Phytoplankton production and taxon-specific growth rates in the Costa Rica Dome.
During summer 2010, we investigated phytoplankton production and growth rates at 19 stations in the eastern tropical Pacific, where winds and strong opposing currents generate the Costa Rica Dome (CRD), an open-ocean upwelling feature. Primary production (14C-incorporation) and group-specific growth and net growth rates (two-treatment seawater dilution method) were estimated from samples incubated in situ at eight depths. Our cruise coincided with a mild El Niño event, and only weak upwelling was observed in the CRD. Nevertheless, the highest phytoplankton abundances were found near the dome center. However, mixed-layer growth rates were lowest in the dome center (∼0.5-0.9 day-1), but higher on the edge of the dome (∼0.9-1.0 day-1) and in adjacent coastal waters (0.9-1.3 day-1). We found good agreement between independent methods to estimate growth rates. Mixed-layer growth rates of Prochlorococcus and Synechococcus were largely balanced by mortality, whereas eukaryotic phytoplankton showed positive net growth (∼0.5-0.6 day-1), that is, growth available to support larger (mesozooplankton) consumer biomass. These are the first group-specific phytoplankton rate estimates in this region, and they demonstrate that integrated primary production is high, exceeding 1 g C m-2 day-1 on average, even during a period of reduced upwelling.


Space-resolved extreme ultraviolet spectrometer for impurity emission profile measurement in Large Helical Device.
A space-resolved extreme ultraviolet (EUV) spectrometer working in 60-400 A range has been developed to observe impurity emission profiles in core and edge plasmas of Large Helical Device (LHD). A flat focus is made for plane surface detector by using a varied line spacing holographic grating with an angle of incidence of 87 degrees. An excellent spectral resolution of 0.22 A at 200 A is then obtained after careful adjustment of the optical components. In the profile measurement of the LHD plasmas, the toroidal resolution is important as well as the radial resolution because the magnetic surfaces of LHD quickly change when the observation chord is tilted at a slightly different toroidal location. Horizontal dispersion is therefore selected for the present spectrometer. As a result, the toroidal resolution of 75 mm is achieved at the plasma position. An enough radial resolution of 10 mm is also obtained at spatial-resolution slit width of 0.2 mm. In order to measure the full radial profile of LHD plasmas the spectrometer is placed at a distance of approximately 9200 mm away from the plasma center and a backilluminated charge-coupled device with a size of 6.6x26.6 mm(2) is set vertical to the horizontal dispersion. Half of the LHD plasma, i.e., approximately 50 cm, can be measured along the vertical direction at horizontally elongated plasma cross section. A full vertical profile can be obtained by changing the vertical angle of the EUV spectrometer. As an example the full vertical profile of edge C IV (312.4 A) emission is presented. A wavelength interval of 35-65 A can be simultaneously observed, which varies according to the wavelength to be measured. A local emission profile of Fe XX (132.67 A) is also presented after Abel inversion as a typical example of the core EUV emission. Finally, the EUV spectrometer is absolutely calibrated using EUV bremsstrahlung continuum profile in comparison with absolute values of visible bremsstrahlung continuum profile because the bremsstrahlung continuum can be easily detected in high-density discharges of LHD.


Electronic diaries as a tool to improve pain management: is there any evidence?
Chronic pain is a common and costly syndrome which affects approximately one in three US adults. Factors such as shortened length of the medical visit, increased availability of technological approaches to care, and a more informed patient all suggest that a new paradigm is required for chronic pain management. Although much has been written about the use of electronic diaries in clinical trials, little has been presented about the use of these diaries in clinic practice and their potential for changing pain behavior. The intent of this preliminary study is to measure accessibility and usability of a software program designed for use on a personal digital assistant and to discuss how the software program may impact clinic practice and patient behavior. We present the results of a preliminary, randomized, comparison, crossover trial of 36 chronic pain patients who were asked to monitor their pain, mood, activity interference, medication use, and pain location on either a paper or electronic diary for 2 weeks. Patients in the electronic diary condition were able to observe changes in their ratings over time and view them on a secure web site. No differences were found between paper and electronic tracking on pain descriptors, pain interference, mood, or helpfulness of medication. Similar to past findings, patients found the electronic diary easier to use (P < 0.0001) and would continue using it (P < 0.05) over paper if given the choice. Importantly, patients using the electronic diary reported more frequently that a provider suggested medication change (P < 0.05) based on feedback from the electronic diary. One trend requiring further investigation is that electronic diary users reported that the diary enabled them and their doctor to make care adjustments according to changes in pain status. This study goes beyond previous research on preference and data quality to investigate how the information provided may affect patient and physician perspectives toward pain management. Although not the initial intent of this study, findings indicate that electronic tracking may provide information which can affect management decisions. A follow-up study is ongoing to investigate these initial results. If found to be true, electronic monitoring may have broad implications for health care, policy, and improvement in quality of care for chronic pain sufferers in the future.


Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons.
We have previously identified 15 genes that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha and ribavirin in the peripheral blood of hepatitis C virus infected patients. An enhanced expression of these genes was also found in the blood of psychiatric patients suffering severe depressive episode. Herein, we demonstrate that the same depression-related interferon-inducible genes (DRIIs) are also upregulated in post-mortem brains of suicidal individuals. Using cultured mouse hippocampal and prefrontal neurons we show that costimulation with murine IFN (mIFN) and the TLR3 agonist poly(I:C) promotes the expression of the described DRIIs, at the same time inducing pro-inflammatory cytokine expression through Stat1 and Stat3 activation, promoting neuronal apoptosis. Consequently, the upregulation of selective DRIIs, production of inflammatory cytokines and inhibition of neuronal plasticity may be involved in the pathogenesis of IFN-associated depression.


Graphene oxide interfaces in serum based autoantibody quantification.
A reliable quantification of protein markers will undoubtedly underpin profound developments in disease surveillance, diagnostics, and improved therapy. Although there potentially exist numerous means of achieving this, electrochemical impedimetric techniques offer scale of sensitivity, cost, convenience, and a flexibility with which few alternatives can compete. Though there have been marked developments in electroanalytical protein detection, the demands associated with accessing the inherent assay sensitivity in complex biological media largely remains. We report herein the use of cysteamine-graphene oxide modified gold microelectrode arrays in underpinning the ultrasensitive and entirely label free non-faradaic quantification of Parkinson's-relevant autoantibodies in human serum.


Coupled oxygen transport analysis in the avascular wall of a post-angioplasty coronary artery stenosis.
The coupled oxygen transport in the avascular wall of a coronary artery stenosis is studied by numerically solving the convection-diffusion equations. Geometry, replicating residual stenosis after percutaneous transluminal coronary angioplasty (PTCA), is used for the analysis. Important physiological aspects, such as oxygen consumption in the wall, oxygen carried by the hemoglobin, non-Newtonian viscosity of the blood, and supply of oxygen from the vasa vasorum are included. Mean blood flow rate in the lumen is varied from basal to hyperemic conditions. The results show that the P(O2) in the medial region of the arterial wall is approximately 10 mmHg. The oxygen flux to the wall increases in the flow acceleration region, whereas it decreases at the flow reattachment zone. Near the location of flow separation there is a small rise and a sharp fall in the oxygen flux. The minimum P(O2) in the avascular wall, P(O2, min ), at the point of flow reattachment reduces to approximately 6 mmHg for a 300 micron wall thickness. For a thinner wall of 200 micron, the P(O2, min ) at the location of flow reattachment increases to 6 times that of a 300 micron wall. The P(O2, min ) in the wall decreases by 60% when volumetric oxygen consumption is increased by 30% for the same avascular wall thickness.


Dissatisfaction with Do Not Attempt Resuscitation Orders: A nationwide study of Irish consultant physician practices.
The legal/ethical status of Do Not Attempt Resuscitation (DNAR) orders in Ireland has not been clarified, nor have national policies been formulated. We questioned 298 consultant physicians in the Republic of Ireland about DNAR orders. 173 replies were received (58%). 85 expressed unsatisfactory understanding of issues relating to Irish DNAR orders (49%). 116 physicians felt that alert patients preferred not to discuss their own resuscitation (67%). 55 physicians felt that if a competent adult patient is the subject of a DNAR order without the patient's knowledge, the reasons for this decision are "almost never" documented in the patient's medical record (32%). 75 consultants "almost never" had advance discussion of resuscitation preferences with the patient (43%). 47 physicians had experienced advance directives for Irish patients (27%). 102 physicians felt that both they and the patient's next of kin had joint responsibility for deciding resuscitation status for an incapacitated patient with no advance directive (59%). 37 respondents described a formal resuscitation policy in their place of work (21%). We feel that physicians require greater national guidance regarding DNAR order-making, and we advocate more widespread use of resuscitation policies.


Agreement and reproducibility of Tono-Pen XL tip covered with ocufilm and fingertip of surgical glove in intra-ocular pressure measurement.
To compare the effect of using the fingertip of a surgical glove over Ocufilm (Reichert Technologies, NY, USA) on the agreement and reproducibility of measuring intra-ocular pressure (IOP) by the Tono-Pen XL (Reichert Technologies, NY USA). Experimental, clinical study. Patients were randomized into two groups to receive IOP measurements using Tono-Pen XL with two different types of tip covers. In Group 1, the IOP of the right eyes were first measured using Ocufilm as the tip cover followed by using the fingertip of a surgical glove. As for the left eyes, the tip of the surgical glove was used first, followed by use of Ocufilm. In Group 2, the IOP of the right eyes was first measured using the tip of the surgical glove,followed by use of Ocufilm, while for the left eye the latter was used first, followed by the tip of the surgical glove. A single operator measured the IOP in each eye twice using each type of tip cover. Agreement between the Tono-Pen XL measurements using the two different tip covers was analyzed using the Bland-Altman analysis. The difference between the repeated measures was assessed for reproducibility of the Tono-Pen XL measurements with regard to each type of tip covers. 100 patients (200 eyes) were recruited into the present study. The mean difference of IOP taken by the Tono-Pen XL covered with Ocufilm and the fingertip of a surgical glove was -0.21 mmHg (95% CI: -0.36 to -0.05). The limits of agreement (confidence interval 95%) as calculated by the Bland-Altman plots for Ocufilm-Fingertip of a surgical glove was -2.43 to +2.02 mmHg. The coefficient of repeatability of the Ocufilm vs. the surgical glove was nearly the same (1.74 vs. 2.37, respectively). A significant agreement exists between using Ocufilm and the fingertip of a surgical glove to cover the tip of a Tono-Pen XL for measuring IOP The coefficient of repeatability was comparable between the two different types of tip covers. When measuring IOP the tip of a Tono-Pen XL could therefore be covered by either Ocufilm or the fingertip of a surgical glove without compromising accuracy.


