Self-concept clarity and Internet addiction disorder among junior high school students: A moderate mediation model.
As the epidemic spreads, the problem of Internet addiction disorder (IAD) stand out and getting serious. The present study aimed to investigate IAD among junior high school students during the spread of the COVID-19, and to explore the mediating role of cognitive failure between self-concept clarity and IAD, and the moderating role of mindfulness. A sample of 1,153 junior high school students from two randomly selected junior high schools in Henan Province were surveyed anonymously with Self-concept Clarity Scale (SCCS), Cognitive Failure Questionnaire (CFQ), Mindfulness Attention Awareness Scale (MAAS) and Internet Addiction disorder Test (IAT). The sample was obtained through random cluster sampling, taking classes as the clusters and students as the elements. (1) Self-concept clarity was negatively correlated with Internet addiction disorder; (2) Self-concept clarity not only had a direct effect on Internet addiction disorder, but also indirectly affect Internet addiction disorder through cognitive failure; (3) Mindfulness moderates the relationship between self-concept clarity and Internet addiction disorder, as well as the relationship between cognitive failure and Internet addiction disorder. Compared with low levels of mindfulness, both the protective effect of self-concept clarity and the effect of cognitive failure on Internet addiction disorder were stronger among junior high school students who were at high levels of mindfulness. This study constructs a moderated mediation model to explain the effect of self-concept clarity on Internet addiction disorder. It is effective to alleviate Internet addiction disorder by improving self-concept clarity and mindfulness level of the junior school students.


N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion.
Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40-60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N-acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection. After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed. Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury. These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection.


Air pollution and acute respiratory infections among children 0-4 years of age: an 18-year time-series study.
Upper and lower respiratory infections are common in early childhood and may be exacerbated by air pollution. We investigated short-term changes in ambient air pollutant concentrations, including speciated particulate matter less than 2.5 μm in diameter (PM2.5), in relation to emergency department (ED) visits for respiratory infections in young children. Daily counts of ED visits for bronchitis and bronchiolitis (n = 80,399), pneumonia (n = 63,359), and upper respiratory infection (URI) (n = 359,246) among children 0-4 years of age were collected from hospitals in the Atlanta, Georgia, area for the period 1993-2010. Daily pollutant measurements were combined across monitoring stations using population weighting. In Poisson generalized linear models, 3-day moving average concentrations of ozone, nitrogen dioxide, and the organic carbon fraction of particulate matter less than 2.5 μm in diameter (PM2.5) were associated with ED visits for pneumonia and URI. Ozone associations were strongest and were observed at low (cold-season) concentrations; a 1-interquartile range increase predicted a 4% increase (95% confidence interval: 2%, 6%) in visits for URI and an 8% increase (95% confidence interval: 4%, 13%) in visits for pneumonia. Rate ratios tended to be higher in the 1- to 4-year age group compared with infants. Results suggest that primary traffic pollutants, ozone, and the organic carbon fraction of PM2.5 exacerbate upper and lower respiratory infections in early life, and that the carbon fraction of PM2.5 is a particularly harmful component of the ambient particulate matter mixture.


Carcinoma en cuirasse associated with zosteriform metastasis in breast adenocarcinoma.
Breast cancer is the first cancer associated with cutaneous metastasis (CM). The clinical presentation of these metastases is comprehensive. We report an original case of carcinoma en cuirasse associated with zosteriform metastasis that indicates the development of contralateral breast cancer.


Traditional Calibration Methods in Atomic Spectrometry and New Calibration Strategies for Inductively Coupled Plasma Mass Spectrometry.
Applications, advantages, and limitations of the traditional external standard calibration, matrix-matched calibration, internal standardization, and standard additions, as well as the non-traditional interference standard method, standard dilution analysis, multi-isotope calibration, and multispecies calibration methods are discussed.


Exon-based clustering of murine breast tumor transcriptomes reveals alternative exons whose expression is associated with metastasis.
In the field of bioinformatics, exon profiling is a developing area of disease-associated transcriptome analysis. In this study, we performed a microarray-based transcriptome analysis at the single exon level in mouse 4T1 primary mammary tumors with different metastatic capabilities. A novel bioinformatics platform was developed that identified 679 genes with differentially expressed exons in 4T1 tumors, many of which were involved in cell morphology and movement. Of 152 alternative exons tested by reverse transcription-PCR, 97 were validated as differentially expressed in primary tumors with different metastatic capability. This analysis revealed candidate progression genes, hinting at variations in protein functions by alternate exon usage. In a parallel effort, we developed a novel exon-based clustering analysis and identified alternative exons in tumor transcriptomes that were associated with dissemination of primary tumor cells to sites of pulmonary metastasis. This analysis also revealed that the splicing events identified by comparing primary tumors were not aberrant events. Lastly, we found that a subset of differentially spliced variant transcripts identified in the murine model was associated with poor prognosis in a large clinical cohort of patients with breast cancer. Our findings illustrate the utility of exon profiling to define novel theranostic markers for study in cancer progression and metastasis.


[Conservative treatment of acute diverticulitis].
Scientific evidence concerning the treatment of acute diverticulitis is scarce. We describe 2 patients with this condition in this article. The first, a 64-year-old man, came to the emergency room because he had experienced persistent abdominal pain for the previous 4 days. He was diagnosed with uncomplicated diverticulitis. The second patient, a 58-year-old woman, had had pain in her left lower abdomen for 4 weeks; the pain appeared to have been caused by complicated diverticulitis. Both patients were treated conservatively. Only the patient with complicated diverticulitis was administered antibiotics; she underwent surgery at a later date because of persistent pain. Several guidelines recommend the administration of antibiotics; however, a number of recent studies have revealed no benefit to the clinical course from the use of antibiotics. The Dutch guideline, therefore, recommends withholding antibiotics in the acute phase. Conclusive evidence on the best treatment for patients with frequent recurrences or chronic symptoms after an episode of acute diverticulitis is not available. Guidelines advise a personalised treatment strategy for each patient. More research is necessary on the effect of mesalazine in these cases.


Winning fights induces hyperaggression via the action of the biogenic amine octopamine in crickets.
Winning an agonistic interaction against a conspecific is known to heighten aggressiveness, but the underlying events and mechanism are poorly understood. We quantified the effect of experiencing successive wins on aggression in adult male crickets (Gryllus bimaculatus) by staging knockout tournaments and investigated its dependence on biogenic amines by treatment with amine receptor antagonists. For an inter-fight interval of 5 min, fights between winners escalated to higher levels of aggression and lasted significantly longer than the preceding round. This winner effect is transient, and no longer evident for an inter-fight interval of 20 min, indicating that it does not result from selecting individuals that were hyper-aggressive from the outset. A winner effect was also evident in crickets that experienced wins without physical exertion, or that engaged in fights that were interrupted before a win was experienced. Finally, the winner effect was abolished by prior treatment with epinastine, a highly selective octopamine receptor blocker, but not by propranolol, a ß-adrenergic receptor antagonist, nor by yohimbine, an insect tyramine receptor blocker nor by fluphenazine an insect dopamine-receptor blocker. Taken together our study in the cricket indicates that the physical exertion of fighting, together with some rewarding aspect of the actual winning experience, leads to a transient increase in aggressive motivation via activation of the octopaminergic system, the invertebrate equivalent to the adrenergic system of vertebrates.


Infarction involving the insula and risk of mortality after stroke.
Cerebral infarction involving the insula has been associated with decreased survival following stroke. We hypothesized that infarct volume may reduce this association. The subjects were acute stroke patients who had consented to 2-year follow-up after stroke as part of the Michigan Acute Stroke Care Overview and Treatment Surveillance System registry. One hundred and eleven subjects exhibited areas of acute ischemic infarction on neuroimaging studies, 25 of whom had infarction involving the insula. Cox proportional hazard ratios (HR) were calculated to determine the association between mortality and acute infarction involving the insula, infarct volume, and other factors known to affect survival after stroke. In unadjusted analysis, subjects with insula infarction had a nonsignificant twofold increase in 1-year mortality (HR = 2.1, 95% CI 0.6-7.0; p = 0.25). When adjusted for infarct volume, however, the HR for insula infarction was reduced to the null value (HR = 1.0, 95% CI 0.2-4.1; p = 1.00), indicating that the effect of insula infarction was entirely confounded by infarct volume. Insula infarction was associated with a nonsignificant twofold increase in mortality after stroke; however, this association was completely eliminated after adjusting for infarct volume. Infarct volume thus should be considered in future studies of insula infarction and mortality.


Predicting continued dizziness after an acute peripheral vestibular disorder.
To identify individuals at risk of developing ongoing dizziness 3 months after an acute peripheral vestibular disorder episode, which is usually functionally compensated or even healed within a few weeks. In a prospective longitudinal study, we assessed fear of bodily sensations and cognitions related to anxiety at the time of hospital admission and 3 months later in 43 patients with an episode of vestibular neuritis (VN) or benign paroxysmal positional vertigo (BPPV). All participants were assessed for mental disorders using a structured clinical interview. Only the interaction between fear of bodily sensations within the first 2 weeks after admission and the type of vestibular disorder predicted the extent of dizzy complaints 3 months later; this accounts for 21% of the variance in a multiple regression analysis. Specifically, the prediction was valid only in patients with VN but not in patients with BPPV. Further analysis demonstrated that the interaction was not due to the peripheral vestibular disorder per se but rather determined by the initial severity of dizziness, which was significantly different in BPPV and VN patients. The present study demonstrates that, for the development of persistent psychogenic dizziness after a peripheral vestibular disorder, the fear of bodily sensations is only relevant in interaction with the initial severity of dizziness experienced during the acute organic episode. To prevent development of persistent psychogenic dizziness, we feel that our results indicate the need to screen patients with vestibular disorders for at-risk status and offer them psychological support to deal with their symptoms.


