pre-VTC care. We propose that these data should prompt further research and education about prehospital care in veterinary medicine.


The funhouse mirror: the I in personalised healthcare.
Precision Medicine is driven by the idea that the rapidly increasing range of relatively cheap and efficient self-tracking devices make it feasible to collect multiple kinds of phenotypic data. Advocates of N = 1 research emphasize the countless opportunities personal data provide for optimizing individual health. At the same time, using biomarker data for lifestyle interventions has shown to entail complex challenges. In this paper, we argue that researchers in the field of precision medicine need to address the performative dimension of collecting data. We propose the fun-house mirror as a metaphor for the use of personal health data; each health data source yields a particular type of image that can be regarded as a 'data mirror' that is by definition specific and skewed. This requires competence on the part of individuals to adequately interpret the images thus provided.


Effect of exercise on serum neutrophil gelatinase-associated lipocalin concentration in racehorses.
Serum neutrophil gelatinase-associated lipocalin (sNGAL) is a marker of renal injury, and its concentrations are affected by inflammation. Therefore, it could serve as a useful biomarker of disease or fitness in high-level competition. However, it has not yet been determined if sNGAL concentrations are affected by exercise. The aim of this study was to determine whether concentrations of equine sNGAL were affected by 1000 m galloping as the form of exercise used in the study. Pre- and post-gallop sNGAL, serum amyloid A, and creatinine concentrations were evaluated in 14 healthy Thoroughbred racehorses. The results showed that short, high-intensity exercise did not significantly affect sNGAL concentrations in healthy horses (P = .42), and no significant difference was found in either creatinine or serum amyloid A before and after galloping (P > .05). Therefore, it was determined that sNGAL was not influenced by the type of exercise used in the study and could have the potential to be used as a routine laboratory screening tool in horses even after strenuous exercise. Future research should clarify its use in a larger population and a broader range of equine sport disciplines, including endurance-related exercise.


Chronic drug exposures during development in nonhuman primates: models of brain dysfunction in humans.
This review of our work presents three specific examples of how nonhuman primates (rhesus monkeys, Macaca mulatta) have been used to study the effects of chronic drug exposures on brain function during different stages of development. In all cases, exposure levels similar to those experienced by humans were employed and the focus was on long-term--not acute--effects. In the case of the marijuana studies, exposures occurred during the adolescent period; for the cocaine studies, exposures occurred in binge-like fashion entirely before birth (in utero); and for the remacemide studies, exposures occurred daily in juveniles, prior to adolescence. An automated battery of behavioral tasks, the National Center for Toxicological Research Operant Test Battery (NCTR OTB), designed to assess aspects of motivation, visual discrimination, time perception, short-term memory, and learning, was used to monitor treatment effects. Chronic marijuana smoke exposure resulted in an 'amotivational' syndrome--even in weekend-only smokers--that resolved within three months of exposure cessation. In utero cocaine exposure was shown to cause behavioral rigidity or lack of plasticity as evidenced by the difficulty of subjects to adjust to rules changes for some OTB tasks. These effects were seen in adult subjects suggesting that the effects of gestational cocaine exposure are long-term or permanent. In addition, animals exposed to cocaine in utero were less sensitive to the behaviorally-disrupting effects of cocaine as adults. Remacemide caused profound and long-lasting, perhaps permanent, changes in learning task performance and because performance of this same task by children is significantly correlated with traditional measures of intelligence (IQ), these data suggest that such treatment may provide a valuable model of chemically-induced mental retardation.


P/Q-type, but not N-type, calcium channels mediate GABA release from fast-spiking interneurons to pyramidal cells in rat prefrontal cortex.
The Cav2.1 (P/Q-) and Cav2.2 (N-type) voltage-gated calcium channels (VGCCs) play a predominant role in neurotransmitter release at central synapses, but their distribution is not uniform across different types of synapses. Although the functional significance of the differential distribution of N- and P/Q-type VGCCs is poorly understood, distinct types of VGCCs appear to differentially affect synaptic properties. For example, P/Q-type VGCCs are located closer to release sites and are less affected by G-protein-mediated inhibition than are N-type VGCCs. Thus P/Q-type VGCCs might be beneficial at synapses with high probability of release and precise timing of neurotransmission, such as the inhibitory inputs from parvalbumin-containing fast-spiking (FS) interneurons to pyramidal cells (PCs) in the neocortex. To determine whether VGCCs types predominate at synapses from FS interneurons to PCs in rat prefrontal cortex, whole cell paired recordings (n = 14) combined with intracellular labeling and fluorescence immunohistochemistry for parvalbumin were performed in acute slices. Bath application of the specific N-type VGCC blocker omega-conotoxin-GVIa (1 microM) did not alter inhibitory postsynaptic potential amplitude, failure rate, or synaptic dynamics; in contrast, application of P/Q-type VGCC blocker omega-agatoxin-IVa (0.5 microM) completely and irreversibly blocked neurotransmission. These results indicate that P/Q-type VGCCs mediate the GABA release from parvalbumin-positive FS interneurons to PCs in the rat neocortex.