A comprehensive test set of epoxidation rate constants for iron(iv)-oxo porphyrin cation radical complexes.
Cytochrome P450 enzymes are heme based monoxygenases that catalyse a range of oxygen atom transfer reactions with various substrates, including aliphatic and aromatic hydroxylation as well as epoxidation reactions. The active species is short-lived and difficult to trap and characterize experimentally, moreover, it reacts in a regioselective manner with substrates leading to aliphatic hydroxylation and epoxidation products, but the origin of this regioselectivity is poorly understood. We have synthesized a model complex and studied it with low-pressure Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry (MS). A novel approach was devised using the reaction of [FeIII(TPFPP)]+ (TPFPP = meso-tetrakis(pentafluorophenyl)porphinato dianion) with iodosylbenzene as a terminal oxidant which leads to the production of ions corresponding to [FeIV(O)(TPFPP+˙)]+. This species was isolated in the gas-phase and studied in its reactivity with a variety of olefins. Product patterns and rate constants under Ideal Gas conditions were determined by FT-ICR MS. All substrates react with [FeIV(O)(TPFPP+˙)]+ by a more or less efficient oxygen atom transfer process. In addition, substrates with low ionization energies react by a charge-transfer channel, which enabled us to determine the electron affinity of [FeIV(O)(TPFPP+˙)]+ for the first time. Interestingly, no hydrogen atom abstraction pathways are observed for the reaction of [FeIV(O)(TPFPP+˙)]+ with prototypical olefins such as propene, cyclohexene and cyclohexadiene and also no kinetic isotope effect in the reaction rate is found, which suggests that the competition between epoxidation and hydroxylation - in the gas-phase - is in favour of substrate epoxidation. This notion further implies that P450 enzymes will need to adapt their substrate binding pocket, in order to enable favourable aliphatic hydroxylation over double bond epoxidation pathways. The MS studies yield a large test-set of experimental reaction rates of iron(iv)-oxo porphyrin cation radical complexes, so far unprecedented in the gas-phase, providing a benchmark for calibration studies using computational techniques. Preliminary computational results presented here confirm the observed trends excellently and rationalize the reactivities within the framework of thermochemical considerations and valence bond schemes.


Swapping Versus Dose Optimization in Patients Losing Response to Adalimumab With Adequate Drug Levels.
In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma-either ADA dose optimization or switching to vedolizumab or ustekinumab. Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Adalimumab was optimized (n = 61 patients, 42 Crohn's disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or ustekinumab (n = 30, 30 Crohn's disease). At 24 months, 11 out of 70 patients (14.8%) in the swap group discontinued treatment compared with 36 out of 61 (59.6%) patients in the optimization group (P < 0.001). The median time without therapeutic discontinuation was significantly longer in the swap group (>24 months) than in the optimization group (13.3 months, P < 0.001). In the optimization group, treatment discontinuation was positively associated with baseline fecal calprotectin >500 μg/g (HR, 3.53; 95% CI, 1.16-10.72; P = 0.026) and inversely associated with variation of trough levels of adalimumab (>2 µg/mL from baseline to week 8 after optimization; HR, 0.51; 95% CI, 0.13-0.82; P = 0.03). In the swap group, no factor was associated with treatment discontinuation. In IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are >4.9µg/mL, swapping to another class is better than optimizing ADA, which is, however, appropriate in a subgroup of patients.


Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.
This study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy. In this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life. This trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46-0.98; P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14-0.57; P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56-1.16; P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild. In patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.


Experimental demonstration of nonuniform frequency distributions of granular packings.
We developed an experimental method to generate mechanically stable (MS) packings of frictionless disks and performed coordinated experiments and simulations to characterize MS packings in small systems. For a given system geometry, MS packings occur as discrete, well-separated points in configuration space with probabilities that vary by many orders of magnitude and are robust with respect to the packing preparation. Over a continuous range of system geometries, MS packings occur as distinct geometrical families and only a small fraction of families are sampled via quasistatic dynamics. These results suggest that the most frequent MS packings may dominate the structural and mechanical properties of dense granular media.


Sponge inventory of the French Mediterranean waters, with an emphasis on cave-dwelling species.
Mediterranean sponges represent about 10 % of the world sponge biodiversity, with these sessile organisms dominating in terms of diversity and biomass in most of the rocky bottoms shaded from light. After 60 years of intensive study of the sponge diversity along the French coast, we present the first comprehensive reference-list for this biogeographic area. A total of 389 sponge species was recorded, of which 222 known in the Marseille region. In this area, special attention was paid to species from underwater caves. Although this particular habitat appeared as one of the richest, a wealth of hidden diversity still requires description. About 37 % of the sponge diversity can be found in underwater caves, most of these species being also distributed in other habitats. However, 23 % of this sponge diversity is cave-exclusive. An easy and rapid assessment method was developed with a selection of 65 representative sponge species, for the monitoring of semi-dark cave communities. This method, based on data acquisition with photoquadrats and their processing using a DataBase built with ACCESS, was deployed in 13 studied sites. Altogether, this study represents a useful contribution for marine environment managers who might refer to this French reference list and apply the rapid and easy assessment method in the framework of several European Directives and international Conventions.