Mediated computer search services relative to instruction services: a survey of one health sciences library.
To assess the quality and usefulness of one health sciences library's mediated computer search service, a survey was undertaken to determine satisfaction rates, why users do or do not use the service, and how useful the service is perceived to be in comparison to instructional service. Satisfaction rates were high, with users indicating librarian expertise and time/cost savings as the main reasons for using the service. Non-users indicated that they preferred to do their own searching, and many were unaware of the service. Though a majority of respondents do not currently use the service, surprisingly a majority of respondents placed significant value on the mediated search service in relation to instruction.


A Simple BODIPY-Based Viscosity Probe for Imaging of Cellular Viscosity in Live Cells.
Intracellular viscosity is a fundamental physical parameter that indicates the functioning of cells. In this work, we developed a simple boron-dipyrromethene (BODIPY)-based probe, BTV, for cellular mitochondria viscosity imaging by coupling a simple BODIPY rotor with a mitochondria-targeting unit. The BTV exhibited a significant fluorescence intensity enhancement of more than 100-fold as the solvent viscosity increased. Also, the probe showed a direct linear relationship between the fluorescence lifetime and the media viscosity, which makes it possible to trace the change of the medium viscosity. Furthermore, it was demonstrated that BTV could achieve practical applicability in the monitoring of mitochondrial viscosity changes in live cells through fluorescence lifetime imaging microscopy (FLIM).


Fracture Load of Different Zirconia Types: A Mastication Simulation Study.
To assess the effect of yttria mol% concentration and material thickness on the biaxial fracture load (N) of zirconia with and without mastication simulation. Disk-shaped specimens (N = 120) of 3 mol% yttria-partially stabilized zirconia, 3Y-PSZ (Katana High Translucent, Kuraray Noritake), 4 mol% yttria-partially stabilized zirconia, 4Y-PSZ (Katana Super Translucent Multi Layered) and 5 mol% Yttria-partially stabilized zirconia, 5Y-PSZ (Katana Ultra Translucent Multi Layered) were prepared to thicknesses of 0.7 and 1.2 mm. For each thickness, the biaxial fracture load (N) was measured with and without mastication simulation with 1.2 million cycles at a 110-N load and simultaneous thermal cycling at 5°C to 55°C. The data were analyzed by three-way Analysis of Variance (α = 0.05) and Tukey-Kramer adjusted multiple comparison test. Yttria mol% concentration and material thickness had a statistically significant effect on the mean biaxial fracture load (F = 388.16, p < 0.001 and F = 714.33, p < 0.001 respectively). The mean biaxial fracture load ranged from the highest to the lowest; 3Y-PSZ, 4Y-PSZ, and 5Y-PSZ (p = 0.012). The mean biaxial fracture load of the 1.2 mm thickness groups was significantly higher than 0.7 mm thickness at any given condition (p = 0.002). Not all specimens survived the mastication simulation protocol. Fifty percent of the 0.7-mm-thick 4Y-PSZ specimens, 70% of the 0.7-mm-thick 5Y-PSZ specimens and 20% of 1.2-mm-thick 5Y-PSZ specimens fractured during mastication simulation. Mastication simulation had no statistically significant effect on the biaxial fracture load (F = 1.24, p = 0.239) of the survived specimens. Lowering yttria mol% concentration and increasing material thickness significantly increases the fracture load of zirconia. At 0.7 mm thickness, only 3Y-PSZ survived masticatory simulation. A minimum material thickness of 1.2 mm is required for 4Y-PSZ or 5Y-PSZ.


An Image Augmentation Method Based on Limited Samples for Object Tracking Based on Mobile Platform.
This paper proposes an image augmentation model of limited samples on the mobile platform for object tracking. The augmentation method mainly aims at the detection failure caused by the small number of effective samples, jitter of tracking platform, and relative rotation between camera and object in the tracking process. Aiming at the object tracking problem, we first propose to use geometric projection transformation, multi-directional overlay blurring, and random background filling to improve the generalization ability of samples. Then, selecting suitable traditional augmentation methods as the supplements, an image augmentation model with an adjustable probability factor is provided to simulate various kinds of samples to help the detection model carry out more reliable training. Finally, combined with a spatial localization algorithm based on geometric constraints proposed by the author's previous work, a framework for object tracking with an image augmentation method is proposed. SSD, YOLOv3, YOLOv4, and YOLOx are adopted in the experiment of this paper as the detection models. And a large number of object recognition and object tracking experiments are carried out by combining with common data sets OTB50 and OTB100 as well as the OTMP data set proposed by us for mobile platform. The augmented module proposed in this paper is conducive for the detection model to improve the detection accuracy by at least 10%. Especially for objects with planar characteristics, the affine and projection transformation used in this paper can greatly improve the detection accuracy of the model. Based on the object tracking framework of our augmented model, the RMSE is estimated to be less than 4.21 cm in terms of the actual tracking of indoor objects.


Self-wrinkling polyelectrolyte multilayers: construction, smoothing and the underlying mechanism.
Introducing wrinkling or rough features into substrates is of great practical significance to construct various functional surfaces. Due to the sensitivity of assembled units towards environmental stimuli, the internals of layer-by-layer films can be readily adjusted to generate various micro- and nanostructures. We previously described a self-roughening polyelectrolyte multilayer (PEM) to facilitate the introduction of surface microstructures. In the present work, the growth process of PEI/PAA multilayer films was investigated and the mean size of the surface microstructures was found to increase linearly with the film thickness. The spontaneous formation of these surface features can be attributed to swelling-induced film deformation during the assembling process, which is similar to the surface wrinkling of hydrogels undergoing a volume phase transition. When exposed to saturated humidity, the internal stress as well as the surface microstructures can be diminished spontaneously, leading to a flat surface over the substrates. Given the effect of the underlying film thickness on the characteristic wavelength of the surface wrinkles, multiscale surface microstructures can be readily realized by means of spatially presetting the distribution of the film thickness.


Female urethral condyloma acuminata mimicking urethral caruncle.
Condyloma acuminata are epidermal lesions caused by the human papillomavirus (HPV) most commonly affecting the anogenital region. Urethral involvement is uncommon, and may mimic other urethral lesions. In this case report, a 62-year-old patient presents with what was believed to be a urethral caruncle and underwent successful resection with the final pathologic diagnosis of urethral condyloma. The clinical features and diagnosis are reviewed. This condition should be considered in the differential diagnosis of females with known HPV or those who are deemed higher risk with unprotected sexual encounters.


Bone marrow mononuclear cells increase retinal ganglion cell survival and axon regeneration in the adult rat.
The central nervous system (CNS) of adult mammals generally does not regenerate, and many studies have attempted to identify factors that could increase neuroprotection and/or axonal outgrowth after CNS lesions. Using the optic nerve crush of rats as a model for CNS injury, we investigated the effect of intravitreal transplantation of syngeneic bone-marrow mononuclear cells (BMMCs) on the survival of retinal ganglion cells (RGC) and on the regeneration of optic axons. Control animals received intravitreal saline injections after lesion. Injections of BMMCs resulted in a 1.6-fold increase in the number of RGCs surviving 14 days after injury. The BMMC-treated animals also had increased numbers of axons, which grew up to 1.5 mm from the crush site, and also had reduced Müller glia activation. Analysis of mRNAs in all conditions revealed an increase in levels of fibroblast growth factor 2 (FGF-2) mRNA in treated animals 14 days after injury. To investigate whether the regenerated axons could reach the brain, we retrograde labeled the RGCs by injecting a lipophilic tracer into the superior colliculus. We also analyzed the expression of NGFI-A in the superficial layers of the superior colliculus as a possible marker of synaptic input from RGC axons. We found evidence that more RGCs were able to reach the brain after treatment and we showed that NGFI-A expression was higher in the treated animals 60 days after injury. These results demonstrate that transplant of BMMCs can increase neuroprotection and neuroregeneration after injury in a model of optic nerve crush, and these effects could be mediated by FGF-2.


A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity.
Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase the response rate to checkpoint blockade, in this study, we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to interleukin (IL)-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 activated both the innate and adaptive immune responses and induced a favorable and immunostimulatory TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in an HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.


A Pentacene-based Nanotube Displaying Enriched Electrochemical and Photochemical Activities.
Unlike previously well-studied, acyclic pentacene oligomers, the first synthesis of a cyclic pentacene trimer with a fixed tubular conformation is reported. A short-step synthesis starting from common pentacenequinone yielded the target molecule with a 1.5 nanometer length and a subnanometer pore. Steady-state spectroscopic analyses revealed that the close proximity of the non-conjugated, three pentacene chromophores allows the nanotube to display stepwise electrochemical/chemical oxidation characteristics. Furthermore, time-resolved transient absorption measurements elucidated the generation of an excited triplet state of the nanotube, with high quantum yield reaching about 180 % through intramolecular singlet fission and a very long triplet lifetime.