Differential sensitivities of morphine and motilin to initiate migrating motor complex in isolated intestinal segments. Regeneration of intrinsic nerves.
The effect of morphine and motilin on surgically isolated segments of small intestine was studied in 8 dogs. In 4 dogs, the small intestine was divided into four segments by simple transection and reanastomosis (group 1); in 4 others, a 2-4-cm colonic segment was interposed at each of the transection sites (group 2). The migrating motor complex initially cycled independently in each segment in group 1 dogs; after that the migration of the migrating motor complex across transection and reanastomosis began to recover and the recovery was complete 100 days after surgery. In contrast, in group 2 dogs the migration of the migrating motor complex from one segment to the next did not recover even 180 days after surgery. Morphine bolus or infusion initiated premature phase III activity in all segments but the sensitivity to morphine decreased distally. Motilin bolus or infusion initiated premature phase III activity only in the first three segments. The sensitivity to motilin also decreased distally. We concluded that (a) the interposition of a foreign segment severely impedes or prevents the regeneration of enteric nerves; (b) the sensitivity of morphine and motilin in initiating premature phase III activity decreases distally in small intestine; and (c) motilin does not initiate premature phase III activity in the ileum, but morphine may initiate premature phase III activity at all sites in the small intestine.


Inertial Navigation on Extremely Resource-Constrained Platforms: Methods, Opportunities and Challenges.
Inertial navigation provides a small footprint, low-power, and low-cost pathway for localization in GPS-denied environments on extremely resource-constrained Internet-of-Things (IoT) platforms. Traditionally, application-specific heuristics and physics-based kinematic models are used to mitigate the curse of drift in inertial odometry. These techniques, albeit lightweight, fail to handle domain shifts and environmental non-linearities. Recently, deep neural-inertial sequence learning has shown superior odometric resolution in capturing non-linear motion dynamics without human knowledge over heuristic-based methods. These AI-based techniques are data-hungry, suffer from excessive resource usage, and cannot guarantee following the underlying system physics. This paper highlights the unique methods, opportunities, and challenges in porting real-time AI-enhanced inertial navigation algorithms onto IoT platforms. First, we discuss how platform-aware neural architecture search coupled with ultra-lightweight model backbones can yield neural-inertial odometry models that are 31-134× smaller yet achieve or exceed the localization resolution of state-of-the-art AI-enhanced techniques. The framework can generate models suitable for locating humans, animals, underwater sensors, aerial vehicles, and precision robots. Next, we showcase how techniques from neurosymbolic AI can yield physics-informed and interpretable neural-inertial navigation models. Afterward, we present opportunities for fine-tuning pre-trained odometry models in a new domain with as little as 1 minute of labeled data, while discussing inexpensive data collection and labeling techniques. Finally, we identify several open research challenges that demand careful consideration moving forward.


Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS.
An overproduction of reactive oxygen species (ROS) mediated by NADPH oxidase 2 (NOX2) has been related to airway inflammation typical of influenza infection. Virus-induced oxidative stress may also control viral replication, but the mechanisms underlying ROS production, as well as their role in activating intracellular pathways and specific steps of viral life cycle under redox control have to be fully elucidated. In this study, we demonstrate that influenza A virus infection of lung epithelial cells causes a significant ROS increase that depends mainly on NOX4, which is upregulated at both mRNA and protein levels, while the expression of NOX2, the primary source of ROS in inflammatory cells, is downregulated. Inhibition of NOX4 activity through chemical inhibitors or RNA silencing blocks the ROS increase, prevents MAPK phosphorylation, and inhibits viral ribonucleoprotein (vRNP) nuclear export and viral release. Overall these data, obtained in cell lines and primary culture, describe a so far unrecognized role for NOX4-derived ROS in activating redox-regulated intracellular pathways during influenza virus infection and highlight their relevance in controlling specific steps of viral replication in epithelial cells. Pharmacological modulation of NOX4-mediated ROS production may open the way for new therapeutic approaches to fighting influenza by targeting cell and not the virus.


Association between depression and vascular disease in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE. A cross-sectional study was conducted from 2002-2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque. In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein. In SLE, depression is independently associated with vascular disease, along with physical factors.


Improving Knowledge and Awareness of Human Papillomavirus-Associated Gynecologic Cancers: Results from the National Comprehensive Cancer Control Program/Inside Knowledge Collaboration.
Over 16,000 women are diagnosed with a human papillomavirus (HPV)-associated gynecologic cancer every year. Because most of these cancers are preventable, correct and appropriate information about the HPV vaccine and cervical cancer screening can help reduce incidence. The Centers for Disease Control and Prevention created Inside Knowledge: Get the Facts About Gynecologic Cancer campaign materials, which were used by seven National Comprehensive Cancer Control Program recipients in tailored educational sessions on gynecologic cancer with women and healthcare providers in the community setting. Session participants completed presession and postsession questionnaires. Differences in knowledge and intentions were assessed using chi-square tests for women in the general public, obstetricians/gynecologists (OB/GYNs), primary care physicians (PCPs), and other healthcare providers. Women's knowledge improved significantly presession to postsession that HPV causes vaginal (39%-65%, p < 0.001) and vulvar cancers (26%-60%, p < 0.001), but postsession few women correctly identified all HPV-associated gynecologic cancers (15%). From presession to postsession, more women were able to correctly identify recommended age groups for whom the HPV vaccine is recommended (15%-30%, p < 0.001), and that the Pap test only screens for cervical cancer (58%-73%, p < 0.001). Among providers, OB/GYNs had more baseline knowledge of HPV-associated gynecologic cancers than other providers. Postsession, PCPs and other providers increased their knowledge of HPV vaccine recommended age groups (33%-71% and 23%-61%, respectively), and the 3-year recommended screening interval for the Pap test (73%-91% and 63%-85%, respectively). HPV vaccine knowledge did not show significant improvement among OB/GYNs postsessions. Women and healthcare providers who attended the Inside Knowledge sessions significantly improved their knowledge of HPV-associated gynecologic cancers. Additional educational activities during the sessions that support distinguishing between HPV-associated versus other gynecologic cancers and clarify HPV vaccine recommendations may help with further increases in knowledge.