Fluoride binding by an anionic receptor: tuning the acidity of amide NH groups for basic anion hydrogen bonding and recognition.
Here we report a family of bis-amide receptors for anion binding that contain carboxylic acid groups vicinal to the amide function. Deprotonation of the carboxylic acids decreases the acidity of amide NHs, switching on the anion binding ability of the deprotonated receptors with selectivity for fluoride complexation. The proposed systems represent a unique example of anionic receptors able to bind anions via H-bonding.


Exploratory study of the association in the United Kingdom between hypertension and inorganic arsenic (iAs) intake from rice and rice products.
Hypertension risks arising from chronic exposure to inorganic arsenic (iAs) are well documented. Consumption of rice is a major iAs exposure route for over 3 billion people; however, there is a lack of epidemiological evidence demonstrating an association of hypertension risks with iAs intake from rice, especially in areas where there is little exposure from drinking water but a growing demand for rice intake. To address this, we conducted an individual-level cross-sectional analysis to quantify the extent to which daily iAs intake from rice and rice products (E-iAsing,rice) modifies the association between hypertension risks and previously well-established risk factors. The analysis was based on secondary dietary, socio-demographic and health status data of 598 participants recorded in the UK National Diet and Nutrition Survey 2014-2016. E-iAsing,rice and five blood pressure endpoints were derived with potential associations explored through generalized linear models. According to the results, a negative but not significant relationship was found between hypertension risks and E-iAsing,rice after adjusting for major risk factors, notably age, gender, diabetes and obesity, with relatively higher risks being observed for male, middle-aged, overweight, alcohol consumer or Asian or Asian British, Black or Black British and mixed ethnic groups. Though inconclusive and mainly limited by potential incomplete adjustment for major confounders and intrinsic disadvantages of a cross-sectional design, this study was the first quantifying the individual level dose-response relationship between E-iAsing,rice and hypertension risks and is consistent with previous studies on the limited associations of hypertension with low-level arsenic exposure from drinking water. Larger scale cohort studies are indicated to quantify the association but in any event it is likely to be weak.


Growth Factors and Astrocytes Metabolism: Possible Roles for Platelet Derived Growth Factor.
Astrocytes exert multiple functions in the brain such as the development of blood-brain barrier characteristics, the promotion of neurovascular coupling, attraction of cells through the release of chemokines, clearance of toxic substances and generation of antioxidant molecules and growth factors. In this aspect, astrocytes secrete several growth factors (BDNF, GDNF, NGF, and others) that are fundamental for cell viability, oxidant protection, genetic expression and modulation of metabolic functions. The platelet derived growth factor (PDGF), which is expressed by many SNC cells, including astrocytes, is an important molecule that has shown neuroprotective potential, improvement of wound healing, regulation of calcium metabolism and mitochondrial function. Here we explore some of these astrocyte-driven functions of growth factors and their possible therapeutic uses in the context of neurodegeneration.


SSVEP-EEG Denoising via Image Filtering Methods.
Steady-state visual evoked potential (SSVEP) is widely used in electroencephalogram (EEG) control, medical detection, cognitive neuroscience, and other fields. However, successful application requires improving the detection performance of SSVEP signal frequency characteristics. Most strategies to enhance the signal-to-noise ratio of SSVEP utilize application of a spatial filter. Here, we propose a method for image filtering denoising (IFD) of the SSVEP signal from the perspective of image analysis, as a preprocessing step for signal analysis. Arithmetic mean, geometric mean, Gaussian, and non-local means filtering methods were tested, and the experimental results show that image filtering of SSVEP cannot effectively remove the noise. Thus, we proposed a reverse solution in which the SSVEP noise signal was obtained by image filtering, and then the noise was subtracted from the original signal. Comparison of the recognition accuracy of the SSVEP signal before and after denoising was used to evaluate the denoising performance for stimuli of different duration. After IFD processing, SSVEP exhibited higher recognition accuracy, indicating the effectiveness of this proposed denoising method. Application of this method improves the detection performance of SSVEP signal frequency characteristics, combines image processing and brain signal analysis, and expands the research scope of brain signal analysis for widespread application.


Quantitative determination of infinite inhibition concentrations of antimicrobial agents.
We developed a method to determine the infinite inhibition concentrations (IICs) of antimicrobial agents. This method was based on finding the relative effectiveness of an inhibitor at various concentrations. Benzoic acid and parabens were tested on Saccharomyces bayanus, Hansenula sp., and Pseudomonas fluorescens. The relative effectiveness values of these compounds were established. A plot of the inhibitor concentration versus the reciprocal of relative effectiveness was linear. The chi-axis intercept was the concentration of the inhibitor which gave infinite microbial inhibition. For S. bayanus the IICs were 330, 930, 480, and 220 ppm (330, 930, 480, and 220 ml/liter) for benzoic acid and methyl-, ethyl-, and propylparabens, respectively. For Hansenula sp. the IIC was 180 ppm for benzoic acid. For P. fluorescens the IICs were 1,310, 960, and 670 ppm for methyl-, ethyl-, and propylparabens, respectively. Our results indicated that the IIC is affected by the growth medium. The advantages and applications of this method are discussed.