Comparative metabolism of 2,4-dichlorophenoxyacetic Acid in cotyledon and leaf callus from two varieties of soybean.
Only quantitative differences were observed in the metabolism of [1-(14)C]2,4-dichlorophenoxyacetic acid (2,4-D) by soybean cotyledon callus as influenced by variety (Acme and Amsoy), source of tissue (cotyledon, leaf and root) and age. All tissues metabolized 2,4-D to water-soluble (glycosides) and ether-soluble (primarily amino acid conjugates) metabolites.In young (3- to 4-week-old) Amsoy cotyledon or leaf callus tissue the free 2,4-D increased proportionately with the external 2,4-D concentration while in older (6- to 8-week-old) tissue the amino acid conjugates increased in this manner. Thus, in the older Amsoy tissue apparent regulation of the internal 2,4-D level (1.5-3.5 nmoles per gram fresh weight) was observed. In 3- or 6-week-old Acme cotyledon callus 2,4-D accumulated with an increase in the external 2,4-D concentration with no evidence for regulation of internal 2,4-D levels.


Nutrition support in hospitalized cancer patients with malnutrition in China.
Malnutrition has adverse impacts on survival of cancer patients. The aim of the present study was to investigate the prevalence of malnutrition, and the nutrition support status in hospitalized patients with cancer in China. A multi-center, cross-sectional study was conducted in 29 tertiary public hospital wards in 14 Chinese cities. Malnutrition was defined as weight loss (WL) >5% over the past 6 months or body mass index (BMI) <20 kg/m2 with WL >2%. The nutrition risk index (NRI) and performance status (PS) were evaluated. 1138 hospitalized cancer patients (93.4% of the initial sample, 662 men, 60.6±14.5 years) were enrolled. Overall, 41.3% of patients were malnourished. The percentage of nutritional disorders as determined by the NRI was 51.4%. PS was 0 in 50.3%, 1 in 15.4%, 2 in 13.9%, and 3 or 4 in 20.4%. Compared with patients with PS of 0-1, patients with PS of 3-4 had a relative risk of malnutrition of 1.275 (95% CI 0.250-0.488, p<0.0001). Only 38.6% of patients received nutrition support, of whom 45.0% of the malnourished and 31.9% of the non-malnourished patients did; 63.2% of patients complained of poor appetite, while merely 14.0% of patients had received nutrition counseling. The prevalence of malnutrition is high in hospitalized cancer patients, and inappropriate use of nutritional interventions highlights the urgent need to define standard operating procedures and quality control process.


DNA Content of Beta vulgaris Chloroplasts during Leaf Cell Expansion.
During the growth of beet leaves from 2 to 3 to 25 to 30 centimeters, the leaf cells increase in size, the average number of chloroplasts per cell increases from 11 to 65 and the amount of chloroplast DNA per cell increases from 1100 to 1900 plastome copies. The average number of copies of the plastome per chloroplast decreases from 104 in 2 to 3-centimeter leaves to 29 in 25 to 30-centimeter leaves during a period when the chloroplasts undergo two to three rounds of division and increase diameter from 1.5 to 4.9 micrometers. This result is at variance with previously published studies of beet chloroplasts but agrees with the conclusions reached in more recent studies of pea and spinach and wheat leaf cell expansion.


Development and qualification of an LC-MS/MS method for investigating the biological implications of micelle entrapped paclitaxel in cell culture and rats.
Paclitaxel is a front-line antineoplastic drug used in chemotherapeutic modalities for treatment of various types of malignancies. However, its efficacy is limited by dose-related toxicities. In this study, we have explored two important biological aspects of entrapping paclitaxel in PEG2000 -DSPE micelles. First, we evaluated the impact of this micellar delivery system on P-glycoprotein (P-gp)-paclitaxel interaction, and we investigated differences in plasma pharmacokinetics of free and micelle-entrapped paclitaxel. For quantification of paclitaxel, an LC-MS/MS method was developed. Paclitaxel was extracted from samples using a simple one-step protein precipitation. Chromatographic conditions included a C18 column with a mobile phase consisting of 0.1% formic acid in acetonitrile-water (60:40, v/v) pumped at 1 mL/min. The lower limit of quantitation in both plasma and cell lysate was 1.0 ng/mL. The quantitative linear range was 1-1000 ng/mL. In addition, P-gp efflux studies on free and micellar paclitaxel showed the proficiency of PEG2000 -DSPE micelles in evading P-gp-mediated efflux, thus increasing paclitaxel uptake. Furthermore, the micellar paclitaxel levels were maintained in the body for longer time as compared with taxol, which is desirable for increasing the efficacy of paclitaxel in cancer treatment.


Towards High Throughput Structuring of Liquid Foams in Microchannels: Effect of Geometry, Flowrate and Formulation.
This work is part of a study aiming to design a high-throughput foaming microsystem. The main focused field of application is the food industry. With the objective of improving the design of the microdevice, the effects of the geometry and the nature of the liquid base are presently investigated through visualizations of the flow typology of bubbles trains, aiming to expand the knowledge on key parameters that lead to an improved gas breakup. The tested set of conditions is not encountered in traditional microfluidics systems: i.e., throughputs up to 19 L·h-1 for the liquid phase, process velocities around 20 m·s-1 and flow of complex fluids. The behavior of solutions based on xanthan gum (XG) and whey proteins (WPI) is compared to that of solutions containing one of these ingredients or other ones (caseinates, glycerol). The structural and end-used properties of the final foams, namely the bubble diameter and rheological behavior, are evaluated. The incorporation of XG induces bubble shape stabilization even at the highest shear rates (~105 s-1) encountered in the mixing channel. "Controlled" interfacial breakup by tip-streaming or binary breakup are only observed with the WPI/XG biopolymers. This study indubitably highlights the essential role of the process/formulation interaction in the development of structural and functional properties of food foams when using microfluidics at high throughput.


Analyzing Response Times and Other Types of Time-to-Event Data Using Event History Analysis: A Tool for Mental Chronometry and Cognitive Psychophysiology.
In this Methods article, we discuss and illustrate a unifying, principled way to analyze response time data from psychological experiments-and all other types of time-to-event data. We advocate the general application of discrete-time event history analysis (EHA) which is a well-established, intuitive longitudinal approach to statistically describe and model the shape of time-to-event distributions. After discussing the theoretical background behind the so-called hazard function of event occurrence in both continuous and discrete time units, we illustrate how to calculate and interpret the descriptive statistics provided by discrete-time EHA using two example data sets (masked priming, visual search). In case of discrimination data, the hazard analysis of response occurrence can be extended with a microlevel speed-accuracy trade-off analysis. We then discuss different approaches for obtaining inferential statistics. We consider the advantages and disadvantages of a principled use of discrete-time EHA for time-to-event data compared to (a) comparing means with analysis of variance, (b) other distributional methods available in the literature such as delta plots and continuous-time EHA methods, and (c) only fitting parametric distributions or computational models to empirical data. We conclude that statistically controlling for the passage of time during data analysis is equally important as experimental control during the design of an experiment, to understand human behavior in our experimental paradigms.


Three key variables involved in feeder preparation for the maintenance of human embryonic stem cells.
Although the development of a feeder-free culture system for future applications of human embryonic stem cells (hESCs), at present the regular culture system uses mitotically inactivated mouse embryonic fibroblasts (mEFs) as feeder cells for maintaining undifferentiated hESCs. Mitomycin C (MMC) is used to inactivate mEFs, but this causes DNA damage, and it is unclear whether MMC remains in the culture system after several washes. Three variables have been evaluated with respect to feeder preparation and MMC involvement, including mEF exposure to MMC, density of feeder cells, and different wash steps during the preparation of feeder cells. These variables are critical to the subsequent planting of hESCs because remnants of MMC would be unsafe with respect to long-term culture of hESCs The novel data here evaluates the remnant amounts of MMC in a hESCs culture system using HPLC/MS/MS. The ultimate objective of this study is the control of MMC within a safe range.


High macrophage lipoprotein lipase expression and secretion are associated in inbred murine strains with susceptibility to atherosclerosis.
To test the possibility that variations in macrophage lipoprotein lipase (LPL) secretion may constitute one of the hereditary components of atherosclerosis, we evaluated LPL gene expression and secretion in macrophages harvested from inbred mouse strains differing in their susceptibility to the diet-induced development of atherosclerosis. Inflammatory peritoneal macrophages harvested from atherosclerosis-susceptible C57BL/6J mice showed twofold to threefold higher basal LPL mass, activity, and mRNA levels than those isolated from atherosclerosis-resistant C3H/HeN mice. We determined LPL secretion and gene expression in the susceptible C57BL/6J (B), resistant A/J (A), and A x B/B x A recombinant inbred strains of mice typed as atherosclerosis resistant (A-like) or atherosclerosis susceptible (B-like). Macrophage LPL secretion and mRNA expression were twofold higher in the susceptible C57BL/6J (B) mice than in the resistant A/J (A) mice. Significantly higher LPL secretion, activity, and gene expression were found in recombinant inbred mouse strains that typed B-like than in those typed A-like. These results indicate that susceptibility to atherosclerosis is associated in inbred mouse strains with high LPL secretion and mRNA levels, whereas lower LPL secretion and mRNA expression are observed in atherosclerosis-resistant mice. These observations suggest a contributive role for LPL in the development of atherosclerosis.


Ancestral deceit and labile evolution of nectar production in the African orchid genus Disa.
An outstanding feature of the orchid family is that approximately 30-40% of the species have non-rewarding flowers and deploy various modes of deception to attract pollinators, whereas the remaining species engage in pollination mutualisms based on provision of floral rewards. Here, we explore the direction, frequency and reversibility of transitions between deceptive and rewarding pollination systems in the radiation of the large African genus Disa, and test whether these transitions had consequences for diversification. By optimizing nectar production data for 111 species on a well-resolved phylogeny, we confirmed that floral deception was the ancestral condition and that nectar production evolved at least nine times and was lost at least once. Transitions to nectar production first occurred ca 17 million years ago but did not significantly affect either speciation or extinction rates. Nectar evolved independently of a spur, which was lost and gained multiple times. These results show that nectar production can be a highly labile trait and highlight the need for further studies of the genetic architecture of nectar production and the selective factors underlying transitions between deception and mutualism.