Electrical switching properties and structural characteristics of GeSe-GeTe films.
Germanium chalcogenides, especially GeSe and GeTe alloys, have recently gained popularity because of their Ovonic threshold (volatile) and memory (non-volatile) switching properties, with great potential for electric storage applications. Materials designed in a pseudo-binary way may possess superior properties in their phase transition, e.g. GeTe-Sb2Te3 materials, and bring about revolutionary advances in optical storage. However, to date, the electrical switching behaviors of films of pseudo-binary GeSe-GeTe have not yet been studied, and neither have the structural characteristics. Herein, we present both the thermally and electrically induced switching behaviors of GeSe-GeTe film, as well as the structural evolution due to composition tuning. The crystallization temperature of GeSe-GeTe films increases with GeSe content quite sensitively. An atom-resolved picture of the GeSe-GeTe alloy with a state-of-the-art atomic mapping technology has been presented, where a randomly mixed arrangement of Se and Te atoms is determined unambiguously in Ge50Se13Te34 with a GeTe-like rhombohedral structure. The local structural motifs in GeSe-GeTe, more specifically, sixfold coordinated octahedra with a distinguished degree of Peierls distortion and geometric variety, are essential to understand its electric properties. GeSe-GeTe alloy, Ge50Se13Te34, based memory cells have been fabricated, showing a fast memory switching behavior and excellent retention of 10 years at 208 °C.


Identification and Mechanistic Characterization of a Peptide Inhibitor of Glycogen Synthase Kinase (GSK3β) Derived from the Disrupted in Schizophrenia 1 (DISC1) Protein.
Glycogen synthase kinase 3-beta (GSK3β) is a critical regulator of several cellular pathways involved in neurodevelopment and neuroplasticity and as such is a potential focus for the discovery of new neurotherapeutics toward the treatment of neuropsychiatric and neurodegenerative diseases. The majority of efforts to develop inhibitors of GSK3β have been focused on developing small molecule inhibitors that compete with adenosine triphosphate (ATP) through direct interaction with the ATP binding site. This strategy has presented selectivity challenges due to the evolutionary conservation of this domain within the kinome. The disrupted in schizophrenia 1 (DISC1) protein has previously been shown to bind and inhibit GSK3β activity. Here, we report the characterization of a 44-mer peptide derived from human DISC1 (hDISCtide) that is sufficient to both bind and inhibit GSK3β in a noncompetitive mode distinct from classical ATP competitive inhibitors. Based on multiple independent biochemical and biophysical assays, we propose that hDISCtide interacts at two distinct regions of GSK3β: an inhibitory region that partially overlaps with the binding site of FRATide, a well-known GSK3β binding peptide, and a specific binding region that is unique to hDISCtide. Taken together, our findings present a novel avenue for developing a peptide-based selective inhibitor of GSK3β.


Clinical problems with HLA sensitization.
There is little question that Frozen-Thawed-Deglycerolized Red Cells (Human) has the least amount of HLA antigen found in any red cell component. Units prepared by any of the several availables methods are indicated for patients with repetitive nonhemolytic febrile reactions, probably should be used in patients waiting for reanl allografts and in immunodeficient patients in whom there is a risk of GVH disease. Still unresolved are questions on the minimal dose of HLA needed to sensitize a recipient, the role of the debris and viable cells and whether transfusion with a small dose of HLA antigen has a beneficial effect on the survival of renal allografts.