N-(4-hydroxyphenyl)retinamide increases ceramide and is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes.
The retinoid, N-(4-hydroxyphenyl)retinamide (4-HPR), mediates p53-independent cytotoxicity and can increase reactive oxygen species and ceramide in solid tumor cell lines. We determined changes in ceramide and cytotoxicity upon treatment with 4-HPR (3-12 microM) in six human acute lymphoblastic leukemia (ALL) cell lines: T cell (MOLT-3, MOLT-4, CEM), pre-B-cell (NALM-6, SMS-SB), and null cell (NALL-1). Exposure to 4-HPR (12 microM) for 96 h caused 4.7 (MOLT-3), 3.5 (MOLT-4), 3.9 (CEM), 2.9 (NALM-6), 4.7 (SMS-SB), AND 4.5 (NALL-1) logs of cell kill. The average 4-HPR concentration that killed 99% of cells (LC(99)) for all six lines was 4.8 microM (range: 1.5-8.9 microM). Treatment with 4-HPR (9 microM) for 24 h resulted in an 8.9 +/- 1.0-fold (range: 4.9-15.7-fold) increase of ceramide. Ceramide increase was time- and dose-dependent and abrogated by inhibitors of de novo ceramide synthesis. Concurrent inhibition of ceramide glycosylation/acylation by d,l-threo-(1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol) (PPMP) further increased ceramide levels, and synergistically increased 4-HPR cytotoxicity in four of six ALL cell lines. 4-HPR was minimally cytotoxic to peripheral blood mononuclear cells and a lymphoblastoid cell line, and increased ceramide <2-fold. Thus, 4-HPR was cytotoxic and increased ceramide in ALL cell lines, but not in non-malignant lymphoid cell types.


Clinical and biochemical studies of high-dose thymidine treatment in patients with solid tumors.
In a clinical study of high-dose thymidine (TdR) treatment, toxic effects, TdR metabolism, and the influence of TdR on pyrimidine and purine metabolism were examined. Ten patients with solid tumors were treated with continuous infusion of TdR at 34-75 g/m2/day for 3 to 5 days. Hematologic toxicity occurred with 5-day TdR infusion at 75 g/m2/day but not when plasma TdR concentration failed to reach millimolar levels. In three patients who received similar TdR doses, plasma TdR levels were related to elimination rates of TdR and its metabolites from plasma. In one patient in whom urinary excretion was studied, 100% of the TdR dose given was recovered in the form of TdR, thymine (Thy), beta-aminoisobutyrate, and 5-hydroxymethyluracil (5-HMUra). The latter metabolite, which had not been previously described in high-dose TdR treatment, was also found in plasma at levels from 5% to 10% of those of TdR. No effects of high-dose TdR infusion on purine levels in plasma were observed, while a substantial increase in uracil levels was noted both in plasma and urine. These data provide further information on high-dose TdR treatment with regard to clinical, pharmacokinetic, and biochemical effects.


Serum insulin and glucose levels and breast cancer incidence: the atherosclerosis risk in communities study.
The authors examined the association of breast cancer incidence with serum levels of insulin and glucose in a cohort of 7,894 women aged 45-64 years from four US communities. Anthropometric factors and fasting levels of insulin and glucose were measured at baseline (1987-1989). Over an average follow-up period of 7.1 years (1987-1995), 187 breast cancer cases were ascertained. Breast cancer was associated positively with body mass index but not with waist:hip ratio or serum insulin level. After adjustment for age, race, and study site, the incidence of breast cancer was 60% higher among diabetic women than among women with fasting glucose levels under 100 mg/dl, but this association was attenuated after further adjustment for body mass index and other covariates (adjusted rate ratio = 1.39, 95% confidence interval: 0.86, 2.23). Circulating insulin levels were not predictive of future breast cancer incidence, but there may be a weak association with type 2 diabetes, perhaps modulated via increased adiposity.


The many faces of actin: matching assembly factors with cellular structures.
Actin filaments are major components of at least 15 distinct structures in metazoan cells. These filaments assemble from a common pool of actin monomers, but do so at different times and places, and in response to different stimuli. All of these structures require actin-filament assembly factors. To date, many assembly factors have been identified, including Arp2/3 complex, multiple formin isoforms and spire. Now, a major task is to figure out which factors assemble which actin-based structures. Here, we focus on structures at the plasma membrane, including both sheet-like protrusive structures (such as lamellipodia and ruffles) and finger-like protrusions (such as filopodia and microvilli). Insights gained from studies of adherens junctions and the immunological synapse are also considered.


Improving the productivity of single-chain Fv antibody against c-Met by rearranging the order of its variable domains.
Single-chain Fv (scFv) antibody against c-Met is expected to be employed in clinical treatment or imaging of cancer cells owing to the important biological roles of c-Met in the proliferation of malignancies. Here, we show that the productivity of scFv against c-Met in Escherichia coli is significantly influenced by the orientation of its variable domains. We generated anti-c-Met scFv antibodies with two different domain orders (i.e., VL-linker-VH and VH-linker-VL), expressed them in the cytoplasm of E. coli trx/ gor deleted mutant, and compared their specific activities as well as their productivities. Productivity of total and functional anti-c-Met scFv with VH/VL orientation was more than five times higher than that with VL/VH format. Coexpression of DsbC enhanced the yield of soluble amounts of anti-c-Met scFv protein for both constructs. The purified scFv antibodies of the two different formats exhibited almost the same antigen-binding activities. We also compared the productivities and specific activities of anti-c-Met diabodies with VH/VL or VL/VH formats and obtained similar results to the case of scFv antibodies.