Changes of Template Activity and Proteins of Chromatin during Wheat Germination.
Relationships between changes in template activity and composition of chromatin during germination of wheat embyros (Triticum aestivum L.) were investigated. The template activity of chromatin was determined with exogenous DNA-dependent RNA polymerase II (EC 18.104.22.168) prepared from wheat embryos. It was essentially constant for 18 hours of germination, corresponding to 2.5% of that of a native calf thymus DNA. Thereafter, the activity increased 2-fold and 5-fold at 24 and 60 hours of germination, respectively.Chromatin-associated proteins were separated into at least 22 distinct bands by sodium dodecyl sulfate gel electrophoresis throughout 60 hours of germination. Significant changes were observed in two nonhistone proteins, approximate molecular weights 59,000 and 39,000: the amount of the former was constant up to 18 hours, reduced for the period from 18 to 60 hours, and that of the latter was decreased for the period from 18 to 60 hours of germination. No change was observed in the number of histone components by acid-urea gel electrophoresis.


Localization phenomena and electronic transport in irradiated Aubry-André-Harper systems.
The role of light irradiation on electronic localization is critically investigated for the first time in a tight-binding lattice where site energies are modulated in the cosine form following the Aubry-André-Harper (AAH) model. The critical point of transition from delocalized-to-localized phase can be monitored selectively by regulating the light parameters that is extremely useful to have controlled electron transmission across the system. Starting with a strictly one-dimensional (1D) AAH chain, we extend our analysis considering a two-stranded ladder model which brings peculiar signatures in presence of irradiation. Unlike 1D system, AAH ladder exhibits a mixed phase (MP) zone where both extended and localized energy eigenstates co-exist. This is the fundamental requirement to have mobility edge in energy band spectrum. A mathematical description is given for decoupling the irradiated ladder into two effective 1D AAH chains. The underlying mechanism of getting a MP zone relies on the availability of two distinct critical points (CPs) of the decoupled chains, in presence of second-neighbor hopping between the two strands. Using a minimal coupling scheme the effect of light irradiation is incorporated following the Floquet-Bloch ansatz. The localization behaviors of different energy eigenstates are studied by calculating inverse participation ratio, and, are further explained in a more compact way by calculating two-terminal transmission probabilities together with average density of states. Finally, the decoupling procedure is extended for a more general multi-stranded AAH ladders where multiple CPs and thus multiple mobility edges are found. Our analysis may provide a new route of engineering localization properties in similar kind of other fascinating quasiperiodic systems.


Meeting the pastoral care needs of an aging population.
As hospitals increasingly operate nursing homes, retirement centers, and home health agencies, pastoral personnel will be challenged to demonstrate to hospital planners the importance of providing pastoral care for the elderly clients of these services. Older persons have significant needs that cannot be met by psychotherapy, social work, or other disciplines. The "young old," for example, are typically in early retirement and often feel useless and without dignity. The "middle old" are in transition between independence and dependence, health and chronic illness, and it is the thought of dying that most haunts them. The major concerns of the "frail old" are suffering and the provident care of God, particularly in the face of crippling or catastrophic illness. Through the process of life review and active listening, pastoral care specialists can help elderly persons find the inner power that produces hope and character. Departmental restructuring may be necessary, however, to meet the increased demand as the hospital moves into geriatric life care. Local church personnel could be used as well to provide hands-on service. Pastoral care departments should be alert to plans for hospital expansion and develop creative, long-range strategies for providing care.


Histochemical staining of nerve endings as an aid to free muscle transplantation.
Histochemical staining techniques that identify intact motor nerve fascicles are available to aid free muscle transplantation. Cholinesterase activity of myelinated axons can be identified by Karnovsky and Roots's technique. Axon viability can be assessed based on the presence of axoplasmic enzyme activity. By reacting serial sections for cholinesterase activity and carbonic anhydrase activity, which labels sensory axons, an accurate cross-sectional map of regenerating or functional sensory and motor nerve fibers can be constructed. Resolving the motor and sensory identities of fascicles in a mixed peripheral nerve should lead to more precise coaptation of recipient motor fibers to the motor nerve of the transferred muscle and enhance reinnervation.


ALK inhibitors in non-small cell lung cancer: crizotinib and beyond.
The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.


Three-Device (3D) Technique for Liver Parenchyma Dissection in Robotic Liver Surgery.
The implementation of robotics in liver surgery offers several advantages compared to conventional open and laparoscopic techniques. One major advantage is the enhanced degree of freedom at the tip of the robotic tools compared to laparoscopic instruments. This enables excellent vessel control during inflow and outflow dissection of the liver. Parenchymal transection remains the most challenging part during robotic liver resection because currently available robotic instruments for parenchymal transection have several limitations and there is no standardized technique as of yet. We established a new strategy and share our experience. We present a novel technique for the transection of liver parenchyma during robotic surgery, using three devices (3D) simultaneously: monopolar scissors and bipolar Maryland forceps of the robot and laparoscopic-guided waterjet. We collected the perioperative data of twenty-eight patients who underwent this procedure for minor and major liver resections between February 2019 and December 2020 from the Magdeburg Registry of minimally invasive liver surgery (MD-MILS). Twenty-eight patients underwent robotic-assisted 3D parenchyma dissection within the investigation period. Twelve cases of major and sixteen cases of minor hepatectomy for malignant and non-malignant cases were performed. Operative time for major liver resections (≥ 3 liver segments) was 381.7 (SD 80.6) min vs. 252.0 (70.4) min for minor resections (p < 0.01). Intraoperative measured blood loss was 495.8 (SD 508.8) ml for major and 256.3 (170.2) ml for minor liver resections (p = 0.090). The mean postoperative stay was 13.3 (SD 11.1) days for all cases. Liver surgery-related morbidity was 10.7%, no mortalities occurred. We achieved an R0 resection in all malignant cases. The 3D technique for parenchyma dissection in robotic liver surgery is a safe and feasible procedure. This novel method offers an advanced locally controlled preparation of intrahepatic vessels and bile ducts. The combination of precise extrahepatic vessel handling with the 3D technique of parenchyma dissection is a fundamental step forward to the standardization of robotic liver surgery for teaching purposing and the wider adoption of robotic hepatectomy into routine patient care.


Polycystic ovarian morphology is associated with primary dysmenorrhea in young Korean women.
This study was aimed at identifying a correlation between polycystic ovarian morphology (PCOM) and the severity of primary dysmenorrhea in young Korean women. A total of 592 patients who visited a tertiary hospital from March 2008 to March 2015 for dysmenorrhea were examined. After excluding those with secondary causes of menstrual pain (for example, myoma, adenomyosis, endometriosis, and pelvic inflammatory disease), 361 women were recruited and retrospectively analyzed. Severe dysmenorrhea was defined as a visual analog scale (VAS) score ≥6. The mean patient age was 23.0±4.0 years, the average menstrual cycle length was 34.4±23.7 days, and the average pain intensity was VAS 6.7±0.1 at baseline. PCOM was assessed by ultrasound in 54 women (15%). Patients with severe menstrual pain were more likely to have irregular menstrual cycles (P=0.03) and heavy menstrual flow (P=0.01) than those with mild menstrual pain. After adjusting for weight, height, menstrual cycle interval, and menstrual flow in the logistic regression analysis, PCOM (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.05-4.97; P=0.04) and heavy menstrual flow (OR, 1.85; 95% CI, 1.05-3.28; P=0.04) were found to be significant independent factors influencing pain. Our study shows that PCOM may have a correlation with the severity of primary dysmenorrhea. Since PCOM may play a role in the development of menstrual pain, patients with PCOM should be under active surveillance with resources for prompt pain management readily available. It may also be necessary to further investigate the molecular mechanisms of pain development in primary dysmenorrhea.


Palliative or curative treatment intent affects communication in radiation therapy consultations.
To assess whether communication in radiotherapy consultations is affected by palliative or curative treatment intent. The study involved 160 patients and 8 radiation oncologists. Eighty patients visited the radiation oncologist (RO) for palliative treatment and 80 for curative treatment. The consultation prior to radiation treatment was analyzed with the Roter Interaction Analysis System (RIAS). Within three days, patients completed a quality of life questionnaire (EORTC-QLQ-C30). In palliative radiotherapy (PRT) consultations, ROs asked more (closed-ended) biomedical and psychosocial questions and provided more information on prognosis than in consultations for curative radiotherapy (CRT). Patients in both groups provided a great deal of psychosocial information but asked few questions. The ROs expressed more concerns in the PRT consultations, while patients did not. PRT patients received fewer supportive remarks than CRT patients. In both groups, explicit decision-making received little attention. Proxies who accompanied the patients took a more active role in PRT than in CRT consultations. Communication in radiotherapy is affected by treatment intent with respect to the main contents of the consultation.


Envelope proteins from clinical isolates of human immunodeficiency virus type 1 that are refractory to neutralization by soluble CD4 possess high affinity for the CD4 receptor.
Recent evidence indicates that primary clinical isolates of human immunodeficiency virus type 1 (HIV-1) require significantly more soluble CD4 (sCD4) to block infection than the prototypic laboratory strain HTLV-IIIB. The currently accepted explanation for these observations is that the envelope glycoproteins from primary clinical isolates possess lower affinities for CD4 than laboratory strains. This observation has far reaching implications for the clinical effectiveness of sCD4. To test whether the resistance of clinical isolates to sCD4 neutralization correlates with low-affinity binding to gp120, we have compared gp120 glycoproteins derived from the clinical isolates HIV-1 JR-CSF and JR-FL with those derived from the prototypic strain HIV-1 BH10 in quantitative sCD4 binding studies. Surprisingly, our results demonstrate that gp120 derived from HIV-1 JR-CSF and JR-FL possess sCD4 binding affinities of equal or greater magnitude than gp120 derived from HIV-1 BH10. Thus primary clinical HIV-1 isolates can and do possess gp120 with high affinity for CD4, and sensitivity to neutralization by sCD4 is dependent upon factors other than the intrinsic affinity of gp120 for CD4.