Ultrasound image segmentation based on Transformer and U-Net with joint loss.
Ultrasound image segmentation is challenging due to the low signal-to-noise ratio and poor quality of ultrasound images. With deep learning advancements, convolutional neural networks (CNNs) have been widely used for ultrasound image segmentation. However, due to the intrinsic locality of convolutional operations and the varying shapes of segmentation objects, segmentation methods based on CNNs still face challenges with accuracy and generalization. In addition, Transformer is a network architecture with self-attention mechanisms that performs well in the field of computer vision. Based on the characteristics of Transformer and CNNs, we propose a hybrid architecture based on Transformer and U-Net with joint loss for ultrasound image segmentation, referred to as TU-Net. TU-Net is based on the encoder-decoder architecture and includes encoder, parallel attention mechanism and decoder modules. The encoder module is responsible for reducing dimensions and capturing different levels of feature information from ultrasound images; the parallel attention mechanism is responsible for capturing global and multiscale local feature information; and the decoder module is responsible for gradually recovering dimensions and delineating the boundaries of the segmentation target. Additionally, we adopt joint loss to optimize learning and improve segmentation accuracy. We use experiments on datasets of two types of ultrasound images to verify the proposed architecture. We use the Dice scores, precision, recall, Hausdorff distance (HD) and average symmetric surface distance (ASD) as evaluation metrics for segmentation performance. For the brachia plexus and fetal head ultrasound image datasets, TU-Net achieves mean Dice scores of 79.59% and 97.94%; precisions of 81.25% and 98.18%; recalls of 80.19% and 97.72%; HDs (mm) of 12.44 and 6.93; and ASDs (mm) of 4.29 and 2.97, respectively. Compared with those of the other six segmentation algorithms, the mean values of TU-Net increased by approximately 3.41%, 2.62%, 3.74%, 36.40% and 31.96% for the Dice score, precision, recall, HD and ASD, respectively.


Decreasing incidence and mortality among hospitalized patients suffering a ventilator-associated pneumonia: Analysis of the Spanish national hospital discharge database from 2010 to 2014.
The aim of this study was to describe trends in the incidence and outcomes of ventilator-associated pneumonia (VAP) among hospitalized patients in Spain (2010-2014).This is a retrospective study using the Spanish national hospital discharge database from year 2010 to 2014. We selected all hospital admissions that had an ICD-9-CM code: 997.31 for VAP in any diagnosis position. We analyzed incidence, sociodemographic and clinical characteristics, procedures, pathogen isolations, and hospital outcomes.We identified 9336 admissions with patients suffering a VAP. Incidence rates of VAP decreased significantly over time (from 41.7 cases/100,000 inhabitants in 2010 to 40.55 in 2014). The mean Charlson comorbidity index (CCI) was 1.08 ± 0.98 and it did not change significantly during the study period. The most frequent causative agent was Pseudomonas and there were not significant differences in the isolation of this microorganism over time. Time trend analyses showed a significant decrease in in-hospital mortality (IHM), from 35.74% in 2010 to 32.81% in 2014. Factor associated with higher IHM included male sex, older age, higher CCI, vein or artery occlusion, pulmonary disease, cancer, undergone surgery, emergency room admission, and readmission.This study shows that the incidence of VAP among hospitalized patients has decreased in Spain from 2010 to 2014. The IHM has also decreased over the study period. Further investigations are needed to improve the prevention and control of VAP.


Norepinephrine exhibits two distinct profiles of action on sensory cortical neuron responses to excitatory synaptic stimuli.
Located within the central gray of the caudal pons, the locus coeruleus (LC) is the sole source of norepinephrine (NE) projections to the forebrain. NE is released both tonically and phasically from axonal varicosities in LC efferent target circuits. NE has been shown to produce a diverse set of actions, including suppression of spontaneous and stimulus evoked discharge, augmentation of synaptically evoked excitation, and inhibition and gating of otherwise subthreshold synaptic inputs. Utilizing an extracellular in vitro tissue slice preparation and microiontophoretic techniques, the dose-dependent actions of NE on glutamate-evoked discharges of layer II/III and layer V sensory cortical neurons were investigated. Noradrenergic effects were further examined in terms of cell and adrenoceptor specificity. The results indicate two exclusive modulatory actions of NE: 1) ejection current-dependent suppression of glutamate evoked discharge, and 2) ejection current-dependent facilitation of glutamate-evoked discharge followed by suppression of the maximal facilitated response. These effects were observed in both normal and low Ca(2+) / high Mg(2+) bathing media, suggesting a postsynaptic site for NE's actions. The facilitation of glutamate evoked discharge was selectively mimicked by the alpha-1 agonist, phenylephrine, whereas the dose-dependent suppression was mimicked by the beta-agonist isoproterenol. These results suggest that the suppressant and facilitating actions of NE are mediated by beta and alpha-1 receptors, respectively. In general, these results are consistent with previous demonstrations of NE modulatory actions on central neurons, but indicate that in the cerebral cortex these effects are both cell- and receptor-specific.


Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver.
The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB(1)R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB(1)R in the control of liver regeneration. Here we report that mice lacking CB(1)R globally or in hepatocytes only and wild-type mice treated with a CB(1)R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB(1)R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB(1)R(-/-) mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB(1)R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.