VEGF-A-related genetic variants protect against Alzheimer's disease.
The Apolipoprotein E (APOE) genotype has been shown to be the strongest genetic risk factor for Alzheimer's disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE, LSR and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls). Genotyping was performed for: the APOE common polymorphism (rs429358 and rs7412), two LSR variants (rs34259399 and rs916147) and 10 VEGF-A-related SNPs (rs6921438, rs7043199, rs6993770, rs2375981, rs34528081, rs4782371, rs2639990, rs10761741, rs114694170, rs1740073), previously identified as genetic determinants of VEGF-A levels in GWAS studies. The prediction model included direct and epistatic interaction effects, age and sex and was developed using the elastic net machine learning methodology. An optimal model including the direct effect of the APOE e4 allele, age and eight epistatic interactions between APOE and LSR, APOE and VEGF-A-related variants was developed with an accuracy of 72%. Two epistatic interactions (rs7043199*rs6993770 and rs2375981*rs34528081) were the strongest protective factors against AD together with the absence of ε4 APOE allele. Based on pathway analysis, the involved variants and related genes are implicated in neurological diseases. In conclusion, this study demonstrated links between APOE, LSR and VEGF-A-related variants and the development of AD and proposed a model of nine genetic variants which appears to strongly influence the risk for AD.


Delayed hypersensitivity in patients with bronchial carcinoma.
Delayed hypersensitivity skin test reactions have been carried out in patients with bronchial carcinoma. Dinitrochlorobenzene, used as a parameter of newly induced cell-mediated immunity, was clearly suppressed, and this suppression was associated with a poor prognosis. Tuberculin reactivity, used as a parameter of the memory function of the cell-mediated immune system, was not altered, and bears no relation to prognosis.


A systematic review and meta-analysis: Association between MGMT hypermethylation and the clinicopathological characteristics of non-small-cell lung carcinoma.
The relationship between O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) has remained controversial and unclear. Therefore, in this study we have undertaken a systematic review and meta-analysis of relevant studies to quantitatively investigate this association. We identified 30 eligible studies investigating 2714 NSCLC patients. The relationship between MGMT hypermethylation and NSCLC was identified based on 20 studies, including 1539 NSCLC patient tissue and 1052 normal and adjacent tissue samples (OR = 4.60, 95% CI = 3.46~6.11, p < 0.00001). MGMT methylation varied with ethnicity (caucasian: OR = 4.56, 95% CI = 2.63~7.92, p < 0.00001; asian: OR = 5.18, 95% CI = 2.03~13.22, p = 0.0006) and control style (autologous: OR = 4.44, 95% CI = 3.32~5.92, p < 0.00001; heterogeneous: OR = 9.05, 95% CI = 1.79~45.71, p = 0.008). In addition, MGMT methylation was observed to be specifically associated with NSCLC clinical stage, and not with age, sex, smoking, pathological types, and differentiation status. Also MGMT methylation did not impact NSCLC patients survival (HR = 1.32, 95% CI = 0.77~2.28, p = 0.31). Our study provided clear evidence about the association of MGMT hypermethylation with increased risk of NSCLC.


Large oriented arrays and continuous films of TiO(2)-based nanotubes.
We report for the first time a one-step, templateless method to directly prepare large arrays of oriented TiO2-based nanotubes and continuous films. These titania nanostructures can also be easily prepared as conformal coatings on a substrate. The nanostructured films were formed on a Ti substrate seeded with TiO2 nanoparticles. SEM and TEM results suggested that a folding mechanism of sheetlike structures was involved in the formation of the nanotubes. The oriented arrays of TiO2 nanotubes, continuous films, and coatings are expected to have potentials for applications in catalysis, filtration, sensing, photovoltaic cells, and high surface area electrodes.


MicroRNAs as prognostic molecular signatures in renal cell carcinoma: a systematic review and meta-analysis.
This is a systematic review of studies investigating the prognostic value of different microRNAs (miRs) in renal cell carcinoma (RCC). Twenty-seven relevant studies were identified, with a total of 2578 subjects. We found that elevated expression of miR-21, miR-1260b, miR-210, miR-100, miR-125b, miR-221, miR-630, and miR-497 was associated with a poor prognosis in RCC patients. Conversely, decreased expression of miR-106b, miR-99a, miR-1826, miR-215, miR-217, miR-187, miR-129-3p, miR-23b, miR-27b, and miR-126 was associated with a worse prognosis. We performed meta-analyses on studies to address the prognostic value of miR-21, miR-126, miR-210, and miR-221. This revealed that elevated miR-21 expression was associated with shorter overall survival (OS; hazard ratio [HR], 2.29; 95% confidence interval [CI], 1.28-4.08), cancer specific survival (CSS; HR, 4.16; 95% CI, 2.49-6.95), and disease free survival (DFS; HR, 2.15; 95% CI, 1.16-3.98). The decreased expression of miR-126 was associated with shorter CSS (HR, 0.35; 95% CI, 0.15-0.85), OS (HR, 0.45; 95% CI, 0.30-0.69), and DFS (HR 0.30; 95% CI, 0.18-0.50). Our comprehensive systematic review reveals that miRs, especially miR-21 and miR-126, could be promising prognostic markers and useful therapeutic targets in RCC.