An Internet-Based Multi-Approach Intervention Targeting University Students Suffering from Psychological Problems: Design, Implementation, and Evaluation.
Despite the widespread prevalence of mental health problems, most psychological distress remains untreated. Internet-based psychological interventions can be an essential tool for increasing treatment availability and accessibility. The main objective of the MindBlooming project is to design and implement an innovative Internet-based multi-approach treatment for university students suffering from psychological or physical problems. The intervention will focus on symptoms of depression, anxiety, sleep problems, self-destructive thoughts, job- and study-related stress and burnout, and chronic pain. It will be based on different approaches, primarily psychoeducation, Cognitive-Behavioral Treatment (CBT), and third-wave CBT. At the end of the treatment, user satisfaction and usability will be assessed. In addition, two further aims will be evaluating the treatment efficacy through a randomized controlled trial and tuning a predictive model through Machine Learning techniques. The intervention consists of a 7-week treatment on two problematic areas according to each students' personal needs, identified through an initial assessment. Besides the treatment assigned following the initial screening, participants will also be assigned to a different module to improve their relational skills. The treatment, which can be accessed through a mobile app, consists of psychoeducational videos followed by related exercises. We expect MindBlooming to be a remarkable tool for promoting the mental health of university students.


[Clinical utility of quantitative bone ultrasonography in the staging of osteoporosis].
Osteoporosis is well recognized as a public health problem in industrialized countries. Because of the efficiency of new treatments to decrease fracture risk, it is of a major interest to detect the patients who should benefit from such treatments. A diagnosis of osteoporosis is necessary before to start a specific treatment. This diagnosis is based on the measurement of the skeleton (hip and spine) with dual X-ray absorptiometry, using diagnostic criteria established by the World Health Organisation (WHO). In Switzerland, indications for bone densitometry are limited to precise situations. This technique cannot be applied for screening. For this purpose, peripheral measurements and particularly quantitative ultrasounds of bone seem to be promising. Indeed, several prospective studies clearly showed their predictive power for hip fracture risk in women aged more than 65 years. In order to facilitate the clinical use of bone ultrasounds, thresholds of risk of fracture and osteoporosis of the hip will be shortly published. This will integrate bone ultrasound in a global concept including bone densitometry and its indications, but also other risk factors for osteoporosis recognized by the Swiss association against osteoporosis (ASCO).


Conformational changes and calcium binding by calretinin and its recombinant fragments containing different sets of EF hand motifs.
Four recombinant fragments, representing different sets of EF-hand motifs of rat calretinin (CR) (I-II, I-III, III-VI, IV-VI), were prepared, and their Ca2+ -induced conformational changes were compared with those of full-length recombinant CR. All fragments were able to bind calcium ions as shown by 45Ca2+ overlay method on nitrocellulose and fluorescence measurements. The intrinsic tryptophan fluorescence intensity (FI) of apo-CR reversibly increased about 3-fold upon addition of calcium, indicating a change of conformation. The FI of fragments I-II (Trp 25) and I-III (Trp 25 and 116) increased about 1.4-fold on calcium binding, but that of fragment III-VI (Trp 116) increased 3.5-fold. Calcium titration of CR monitored by Trp fluorescence intensity showed that recombinant CR and some fragments bound Ca2+ with high affinity (Kd below 0.4 microM) and with high cooperativity. An apparent Hill coefficient for Ca2+ -induced fluorescence changes in CR was about 3.7. CR bound to organomercurial-agarose Cys 101 and 266 did not form cystine. The fluorescence intensities of cysteine-linked fluorescent probes 5-iodoacetamidofluorescein and N-(1-pyreneiodoacetamide) were increased approximately 1.3-fold upon calcium binding by CR. These data indicate that CR binds Ca2+ with high affinity and cooperativity and that this binding induces a change of conformation that involves the interaction of different parts of the molecule. Taken together, our results suggest that CR works as an on/off switch within a narrow range of free Ca2+ by interacting with as yet unidentified targets.


Design, synthesis, and evaluation of matrix metalloprotease inhibitors bearing cyclopropane-derived peptidomimetics as P1' and P2' replacements.
We have previously used trisubstituted cyclopropanes as peptide replacements to induce conformational constraints in known pseudopeptide inhibitors of a number of important enzymes. Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche(-) conformation of chi(1)-space, their ability to project the side chains into an anti orientation has not been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides 8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to correspond to the known orientations of the P1' and P2' side chains of 5 when bound to MMPs. Hence, 8 and 10 were designed explicitly to probe topological features of the S1' or the S2' binding pockets of the MMPs. They were also designed to explore the importance of the P1'-P2' amide group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor complexes, and the viability of introducing a retro amide linkage between P2' and P3'. Pseudopeptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically favorable conformational constraints that were induced by the cyclopropane in 8 were thus overwhelmed by the loss of the hydrogen bonding capability associated with the P1'-P2' amide group. On the other hand, compounds 10 and 11, which contain a P2'-P3' retro amide group, were modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that there may be a loss of hydrogen bonding capability associated with introducing the P2'-P3' retro amide group. However, because the conformationally constrained pseudopeptide 10 was significantly more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as useful rigid dipeptide replacements in some biologically active pseudopeptides.


separation and Immunological Characterization of Membrane Fractions from Barley Roots.
Tonoplast and plasma membranes (PM) were isolated from barley roots (Hordeum vulgare L. cv California Mariout 72) using sucrose step gradients. The isolation procedure yielded sufficient quantities of PM and tonoplast vesicles that were sealed and of the right orientation to measure ATP-dependent proton transport in vitro. The proteins of the endoplasmic reticulum, tonoplast-plus-Golgi membrane (TG) and PM fractions were separated on sodium dodecyl sulfate gels, and immunoblots were used to test for cross-contamination between the fractions. Proteins that cross-reacted with antibodies to the PM ATPase from corn roots and Neurospora were greatly enriched in the PM fraction, as were proteins that cross-reacted with monoclonal antibodies to an arabinogalactan protein from the PM of tobacco cells. Proteins that cross-reacted with antibodies to the 58- and 72-kilodalton subunits of the tonoplast ATPase of red beet storage tissue were greatly enriched in the TG fraction. The results with immunoblots and enzyme assays indicated that there was little cross-contamination between the tonoplast and PM vesicles. The molecular weights and isoelectric points of the PM ATPase and the tonoplast ATPase subunits were also determined using immunoblots of two-dimensional gels of the PM and TG proteins.


Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity.
Amyloid β (Aβ) is a key mediator for synaptic dysfunction and cognitive impairment implicated in Alzheimer's disease (AD). However, the precise mechanism of the toxic effect of Aβ is still not completely understood. Moreover, there is currently no treatment for AD. Protein kinase B (PKB, also termed Akt) is known to be aberrantly regulated in the AD brain. However, its potential function as a therapeutic target for AD-associated memory impairment has not been studied. Here, we examined the role of a direct Akt activator, SC79, in hippocampus-dependent memory impairments using Aβ-injected as well as 5XFAD AD model mice. Oligomeric Aβ injections into the 3rd ventricle caused concentration-dependent and time-dependent impairments in learning/memory and synaptic plasticity. Moreover, Aβ aberrantly regulated caspase-3, GSK-3β, and Akt signaling, which interact with each other in the hippocampus. Caspase-3 and GSK-3β inhibitor ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. We also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in both Aβ-treated and 5XFAD mice. These results suggest that Akt could be a therapeutic target for memory impairment observed in AD.


Recoded signed-digit binary addition-subtraction using opto-electronic symbolic substitution.
Two opto-electronic implementations of carry-free addition and borrow-free subtraction of recoded signed-digit binary numbers that use optical symbolic substitution are proposed.


Oral health-seeking behavior among different population groups in Enugu Nigeria.
This study investigates the oral health-seeking behaviour of households and its influence on demand for dental caries treatment services in Enugu state Nigeria. A quantitative descriptive cross-sectional study was used to explore the oral health seeking pattern of 378 urban and 348 rural household respondents in Enugu state Nigeria. The study explored dental caries treatment-seeking, oral health behavior of respondents using the three dynamics of the Andersen and Newman health utilization model; predisposing, enabling and need factors. Recommendations from community members (48.9%), severity of disease (22.1%), and cost of treatment (19.4%) all influenced where oral healthcare was first sought. Gender and type of occupation, influenced positive oral health-seeking behavior (p<0.05). The least poor socioeconomic status (SES) group, sought dental treatment in the private dental clinics, while the very poor and most poor SES groups used traditional healers, home treatment and patent medicine dealers more. Dental fillings and extractions were generally the most accessed treatment options for dental caries. The tendency for all the SES groups (especially the least poor), to choose tooth extraction more as a treatment option for dental caries was influenced by the oral health awareness level of respondents and the cost of dental fillings. (p<0.05). The findings suggest that interventions to create increased oral health awareness targeted at education on preventive strategies, appropriate time and place to seek oral health care and dental caries treatment, as well devising and implementing health financing options such as dental insurance would enable individuals to seek appropriate treatment for dental caries on time. In addition, it will reduce the proportion of people visiting unorthodox healthcare providers for their oral health problems or choosing cheaper but inappropriate treatment options.