Gene expression and TCR amino acid sequences selected by HLA-A02:01-restricted CTLs specific to HTLV-1 in ATL patients.
Adult T-cell leukaemia/lymphoma (ATL) is an aggressive malignancy of peripheral T cells caused by human T-cell lymphotropic virus type-1 (HTLV-1). Tax is the most important regulatory protein for HTLV-1. We aimed to reveal a unique amino acid sequence (AA) of complementarity-determining region 3 (CDR3) of the T-cell receptor (TCR)β and TCRα chains of HLA-A*02:01-restricted Tax11-19 -specific cytotoxic T cells (Tax-CTLs). The gene expression profiles (GEP) of Tax-CTLs were assessed by the next-generation sequence (NGS) method with SMARTer technology. Tax-CTLs seemed to be oligoclonal, and their gene compositions were skewed. The unique motifs of 'DSWGK' in TCRα and 'LAG' in TCRβ at CDR3 were observed in almost all patients. Tax-CTL clones harbouring the 'LAG' motif with BV28 had a higher binding score than those without either of them, besides a higher binding score associated with longer survival. Tax-CTLs established from a single cell showed killing activities against Tax-peptide-pulsed HLA-A2+ T2 cell lines. GEP of Tax-CTLs revealed that genes associated with immune response activity were well preserved in long-term survivors with stable status. These methods and results can help us better understand immunity against ATL, and should contribute to future studies on the clinical application of adoptive T-cell therapies.


The role of noninvasive imaging in coronary artery disease detection, prognosis, and clinical decision making.
A vast array of noninvasive imaging modalities is available for the evaluation of the presence and severity of coronary artery disease (CAD). Choosing the right test can be challenging but is critical for proper patient diagnosis and management. Presently available imaging tests for CAD include: (1) nuclear myocardial perfusion imaging procedures (single-photon emission tomography) and positron emission tomography, (2) stress echocardiography, (3) computed tomography coronary angiography, and (4) cardiac magnetic resonance imaging. Exercise treadmill testing electrocardiography is another alternative that we will discuss briefly. Selection of the most appropriate imaging modality requires knowledge of the clinical question being addressed, patient characteristics (pretest probability and prevalence of disease), the strengths, limitations, risks, costs, and availability of each procedure. To assist with test selection, we review the relevant literature in detail to consider the relative merits of cardiac imaging modalities for: (1) detection of CAD, (2) risk stratification and prognostication, and (3) guiding clinical decision making.


Chlamydial infections of the urethra in women.
Cervical and endourethral swabs from 360 untreated women attending a sexually transmitted disease (STD) clinic were cultured for Chlamydia trachomatis and other genitourinary pathogens. The patients included contacts of men with non-gonococcal urethritis, women with gonorrhoea, and those in whom symptoms suggestive of urinary tract infection were the main reasons for their attendance. Chlamydial infection of the urethra was less common than, and seldom occurred in the absence of, cervical chlamydial infection; it was frequently silent, producing no signs or symptoms of urethritis. Only 33/96 women with evidence of urethritis gave chlamydia positive urethral swabs, and 14 of them had other concurrent infections of the genitourinary tract. Chlamydia trachomatis thus does not appear to be a major cause of the signs and symptoms of urethritis commonly found in women attending STD clinics, and there seems to be no indication for taking routine urethral swabs to aid in the diagnosis of chlamydial infection in women.


Engineering antibodies by yeast display.
Since its first application to antibody engineering 15 years ago, yeast display technology has been developed into a highly potent tool for both affinity maturing lead molecules and isolating novel antibodies and antibody-like species. Robust approaches to the creation of diversity, construction of yeast libraries, and library screening or selection have been elaborated, improving the quality of engineered molecules and certainty of success in an antibody engineering campaign and positioning yeast display as one of the premier antibody engineering technologies currently in use. Here, we summarize the history of antibody engineering by yeast surface display, approaches used in its application, and a number of examples highlighting the utility of this method for antibody engineering.


Soil application of biochar produced from biomass grown on trace element contaminated land.
Trace element (TE) contamination of soils is a worldwide problem. However, although not considered safe anymore for food production without clean-up, many of these soils may still be used to produce biomass for non-food purposes such as biochar. Exploring the suitability of such biochar for the amendment of low-fertility soil, we investigated growth and metal accumulation of ryegrass (Lolium perenne, var. Calibra) as well as soil microbial abundance on a non-contaminated soil after amendment with biochar from birch (Betula pendula) wood produced on TE contaminated soil in comparison to a treatment with birch wood biochar originating from non-contaminated soil. Biochars were produced from both feedstocks by pyrolysis at two temperatures: 450 and 700 °C. During the pyrolysis, in contrast to Cu, Fe, Mg, K, Mn and P, the elements Cd, Pb, S and Na volatilized. The root biomass of the biochar treated plants was lower than that of the non-amended plants, while that of the shoot was higher. Plant shoot K and Zn concentrations were increased significantly by up to 7- and 3.3-fold respectively. For P, Mg, Mn, Fe and Cu no significant increase in shoot concentration could be detected. Neither the TE-contaminated biochar, nor the non-contaminated biochar had adverse effect on the bacterial community of the soil.


Olivines: revelation of tracks of charged particles.
A one-step, three-component aqueous etchant was developed for revealing the tracks of charged particles in olivine. The etchant reveals tracks of small cone angle, which are equally well developed in all the crystallographic directions. The scope of fossil cosmic-ray track studies in extraterrestrial samples has thus been increased, because olivine is often an abundant constituent and because it has a higher threshold ionization for track registration and has lower uranium, thorium, and trace element concentrations as compared with pyroxenes and feldspars. The etchant does not attack any of the principal rock-forming minerals in normal etching time, which allows a nondestructive study of fossil tracks in thin-section mounts. The study of fossil cosmic-ray tracks in olivine is particularly valuable for investigations of very, very heavy cosmic-ray nuclei and for highly irradiated samples such as those found in the lunar regolith.


Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation.
Intracellular amyloid β-protein (Aβ) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL) /PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular Aβ degradation, activity of Aβ-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells. 3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.


Pre- and Post-Activity Stretching Practices of Collegiate Athletic Trainers in the United States.
Popp, JK, Bellar, DM, Hoover, DL, Craig, BW, Leitzelar, BN, Wanless, EA, and Judge, LW. Pre- and post-activity stretching practices of collegiate athletic trainers in the United States. J Strength Cond Res 31(9): 2347-2354, 2017-The aim of the study was to investigate the knowledge and practices of collegiate-certified athletic trainers (ATs) in the United States. Participants (n = 521) were provided an overview of the study and a hyperlink to a web-based survey. The "pre- and post-activity practices in athletic training questionnaire" consisted of demographic items and elements to measure knowledge and practices related to pre- and post-activity stretching routines. In previous studies, the survey demonstrated construct validity, α = 0.722. Pearson chi-square test was used to evaluate goodness of fit, and kappa was calculated to measure agreement between items. Only 32.2% of ATs recommended dynamic stretching (DS) to be performed pre-activity, whereas a larger percentage (42.2%) recommended a combination of static stretching (SS) and DS. Athletic trainers reported that only 28.0% of athletes are performing DS before activity. Conversely, 60.6% of collegiate ATs recommended SS postexercise, and 61.0% of athletes agree and perform after workout SS (κ = 0.761, p < 0.001). Collegiate ATs seem to underuse the current research evidence, which indicates that DS is more beneficial than SS when used pre-activity, and ATs continue to regularly incorporate SS in their pre-activity routines. However, there is evidence that collegiate ATs in the United States emphasize SS postactivity in a manner consistent with current research.


Peripheral inflammatory markers associated with brain volume reduction in patients with bipolar I disorder.
Neuroinflammation and brain structural abnormalities are found in bipolar disorder (BD). Elevated levels of cytokines and chemokines have been detected in the serum and cerebrospinal fluid of patients with BD. This study investigated the association between peripheral inflammatory markers and brain subregion volumes in BD patients. Euthymic patients with bipolar I disorder (BD-I) aged 20-45 years underwent whole-brain magnetic resonance imaging. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), chitinase-3-like protein 1 (also known as YKL-40), fractalkine (FKN), soluble tumour necrosis factor receptor-1 (sTNF-R1), interleukin-1β, and transforming growth factor-β1 were measured on the day of neuroimaging. Clinical data were obtained from medical records and interviewing patients and reliable others. We recruited 31 patients with a mean age of 29.5 years. In multivariate regression analysis, plasma level YKL-40, a chemokine, was the most common inflammatory marker among these measurements displaying significantly negative association with the volume of various brain subareas across the frontal, temporal, and parietal lobes. Higher YKL-40 and sTNF-R1 levels were both significantly associated with lower volumes of the left anterior cingulum, left frontal lobe, right superior temporal gyrus, and supramarginal gyrus. A greater number of total lifetime mood episodes were also associated with smaller volumes of the right caudate nucleus and bilateral frontal lobes. The volume of brain regions known to be relevant to BD-I may be diminished in relation to higher plasma level of YKL-40, sTNF-R1, and more lifetime mood episodes. Macrophage and macrophage-like cells may be involved in brain volume reduction among BD-I patients.


Pathogenicity and virulence of henipaviruses.
Paramyxoviruses are a family of single-stranded negative-sense RNA viruses, many of which are responsible for a range of respiratory and neurological diseases in humans and animals. Among the most notable are the henipaviruses, which include the deadly Nipah (NiV) and Hendra (HeV) viruses, the causative agents of outbreaks of severe disease and high case fatality rates in humans and animals. NiV and HeV are maintained in fruit bat reservoirs primarily in the family Pteropus and spillover into humans directly or by an intermediate amplifying host such as swine or horses. Recently, non-chiropteran associated Langya (LayV), Gamak (GAKV), and Mojiang (MojV) viruses have been discovered with confirmed or suspected ability to cause disease in humans or animals. These viruses are less genetically related to HeV and NiV yet share many features with their better-known counterparts. Recent advances in surveillance of wild animal reservoir viruses have revealed a high number of henipaviral genome sequences distributed across most continents, and mammalian orders previously unknown to harbour henipaviruses. In this review, we summarize the current knowledge on the range of pathogenesis observed for the henipaviruses as well as their replication cycle, epidemiology, genomics, and host responses. We focus on the most pathogenic viruses, including NiV, HeV, LayV, and GAKV, as well as the experimentally non-pathogenic CedV. We also highlight the emerging threats posed by these and potentially other closely related viruses.


[Surgical results in recurrent inguinal hernias].
Remote results of 213 operations for recurrent inguinal hernias are analyzed. Repeated recurrences were noted in 58 patients (27.2%). Strengthening of the frontal wall or the posterior wall of the inguinal canal by using the inguinal ligament in recurrent inguinal hernias is responsible for high percentage of recidivation. The operation of choice is thought to be plasty of the inguinal canal after Kukudzhanov.