Takotsubo Cardiomyopathy: A Cardiac Syndrome Mimicking Acute Myocardial Infarction in a Liver Transplant Recipient.
Takotsubo cardiomyopathy (TTC) is a rare clinical syndrome defined as a profound but reversible left ventricular dysfunction in the absence of coronary artery disease. We describe the clinical features and management of TC manifesting in the postoperative period in a patient undergoing liver transplantation. Two days after surgery, the patient developed clinical features of acute myocardial infarction. Ecochardiography revealed hypokinesis of the left ventricle. Coronary angiography revealed normal arteries without any stenosis or obstruction. The patient required vasopressor and inotropic support. The placement of intra-aortic balloon pump had a beneficial effect on the management of heart failure. The patient had a complete recovery of cardiac function 40 days after surgery. TC is a possible occurrence after liver transplant. Awareness of this condition is essential as early diagnosis and prompt management can save the patient's life.


Polarization Variability in Age-related Macular Degeneration.
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss. Complementary imaging techniques can be used to better characterize and quantify pathological changes associated with AMD. By assessing specific light-tissue interactions, polarization-sensitive imaging can be used to detect tissue disruption early in the disease process. The aim of this study was to compare variability in central macular polarization properties in patients with nonexudative AMD and age-matched control subjects. A scanning laser polarimeter (GDx, LDT/CZM) was used to acquire 15 × 15-degree macular images in 10 subjects diagnosed with nonexudative AMD and 10 age-matched control subjects. The coefficient of variation (COV, SD/mean) was used to quantify variability in pixel intensity in the central 3.3° of the macula for custom images emphasizing multiply scattered light (the depolarized light image) and polarization-retaining light (the maximum of the parallel detector image). The intensity COV was compared across subject categories using paired t tests for each image type. The COV in the central macula was significantly higher in the AMD subject group (average, 0.221; 95% confidence interval [CI], 0.157 to 0.265) when compared with matched control subjects (average 0.120; 95% CI, 0.107 to 0.133) in the depolarized light image (P = .01). The COV in the maximum of the parallel detector image was not statistically different between the two subject groups (AMD average, 0.162 [95% CI, 0.138 to 0.185]; control average, 0.137 [95% CI, 0.115 to 0.158]; P = .21). Variability in multiply scattered light is higher than that of light that is more polarization preserving in patients with nonexudative AMD. Multiple scattering may act as an early indicator representing disruption to the macula in early AMD.


Controlling chaos in ecology: from deterministic to individual-based models.
The possibility of chaos control in biological systems has been stimulated by recent advances in the study of heart and brain tissue dynamics. More recently, some authors have conjectured that such a method might be applied to population dynamics and even play a nontrivial evolutionary role in ecology. In this paper we explore this idea by means of both mathematical and individual-based simulation models. Because of the intrinsic noise linked to individual behavior, controlling a noisy system becomes more difficult but, as shown here, it is a feasible task allowed to be experimentally tested.


Adolescent Community Reinforcement Approach implementation and treatment outcomes for youth with opioid problem use.
This paper compares adolescents with primary opioid problem use (OPU) to those with primary marijuana or alcohol problem use (MAPU) who received up to six months of Adolescent Community Reinforcement Approach (A-CRA), an empirically supported treatment. Intake clinical characteristics, treatment implementation measures, and clinical outcomes of two substance problem groups (OPU and MAPU) were compared using data from 1712 adolescents receiving A-CRA treatment. Data were collected at intake and 3, 6, and 12 months post-intake. At intake, adolescents in the OPU group were more likely than those in the MAPU group to be Caucasian, older, female, and not attending school; report greater substance and mental health problems; and engage in social and health risk behaviors. There was statistical equivalence between groups in rates of A-CRA treatment initiation, engagement, retention, and satisfaction. Both groups decreased significantly on most substance use outcomes, with the OPU group showing greater improvement; however, the OPU group had more severe problems at intake and continued to report higher frequency of opioid use and more days of emotional problems and residential treatment over 12 months. The feasibility and acceptability of A-CRA for OPUs was demonstrated. Despite significantly greater improvement by the OPU group, they did not improve to the level of the MAPU group over 12 months, suggesting that they may benefit from A-CRA continuing care up to 12 months, medication to address opioid withdrawal and craving, and the inclusion of opioid-focused A-CRA procedures.