Cervical screening history in patients with early stage carcinoma of the cervix.
This study aimed to examine whether a decade of heightened publicity on issues relating to cervical screening has changed the screening profile of women presenting with cervical cancer at the National Maternity Hospital. The screening history of 100 women diagnosed with early/surgically treated cervical cancer between 1998 and 2002 was compared with a similar study conducted in 1982 /1990. The percentage of women never screened was similar - 24 %( 2002) and 23% (1990). The interval between last recorded smear and diagnosis of disease was greater than 5 years in 45.6% and 41.7% respectively. Overall 60% of women in the recent period had either failed to avail of screening or were not screened within 5 years of diagnosis compared with 64% in 1990. Multiparous women comprised 90% of the study group and 50% of those inadequately screened were attending their general practitioner on a regular basis - therefore affording a potential for opportunistic screening The current method of screening has failed in this group and has not improved in 10 years despite of increased population awareness and greater opportunities for screening than ever before and would support an argument for a National Screening Program.


Does intravenous acetaminophen reduce perioperative opioid use in pediatric tonsillectomy?
Postoperative pain control is of significant interest in pediatric otolaryngology given the safety concerns with opioid use. We sought to determine if addition of intraoperative intravenous acetaminophen decreases perioperative morphine use in pediatric tonsillectomy. This study is a retrospective cohort study performed at a tertiary care academic children's hospital. 166 pediatric patients (aged 1-16 years) who underwent tonsillectomy with or without adenoidectomy were for review. Seventy-four patients received intraoperative intravenous acetaminophen (intervention cohort), while ninety-two patients served as our control and did not receive any intraoperative intravenous acetaminophen. Perioperative (intraoperative and postoperative) morphine use was our primary outcome measure. Rate of adverse events in the post anesthesia care unit and time for discharge readiness were secondary outcome measures. Wilcoxon two-sample t-test approximation and Fisher's exact test were used for data analyses. Patients in the intravenous acetaminophen cohort received less morphine (mg/kg) intraoperatively (0.058 versus 0.070, p = 0.089) and in the post anesthesia care unit (0.034 versus 0.051, p = 0.034) than the control cohort. The median time to discharge readiness for the intravenous acetaminophen and control groups was 108.5 versus 105 min (p = 0.018). There was no adverse respiratory event (oxygen desaturation <92% lasting more than a minute, requiring bag mask ventilation or reintubation) in either group in the post anesthesia care unit. There were 5 (7%) episodes of postoperative vomiting in the IV APAP, while 2 (2%) were recorded in the control cohort (p = 0.244). Our findings suggest intraoperative intravenous acetaminophen use in pediatric tonsillectomy can decrease the perioperative use of opioid for optimal pain management.


Distinct differentiation profiles of HIV-Gag and Nef-specific central memory CD8+ T cells associated with HLA-B57/5801 and virus control.
A superior capacity of controlling HIV has been attributed to CD8(+) T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA) alleles. To further elucidate this protective effect, we compared the multifunctional and differentiation characteristics of CD8(+) T cells specific for HIV-Gag and Nef in HLA-B57/5801-positive and negative nonprogressors. A head-to-head comparison of CD8(+) T cells specific for HIV-Gag and Nef frequencies, cytokine production and differentiation was conducted, in 11 HLA-B57/5801 and 11 HLA-B57/5801 HIV-infected individuals selected from a cohort of 53 nonprogressors by using IFN-gamma-ELISpot assay and flow cytometry analysis of intracellular cytokine production and differentiation profile. Correlations with HIV parameters were studied. Frequencies of Gag-specific but not of Nef-specific CD8(+) T cells correlated with peripheral blood mononuclear cell (PBMC)-associated HIV-DNA. The HIV-Gag and Nef-specific CD8(+) T cells did not differ for IL-2 production in either HLA-B57/5801 or HLA-B57/5801 individuals. The IFN-gamma-producing Gag-specific CD8(+) T cells in HLA-B57/5801 individuals significantly differed from their Nef-specific counterparts by displaying higher proportions of central memory CD45RACCR7 cells positive for CD27(+). This differentiation pattern was not observed in HLA-B57/5801 individuals. Only these HLA-B57/5801-positive Gag-specific CD27(+) central memory CD8(+) T cells, but not their Nef-specific counterparts, negatively correlated with cell-associated HIV-DNA. HLA-B57/5801 drives a preferential CD27(+) differentiation of central memory CD8(+) T cells directed against HIV-Gag but not Nef that may contribute to the ability of Gag-specific CD8(+) T cells to better control HIV in HLA-B57/5801 nonprogressors.


Challenges and future prospects in gene therapy.
Gene therapy is a promising technique for treating disease through the modification of gene expression. It is currently being tested not only for correcting genetic defects, but also for treating cancer and other acquired diseases. Although this field is still relatively young, evidence for clinical efficacy has been observed and continued progress seems assured, as clinical trials continue to yield insights into how gene therapy can be applied and improvements are made in gene therapy tools.


Calcium sulphate dihydrate: an useful excipient for tablets containing labile actives.
Tablets containing an angiotensin-converting enzyme inhibitor and either calcium sulphate dihydrate or lactose monohydrate as main excipients (fillers) exhibited similar technical properties and stability.


Management strategy for dirty abdominal incisions: primary or delayed primary closure? A randomized trial.
It is still a matter of debate whether delayed primary closure (DPC) of dirty abdominal incisions reduces surgical site infections (SSIs) compared with primary closure (PC). Our objective was to determine whether DPC of dirty abdominal incisions reduces SSIs. A controlled randomized study was conducted at an academic tertiary care 1,500-bed university hospital in Western India involving 81 consecutive patients with dirty abdominal incisions. Only 77 patients (DPC = 37, PC = 40) were evaluable because of the deaths of four patients. A total of 52 patients had peptic or typhoid perforations, whereas the rest had appendicular perforations/abscesses, penetrating or blunt abdominal injuries with gastrointestinal perforation, or intra-peritoneal abscesses. Patients were randomized to have their surgical incisions (skin and subcutaneous tissue) either closed primarily (PC) or left open with saline-soaked gauze dressings for DPC on the 3(rd) postoperative day or later if the incision conditions were inappropriate for closure. The main outcome measure was the incidence of postoperative SSI. In the entire series, SSI developed after incision closure in 23% of the patients. Infections were significantly more common in the PC group (42.5% vs. 2.7% for DPC; p = 0.0000375). There also were significantly more cases of abdominal dehiscence in the PC group (DPC 1 [2.7%] vs. PC 10 [25%]; p = 0.005). The mean complete incision healing (CIH) time and length of hospital stay (LOS) were longer after PC (18.52 days) than DPC (13.86 days), resulting in a significant difference in the end point of healing and LOS (p = 0.0207). Short-term cosmetic results for PC incisions were significantly inferior to those for DPC (p = 0.03349). Delayed primary closure is a sound incision management technique that should be utilized for dirty abdominal incisions. It significantly lowers the rate of superficial SSI as well as fascial dehiscence and reduces the mean CIH time and hospitalization. The short-term cosmetic appearance is superior.


Cloning and characterization of human TNF alpha promoter region.
We report the sequence of a 1.2-kb human tumor necrosis factor alpha (TNF alpha) promoter region, which was cloned using PCR. The sequence has several variations from two previous reports and exhibits many potential DNA-binding sites specific to mammalian gene regulatory proteins inducible by lipopolysaccharides.


Metamaterial-Engineered Silicon Beam Splitter Fabricated with Deep UV Immersion Lithography.
Subwavelength grating (SWG) metamaterials have garnered a great interest for their singular capability to shape the material properties and the propagation of light, allowing the realization of devices with unprecedented performance. However, practical SWG implementations are limited by fabrication constraints, such as minimum feature size, that restrict the available design space or compromise compatibility with high-volume fabrication technologies. Indeed, most successful SWG realizations so far relied on electron-beam lithographic techniques, compromising the scalability of the approach. Here, we report the experimental demonstration of an SWG metamaterial engineered beam splitter fabricated with deep-ultraviolet immersion lithography in a 300-mm silicon-on-insulator technology. The metamaterial beam splitter exhibits high performance over a measured bandwidth exceeding 186 nm centered at 1550 nm. These results open a new route for the development of scalable silicon photonic circuits exploiting flexible metamaterial engineering.


Human hair tests to document drug environmental contamination: Application in a family law case involving N,N-dimethyltryptamine.
For 40 years, hair tests have been presented as the best approach to document long-term consumption of a drug. This unique property has found numerous applications in clinical, forensic, and occupational toxicology. However, since the beginning of its implementation in biology, external contamination, with an associated risk of false positive result, has been presented as the key in the final interpretation. Evidence of environmental contamination and subsequent health issues can be the task of any toxicologist. Because of recent progress of analytical equipment, it is now possible to quantify drugs in hair with high level of accuracy and specificity at the pg/mg range. Therefore, segmental hair tests can be used to document environmental contamination and are the objective of this publication. In a family law case, N,N-dimethyltryptamine (DMT), a powerful hallucinogen, has been found in the hair of the partner of a repetitive DMT smoker at 4 to 13 pg/mg in 6 × 1 cm segments, with a regular increase of concentrations from the proximal to the distal hair end. The low measured concentrations and the particular pattern of DMT distribution along the hair shaft seem to be typical of environmental contamination, the older hair (those of the distal part) being for a longer time in contact with the drug. Despite strong decontamination, drugs from the environment can remain bound to the hair matrix and therefore be able to be used to document environmental contamination.