The Influence of Neck Muscle Tonus and Posture on Brain Tissue Strain in Pedestrian Head Impacts.
Pedestrians are one of the least protected groups in urban traffic and frequently suffer fatal head injuries. An important boundary condition for the head is the cervical spine, and it has previously been demonstrated that neck muscle activation is important for head kinematics during inertial loading. It has also been shown in a recent numerical study that a tensed neck musculature also has some influence on head kinematics during a pedestrian impact situation. The aim of this study was to analyze the influence on head kinematics and injury metrics during the isolated time of head impact by comparing a pedestrian with relaxed neck and a pedestrian with increased tonus. The human body Finite Element model THUMS Version 1.4 was connected to head and neck models developed at KTH and used in pedestrian-to-vehicle impact simulations with a generalized hood, so that the head would impact a surface with an identical impact response in all simulations. In order to isolate the influence of muscle tonus, the model was activated shortly before head impact so the head would have the same initial position prior to impact among different tonus. A symmetric and asymmetric muscle activation scheme that used high level of activation was used in order to create two extremes to investigate. It was found that for the muscle tones used in this study, the influence on the strain in the brain was very minor, in general about 1-14% change. A relatively large increase was observed in a secondary peak in maximum strains in only one of the simulated cases.


Gender differences in the VDR-FokI polymorphism and conventional non-genetic risk factors in association with lumbar spine pathologies in an Italian case-control study.
Recently, the FokI polymorphism (rs2228570) in the vitamin D receptor gene (VDR) and conventional risk factors were associated with spine disorders in the Italian population, but without gender analysis. Two-hundred and sixty-seven patients (149 males, 118 females) with lumbar spine disorders were assessed by magnetic resonance imaging (MRI) and 254 (127 males, 127 females) asymptomatic controls were enrolled. The exposure to putative risk factors was evaluated and FokI polymorphism was detected by PCR-restriction fragment length polymorphism (PCR-RFLP). An association between lumbar spine pathologies and higher than average age; overweight; family history; lower leisure physical activity; smoking habit; higher number of hours/day exposure to vibration and more sedentary or intense physical job demand was observed in male patients. In contrast, in females, only higher age, overweight, family history and lower leisure physical activity were risk factors. FF genotype was a 2-fold risk factor to develop discopathies and/or osteochondrosis concomitant with disc herniation for both gender patients, while heterozygous Ff was protective for females only. In males only ff genotype was protective for discopathies and/or osteochondrosis and F allele was a 2-fold risk factor for hernia; discopathies; discopathies and/or osteochondrosis. Sex-related differences in voluntary behaviors, exposure to environmental risks and genetic background could be crucial for a gender-differentiated management of patients with spine disorders.


Dramatic action: A theater-based paradigm for analyzing human interactions.
Existing approaches to describe social interactions consider emotional states or use ad-hoc descriptors for microanalysis of interactions. Such descriptors are different in each context thereby limiting comparisons, and can also mix facets of meaning such as emotional states, short term tactics and long-term goals. To develop a systematic set of concepts for second-by-second social interactions, we suggest a complementary approach based on practices employed in theater. Theater uses the concept of dramatic action, the effort that one makes to change the psychological state of another. Unlike states (e.g. emotions), dramatic actions aim to change states; unlike long-term goals or motivations, dramatic actions can last seconds. We defined a set of 22 basic dramatic action verbs using a lexical approach, such as 'to threaten'-the effort to incite fear, and 'to encourage'-the effort to inspire hope or confidence. We developed a set of visual cartoon stimuli for these basic dramatic actions, and find that people can reliably and reproducibly assign dramatic action verbs to these stimuli. We show that each dramatic action can be carried out with different emotions, indicating that the two constructs are distinct. We characterized a principal valence axis of dramatic actions. Finally, we re-analyzed three widely-used interaction coding systems in terms of dramatic actions, to suggest that dramatic actions might serve as a common vocabulary across research contexts. This study thus operationalizes and tests dramatic action as a potentially useful concept for research on social interaction, and in particular on influence tactics.


Latest developments in the matrics process.
The Measurement and Treatment Research to Improve Cognition in Schizophrenia Research process has led to several developments in the assessment of cognitive functioning for schizophrenia-treatment studies. The first development was the development of a consensus cognitive battery and a United States Food and Drug Administration-endorsed research design. Since the development of the cognitive battery, interest has been spurred in clinical trials in different countries and the development of co-primary functional outcomes measures for these. The MATRICS Consensus Cognitive Battery has been translated into 11 different languages and is being translated into even more. A study has been completed that compared the usefulness of multiple potential co-primary measures, suggesting that the University of California San Diego Performance-Based skills assessment, version II (UPSA-II) is the most suitable for studies conducted in English. These findings suggest that reliable performance-based measures that are easy to administer and highly correlated with cognitive functioning are now available for use in treatment studies.


IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence.
Cellular senescence, a state of sustained cell cycle arrest, has been identified as an important anti-tumor barrier. Senescent cells secrete various growth factors and cytokines, such as IL6 and IL8, which collectively constitute the senescence-associated secretory phenotype (SASP). The SASP can signal to the tumor environment and elicit the immune-mediated clearance of tumor cells or, depending on the context, could potentially promote tumor progression. Despite the importance of the SASP to tumor biology, its regulation remains relatively unknown. Here, we show that IκBζ, an atypical member of the inhibitor of NFκB proteins and selective coactivator of particular NFκB target genes, is an important regulator of SASP expression. Several models of DNA damage- and oncogene-induced senescence revealed a robust induction of IκBζ expression. RNAi-mediated knockdown of IκBζ impaired IL6 and IL8 expression, whereas transgenic IκBζ expression resulted in enhanced SASP cytokine expression. Importantly, during senescence of IκBζ knockout cells induction of IL6 and IL8, but not of the cell cycle inhibitor p21(WAF/CIP1), was completely abolished. Thus, we propose an important and hitherto unappreciated role of IκBζ in SASP formation in both DNA damage- and oncogene-induced senescence.


GATA4 immunolocalization in breast carcinoma as a potent prognostic predictor.
Transcriptional GATA factors are known lineage selector genes and regulate a variety of biological processes including specification and differentiation of tissues. In the present study, we examined expression profiles of six GATA factor genes in invasive ductal carcinomas (IDC) of the breast using microarray analysis (n = 20) and found that GATA4 expression was closely correlated with recurrence in patients. Because the significance of GATA4 has remained largely unknown in breast carcinoma, we further immunolocalized GATA4 in ductal carcinoma in situ (DCIS) of the breast (n = 48) and IDC (n = 163). GATA4 immunoreactivity was detected in the nuclei of carcinoma cells and was positive in 27% of DCIS and 31% of IDC cases. GATA4 status was significantly associated with nuclear grade and van Nuys classification in DCIS and was positively associated with distant metastasis, histological grade and HER2 status, but negatively correlated with progesterone receptor labeling index in IDC. Subsequent multivariate analysis demonstrated that GATA4 status was an independent prognostic factor for both disease-free and breast cancer-specific survival of IDC patients. All of these results indicate that GATA4 plays important roles in the progression of breast carcinoma from an early stage and that immunohistochemical GATA4 status is considered a potent prognostic factor in human breast cancer patients.


A novel method of resistance for influenza against a channel-blocking antiviral drug.
Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H(+) channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease.


Endothelial progenitor cell research in stroke: a potential shift in pathophysiological and therapeutical concepts.
Stroke is the leading cause of disability in the Western world; however, few therapies are at hand to decrease this burden. Endothelial progenitor cells (EPCs) have been introduced in cardiovascular medicine as factotums. EPCs can repair damaged endothelium and attenuate the development and progression of atherosclerosis. Also, EPCs can form new vessels in ischemic areas and thus promote recovery after ischemic events. In stroke, however, EPC research is limited. In our overview, we provide background information on EPC use as a risk marker and as a potential therapeutic agent. In our opinion, the lack of EPC studies in stroke should instigate vascular neurologists to participate in EPC research, as EPCs could also change pathophysiological concepts and improve clinical treatments in vascular neurology.


An efficient screening tool for preoperative depression: the Geriatric Depression Scale-Short Form.
Depression is highly prevalent in patients before surgery, and it has been widely shown to have a serious impact on their postoperative outcomes. It would therefore be desirable for physicians to obtain a quick, simple screen to evaluate depression to consider treatment of symptomatology and potentially optimize postoperative outcomes. In this study, we investigated the prevalence of depression in a presurgical inpatient sample undergoing major, noncardiac surgery. In addition, we sought to establish the Geriatric Depression Scale-Short Form (GDS-SF) as a valid screening tool for depression by examining its relationship to the Beck Depression inventory (BDI) by age and gender. In our sample of 1043 presurgical candidates, prevalence of depression as established by the BDI was significantly higher than rates consistently found in healthy community samples. Depression was more common in women than in men (P = 0.02), and depression rates were lower in elders relative to middle-aged and younger groups (P = 0.003 and 0.003, respectively). In addition, we found that there was a high correlation between the BDI and the GDS-SF within each of the age groups. These data further support the need for depression screens in presurgical populations and establish the validity of the GDS-SF as a valid quick assessment alternative available to physicians.


SCCA2-like serpins mediate genetic predisposition to skin tumors.
Reasons for early onset skin cancer are poorly understood. Microarray analysis revealed overexpression of the Scca2 gene in the 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-S mice, or line phenotypically selected for high susceptibility to two-stage skin carcinogenesis, as compared with 12-O-tetradecanoylphorbol-13-acetate-treated skin of Car-R mice, which is resistant. A human skin squamous cell carcinoma cell line (NCI-H520) transfected with mouse Scca2 or a related gene, Scca2-rs1, both expressed in the skin, showed significantly increased tumor growth as compared with controls when injected in nude mice. Immunohistochemical analysis of samples from two independent series of Italian and Korean patients with squamous cell carcinoma of the skin indicated a significant association between SCCA2 protein expression and younger age at tumor onset. These findings provide evidence that SCCA2-like serpins mediate genetic predisposition to skin cancer in a mouse model and in humans.