The Subtemporal Approach to the Lateral Midbrain with and without Zygomatic Osteotomy: An Anatomical Study.
The subtemporal approach provides a narrow operative corridor to the crus cerebrum and adjacent structures of the crural, interpeduncular, and ambient cistern. Addition of a zygomatic osteotomy widens this narrow corridor and spares retraction of the temporal lobe. We investigate and compare the morphometric parameters of the subtemporal approach with versus without zygomatic osteotomy. On each side of four cadaveric heads, a temporal craniotomy was performed to gain access to the crus cerebrum and adjacent subarachnoid cisterns using a subtemporal approach. Operative corridor width and corridor working angle were measured with and without brain retraction on each specimen side. Next, a zygomatic osteotomy was performed followed by full downward reflection of the temporalis muscle and further drilling of the squamous part of the temporal bone. Lastly, operative corridor width and corridor working angle were measured again for comparison. The subtemporal operating corridor was (mean/SD): 5.8/2.6 mm without retraction, 11.4/4.3 mm with retraction, and 13.5/6.5° working angle. After addition of a zygomatic osteotomy, the operative corridor was 8/9.2/4.3 mm without retraction, 14.7/4.5 mm with retraction, 31.8/3.1° working angle. Zygomatic osteotomy significantly increased the operative corridor working angle of the subtemporal approach. Furthermore, we demonstrate a direct approach into the interpeduncular fossa. Clin. Anat. 32:710-714, 2019. © 2019 Wiley Periodicals, Inc.


Heterologous expression and folding analysis of a beta-tubulin isotype from the Antarctic ciliate Euplotes focardii.
Mammalian tubulins and actins attain their native conformation following interactions with CCT (the cytosolic chaperonin containing t-complex polypeptide 1). To study the beta-tubulin folding in lower eukaryotes, an isotype of beta-tubulin (beta-T1) from the Antarctic ciliate Euplotes focardii, was expressed in Escherichia coli. Folding analysis was performed by incubation of the 35S-labeled, denatured beta-T1 in the presence, or absence, of purified rabbit CCT and cofactor A, a polypeptide that stabilizes folded monomeric beta-tubulin. We show for the first time in protozoa that beta-tubulin folding is assisted by CCT and requires cofactor A. In addition, we observed that E. focardiibeta-T1 competes with human beta5 tubulin isotype for binding to CCT. The affinity of CCT to E. focardiibeta-T1 and beta5 tubulin are compared. Finally, the mitochondrial chaperonin mt-cpn60 binds to beta-T1 but is unable to release it in a native or quasi-native state.


Dissemination of fluoroquinolone-resistant Campylobacter spp. within an integrated commercial poultry production system.
While characterizing the intestinal bacterial community of broiler chickens, we detected epsilon-proteobacterial DNA in the ilea of 3-day-old commercial broiler chicks (J. Lu, U. Idris, B. Harmon, C. Hofacre, J. J. Maurer, and M. D. Lee, Appl. Environ. Microbiol. 69:6816-6824, 2003). The sequences exhibited high levels of similarity to Campylobacter jejuni and Campylobacter coli sequences, suggesting that chickens can carry Campylobacter at a very young age. Campylobacter sp. was detected by PCR in all samples collected from the ilea of chicks that were 3 to 49 days old; however, it was detected only in the cecal contents of chickens that were at least 21 days old. In order to determine whether the presence of Campylobacter DNA in young chicks was due to ingestion of the bacteria in food or water, we obtained commercial broiler hatching eggs, which were incubated in a research facility until the chicks hatched. DNA sequencing of the amplicons resulting from Campylobacter-specific 16S PCR performed with the ileal, cecal, and yolk contents of the day-of-hatching chicks revealed that Campylobacter DNA was present before the chicks consumed food or water. The 16S rRNA sequences exhibited 99% similarity to C. jejuni and C. coli sequences and 95 to 98% similarity to sequences of other thermophilic Campylobacter species, such as C. lari and C. upsaliensis. The presence of C. coli DNA was detected by specific PCR in the samples from chicks obtained from a commercial hatchery; however, no Campylobacter was detected by culturing. In order to determine whether the same strains of bacteria were present in multiple levels of the integrator, we cultured Campylobacter sp. from a flock of broiler breeders and their 6-week-old progeny that resided on a commercial broiler farm. The broiler breeders had been given fluoroquinolone antibiotics, and we sought to determine whether the same fluoroquinolone-resistant strain was present in their progeny. The isolates were typed by pulsed-field gel electrophoresis, which confirmed that the parental and progeny flocks contained the same strain of fluoroquinolone-resistant C. coli. These data indicate that resistant C. coli can be present in multiple levels of an integrated poultry system and demonstrated that molecular techniques or more sensitive culture methods may be necessary to detect early colonization by Campylobacter in broiler chicks.


Effects of Microscopic Properties on Macroscopic Thermal Conductivity for Convective Heat Transfer in Porous Materials.
Porous materials are widely used in many heat transfer applications. Modeling porous materials at the microscopic level can accurately incorporate the detailed structure and substance parameters and thus provides valuable information for the complex heat transfer processes in such media. In this study, we use the generalized periodic boundary condition for pore-scale simulations of thermal flows in porous materials. A two-dimensional porous model consisting of circular solid domains is considered, and comprehensive simulations are performed to study the influences on macroscopic thermal conductivity from several microscopic system parameters, including the porosity, Reynolds number, and periodic unit aspect ratio and the thermal conductance at the solid-fluid interface. Our results show that, even at the same porosity and Reynolds number, the aspect ratio of the periodic unit and the interfacial thermal conductance can significantly affect the macroscopic thermal behaviors of porous materials. Qualitative analysis is also provided to relate the apparent thermal conductivity to the complex flow and temperature distributions in the microscopic porous structure. The method, findings and discussions presented in this paper could be useful for fundamental studies, material development, and engineering applications of porous thermal flow systems.


Fate of manuscripts declined by the British Journal of Surgery.
The fate of papers submitted and subsequently rejected by the British Journal of Surgery (BJS) is currently unknown. The present study was designed to investigate whether, when and where these papers are published following rejection. All rejected manuscripts in the year 2006 were identified from the Manuscript Central electronic database. Between December 2008 and February 2009, a PubMed search was conducted spanning the period 2006-2009 using the corresponding author's last name and initials to identify whether and when manuscripts had been published elsewhere. From the 926 manuscripts rejected by BJS, 609 (65.8 per cent) were published in 198 different journals with a mean(s.d.) time lapse of 13.8(6.5) months. Some 165 manuscripts (27.1 per cent) were published in general surgical journals, 250 (41.1 per cent) in subspecialty surgical journals and 194 (31.9 per cent) in non-surgical journals. The mean(s.d.) impact factor of the journals was 2.0(1.1). Only 14 manuscripts (2.3 per cent) were published in journals with a higher impact factor than that of BJS. Rejection of a manuscript by BJS does not preclude publication, but rejected manuscripts are published more often in surgical subspecialty journals and journals with a lower impact factor, although the occasional exception exists.


Parathyroid hormone-related protein: hormone and cytokine.
While PTHrP acts as a hormone when it is produced in excess by certain cancers, and perhaps also in lactating women, the foetus, and lower vertebrates, it seems clear that PTHrP is an important paracrine regulator of several tissue-specific functions. Its roles in smooth muscle relaxation, placental calcium transport, and bone development are becoming firmly established. However, it is likely to be an important player in the control of cellular growth and differentiation, although much of our understanding of this role to date comes from indirect evidence. The next decade will be an exciting time in defining further both the hormonal and paracrine actions of PTHrP.


Soft tissue abscesses associated with parenteral drug abuse: presentation, microbiology, and treatment.
Abscess formation at the site of drug injection is the commonest infectious complication in drug addicts. This study characterizes the clinical presentation of the condition, its current microbiology, and treatment outcome. All patients presenting for treatment of soft tissue abscesses associated with parenteral drug abuse over a 21-month period were studied. Sixty-six patients with 70 subcutaneous abscesses after injection of cocaine (85%), heroin (5%), or unreported drugs (10%) were identified. Only 42% were febrile (T > 37.5 degrees C), 54 percent had leukocytosis, and 47 percent had wound fluctuance. Wound cultures (243 isolates in 57 patients) grew predominately anaerobes (143 isolates) and facultative gram-positive cocci (88 isolates). Twenty-six blood cultures were obtained, and five (19%) were positive, two with the same bacteria isolated from the wound. Of the patients tested, 29 percent were positive for hepatitis B surface antigen and 9 percent for HIV. Simple incision and drainage was effective in all cases. Classical signs and symptoms of infection and abscess formation may be absent in this patient population. Many of these patients carry other blood-borne infections which the health professional must guard against. Cocaine injection, and "mixed" aerobic-anaerobic infections predominated, in contrast to earlier reports, when narcotics and aerobes predominated. Simple incision and drainage is adequate treatment; antibiotics, when given, should cover gram-positive and anaerobic bacteria; gram-negative coverage is unnecessary.


Efficacy of Milrinone and Dobutamine in Cardiogenic Shock: An Updated Systematic Review and Meta-Analysis.
Inotropic support is commonly used in patients with cardiogenic shock (CS). High-quality data guiding the use of dobutamine or milrinone among this patient population is limited. We compared the efficacy and safety of these two inotropes among patients with low cardiac output states (LCOS) or CS. MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched up to February 1, 2023, using key terms and index headings related to LCOS or CS and inotropes. Two independent reviewers included studies that compared dobutamine to milrinone on all-cause in-hospital mortality, length of ICU stay, length of hospital stay, and significant arrhythmias in hospitalized patients. A total of eleven studies with 21,084 patients were included in the meta-analysis. Only two randomized controlled trials were identified. The primary outcome, all-cause mortality, favored milrinone in observational studies only (odds ratio [OR] 1.19 (95% CI, 1.02-1.39; p = 0.02). In-hospital length of stay (LOS) was reduced with dobutamine in observational studies only (mean difference -1.85 d; 95% CI -3.62 to -0.09; p = 0.04). There was no difference in the prevalence of significant arrhythmias or in ICU LOS. Only limited data exists supporting the use of one inotropic agent over another exists. Dobutamine may be associated with a shorter hospital LOS; however, there is also a potential for increased all-cause mortality. Larger randomized studies sufficiently powered to detect a difference in these outcomes are required to confirm these findings.


Towards developing a diagnostic regimen for the treatment follow-up of Trypanosoma brucei gambiense.
BALB/c mice infected with a high virulent strain of Trypanosoma brucei gambiense IL3707 were treated intraperitoneally (i.p.) with either Melarsoprol (Mel-B) or PSG(+) buffer as controls. The mice were subsequently monitored regularly for parasites by direct microscopic examination of their tail blood or buffy coat and by polymerase chain reaction (PCR). Mel-B was found to be an effective drug for treatment against T.b. gambiense because at the end of the first treatment schedule, all treated mice were negative for parasites even by PCR, while all the control animals were positive. Three of the five Mel-B treated mice, while parasitologically negative, were PCR positive between 53 and 80 days post infection (DPI), indicating that they still harbored an infection. All treated mice were subsequently negative for parasites even by PCR at 88 DPI. A combination of conventional microscopic examination and PCR offers a good prediction of cure following treatment of trypanosomosis.


Reducing mutans streptococci and caries development by Lactobacillus paracasei SD1 in preschool children: a randomized placebo-controlled trial.
To examine a reducing effect of Lactobacillus paracasei SD1 on MS and caries in preschool children. A total of 124 children, aged 1.5-5 years old, participated and were randomly assigned to the probiotic or control group. The probiotic group received L. paracasei SD1-milk and the control group received standard-milk once daily for 3 months. MS/lactobacilli were enumerated and the caries score was examined. Association between probiotic consumption and bacterial level, or caries progression was assessed by a multivariate logistic regression. This study was registered at the Thai-Clinical-Trials-Registry (TCTR20140903001). Probiotic was found to be a factor associated with the MS level. Children in the probiotic group had a significantly lower risk of an increase in the MS level than in the control group after receiving the probiotic milk at 3- and 4-months with p < .001 and p = .040, respectively. Probiotic significantly reduced the risk for caries compared to the control group (p = .016). There were no adverse effects or non-compliance reported in either group. Consumption of milk powder containing L. paracasei SD1 resulted in a reduction of both salivary MS and delayed new caries development, and the strain is safe for use in young children. Results suggest that L. paracasei SD1 may be an alternative way for caries prevention in young children.


Carotid intraplaque hemorrhage imaging at 3.0-T MR imaging: comparison of the diagnostic performance of three T1-weighted sequences.
To compare the diagnostic performances of three T1-weighted 3.0-T magnetic resonance (MR) sequences at carotid intraplaque hemorrhage (IPH) imaging, with histo logic analysis as the reference standard. Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty patients scheduled for carotid endarterectomy underwent 3.0-T carotid MR imaging, including two-dimensional fast spin-echo, three-dimensional time-of-flight (TOF), and three-dimensional magnetization-prepared rapid acquisition gradient-echo (RAGE) sequences. Two reviewers blinded to the histologic findings assessed the presence, area, and signal intensity of IPH with each sequence. Detection statistics (sensitivity, specificity, and Cohen kappa values) and agreement between area measurements (Pearson correlation coefficient [r] values) were calculated for each sequence. When all 231 available MR sections were included for analysis, the magnetization-prepared RAGE (kappa = 0.53) and fast spin-echo (kappa = 0.42) sequences yielded moderate agreement between MR and histologic measurements, while the TOF sequence yielded fair agreement (k = 0.33). However, when 47 sections with either small IPHs or heavily calcified IPHs were excluded, sensitivity, specificity, and kappa values, respectively, were 80%, 97%, and 0.80 for magnetization-prepared RAGE imaging; 70%, 92%, and 0.63 for fast spin-echo imaging; and 56%, 96%, and 0.57 for TOF imaging. MR imaging-histologic analysis correlation for IPH area was highest with magnetization-prepared RAGE imaging (r = 0.813), followed by TOF (r = 0.745) and fast spin-echo (r = 0.497) imaging. The capability of these three sequences for IPH detection appeared to be in good agreement with the quantitative contrast of IPH versus background plaque tissue. The magnetization-prepared RAGE sequence, as compared with the fast spin-echo and TOF sequences, demonstrated higher diagnostic capability for the detection and quantification of IPH. Potential limitations of 3.0-T IPH MR imaging are related to hemorrhage size and coexisting calcification.


Invited review: Management strategies capable of improving the reproductive performance of heat-stressed dairy cattle.
Impaired fertility during periods of heat stress is the culmination of numerous physiological responses to heat stress, ranging from reduced estrus expression and altered follicular function to early embryonic death. Furthermore, heat-stressed dairy cattle exhibit a unique metabolic status that likely contributes to the observed reduction in fertility. An understanding of this unique physiological response can be used as a basis for improving cow management strategies, thereby reducing the negative effects of heat stress on reproduction. Potential opportunities for improving the management of dairy cattle during heat stress vary greatly and include feed additives, targeted cooling, genetic selection, embryo transfer and, potentially, crossbreeding. Previous studies indicate that dietary interventions such as melatonin and chromium supplementation could alleviate some of the detrimental effects of heat stress on fertility, and that factors involved in the methionine cycle would likely do the same. These supplements, particularly chromium, may improve reproductive performance during heat stress by alleviating insulin-mediated damage to the follicle and its enclosed cumulus-oocyte complex. Beyond feed additives, some of the simplest, yet most effective strategies involve altering the timing of feeding and cooling to take advantage of comparatively low nighttime temperatures. Likewise, expansion of cooling systems to include breeding-age heifers and dry cows has significant benefits for dams and their offspring. More complicated but promising strategies involve the calculation of breeding values for thermotolerance, the identification of genomic markers for heat tolerance, and the development of bedding-based conductive cooling systems. Unfortunately, no single approach can completely rescue the fertility of lactating dairy cows during heat stress. That said, region-appropriate combinations of strategies can improve reproductive measures to reasonable levels.


Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus.
Macro and microvascular diseases are the principal causes of morbidity and mortality in patients with type I and II diabetes mellitus. Growing evidence implicates reactive nitrogen species (RNS), such as peroxynitrite (ONOO-), derived from nitric oxide (NO) and superoxide anion (O2*-), are important in diabetes. The mechanisms by which diabetes increases RNS, and those by which RNS modifies vascular function, are poorly understood. The authors recently discovered that physiologically relevant concentrations of ONOO- oxidize the zinc thiolate center in endothelial nitric oxide synthase (eNOS). In active eNOS dimers, a tetracoordinated zinc ion is held by four thiols, two from each 135-kDa monomer. Because it remains partially positively charged, the zinc thiolate center is subject to attack by the ONOO-. This oxidant disrupts the zinc thiolate center, releasing zinc, and oxidizing the thiols. Upon thiol reduction, eNOS dimers dissociate into monomers. This modification of eNOS results in reduced NO bioactivity and enhanced endothelial O2*- production, which reacts with NO, further generating ONOO- (eNOS uncoupling). In addition, the authors' studies also demonstrate that low concentrations of ONOO- selectively nitrate and inactivate prostacyclin synthase (PGIS), which not only eliminates the vasodilatory, growth-inhibiting, antithrombotic, and antiadhesive effects of prostacyclin (PGI2), but also increases release of the potent vasoconstrictor, prothrombotic, growth- and adhesion-promoting agents, prostaglandin H2 (PGH2) and thromboxane A2 (TxA2). In diabetic mice and rats, eNOS is uncoupled resulting in an increased tyrosine nitration of PGIS. The authors' studies indicate that in diabetes the synthetic enzymes of the two major endogenous vasodilators undergo oxidative inactivation by different mechanisms, which are, however, tightly interdependent.


Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells.
DNA polymerase theta (Polθ) is a specialized A-family DNA polymerase that functions in processes such as translesion synthesis (TLS), DNA double-strand break repair and DNA replication timing. Overexpression of POLQ, the gene encoding Polθ, is a prognostic marker for an adverse outcome in a wide range of human cancers. While increased Polθ dosage was recently suggested to promote survival of homologous recombination (HR)-deficient cancer cells, it remains unclear whether POLQ overexpression could be also beneficial to HR-proficient cancer cells. By performing a short interfering (si)RNA screen in which genes encoding druggable proteins were knocked down in Polθ-overexpressing cells as a means to uncover genetic vulnerabilities associated with POLQ overexpression, we could not identify genes that were essential for viability in Polθ-overexpressing cells in normal growth conditions. We also showed that, upon external DNA replication stress, Polθ expression promotes cell survival and limits genetic instability. Finally, we report that POLQ expression correlates with the expression of a set of HR genes in breast, lung and colorectal cancers. Collectively, our data suggest that Polθ upregulation, besides its importance for survival of HR-deficient cancer cells, may be crucial also for HR-proficient cells to better tolerate DNA replication stress, as part of a global gene deregulation response, including HR genes.