Computational Insights into Electronic Excitations, Spin-Orbit Coupling Effects, and Spin Decoherence in Cr(IV)-Based Molecular Qubits.
The great success of point defects and dopants in semiconductors for quantum information processing has invigorated a search for molecules with analogous properties. Flexibility and tunability of desired properties in a large chemical space have great advantages over solid-state systems. The properties analogous to point defects were demonstrated in the Cr(IV)-based molecular family, Cr(IV)(aryl)4, where the electronic spin states were optically initialized, read out, and controlled. Despite this kick-start, there is still a large room for enhancing properties crucial for molecular qubits. Here, we provide computational insights into key properties of the Cr(IV)-based molecules aimed at assisting the chemical design of efficient molecular qubits. Using the multireference ab initio methods, we investigate the electronic states of Cr(IV)(aryl)4 molecules with slightly different ligands, showing that the zero-phonon line energies agree with the experiment and that the excited spin-triplet and spin-singlet states are highly sensitive to small chemical perturbations. By adding spin-orbit interaction, we find that the sign of the uniaxial zero-field splitting (ZFS) parameter is negative for all considered molecules and discuss optically induced spin initialization via non-radiative intersystem crossing. We quantify (super)hyperfine coupling to the 53Cr nuclear spin and to the 13C and 1H nuclear spins, and we discuss electron spin decoherence. We show that the splitting or broadening of the electronic spin sub-levels due to superhyperfine interaction with 1H nuclear spins decreases by an order of magnitude when the molecules have a substantial transverse ZFS parameter.


The dilemma of treating pyoderma gangrenosum associated with monoclonal gammopathy of undetermined significance.
Pyoderma gangrenosum (PG) is a rare ulcerative skin condition. It can be associated with a number of systemic diseases. Association with monoclonal gammopathy of undetermined significance (MGUS) is uncommon, but prognosis may be different depending upon the type of MGUS. Cases of MGUS- related PG reported in the literature with data concerning evolution and treatment were identified through a PubMed search. A patient with recurrent PG in the setting of a MGUS-IgA-? in our department was also included. In total, 10 cases were identified. Only the two cases with Ig populations other than IgA improved without recurrence after treatment of the PG. All the patients with MGUS-IgA showed recurrences. Early multiple myeloma was proposed for three patients with MGUS-IgA-related PG. Second or third line treatments were necessary in some cases.


P53 codon 72 polymorphism and correlation with ovarian and endometrial cancer in Greek women.
The polymorphism of codon 72 in the p53 tumour suppressor gene has been associated in the last decade with the risk of developing various neoplasias. An influence of this polymorphism on ovarian and endometrial cancer has also been suggested. We examined the genotype frequency of this polymorphism in archival samples from 56 patients with endometrial neoplasias and 51 patients with ovarian neoplasias. Cervical smears from 30 healthy, human papillomavirus (HPV)-negative women with normal cytology and colposcopy, served as control sample. Women with ovarian neoplasias, especially adenocarcinomas, had Arg/Arg more often than healthy controls [odds ratio (OR) 4.16 at P = 0.0058]. No statistically significant difference was found between women with endometrial cancer and controls. Differentiation of ovarian tumours did not appear to be associated in a statistically significant manner with the genotype, whereas a positive linear trend of Arg/Arg towards poor differentiation was noted in endometrial malignancies (mainly endometrioid adenocarcinomas). Our results suggest that homozygous arginine at codon 72 of p53 may represent a risk factor for developing ovarian malignancies and may affect the differentiation of endometrial cancer. Further studies need to be carried out in order to establish the clinical use of this polymorphism for risk assessment and possibly outcome prediction of ovarian and endometrial neoplasias.


Antioxidants and Phenolic Acid Composition of Wholemeal and Refined-Flour, and Related Biscuits in Old and Modern Cultivars Belonging to Three Cereal Species.
Cereals are a good source of phenolics and carotenoids with beneficial effects on human health. In this study, a 2-year evaluation was undertaken on grain, wholemeal and refined-flour of two cultivars, one old and one modern, belonging to three cereal species. Wholemeal of selected cultivars for each species was used for biscuit making. In the grain, some yield-related traits and proteins (PC) were evaluated. In the flours and biscuits, total polyphenols (TPC), flavonoids (TFC), proanthocyanidins (TPAC), carotenoids (TYPC) and antioxidant activities (DPPH and TEAC) were spectrophotometrically determined, whereas HPLC was used for the composition of soluble free and conjugated, and insoluble bound phenolic acids. Species (S), genotype (G) and 'SxG' were highly significant for yield-related and all antioxidant traits, whereas cropping year (Y) significantly affected yield-related traits, PC, TPC, TPAC, TEAC and 'SxGxY' interaction was significant for yield-related traits, TPAC, TYPC, TEAC, DPPH and all phenolic acid fractions. Apart from the TYPC that prevailed in durum wheat together with yield-related traits, barley was found to have significantly higher values for all the other parameters. Generally, the modern cultivars are richest in antioxidant compounds. The free and conjugated fractions were more representative in emmer, while the bound fraction was prevalent in barley and durum wheat. Insoluble bound phenolic acids represented 86.0% of the total, and ferulic acid was the most abundant in all species. A consistent loss of antioxidants was observed in all refined flours. The experimental biscuits were highest in phytochemicals than commercial control. Although barley biscuits were nutritionally superior, their lower consumer acceptance could limit their diffusion. New insights are required to find optimal formulations for better nutritional, sensorial and health biscuits.


Demographic and clinical characteristics of carbon monoxide poisoning: nationwide data between 1999 and 2012 in Taiwan.
Carbon monoxide poisoning (COP) is not uncommon, but nationwide epidemiological data are limited. We conducted a study in Taiwan to fill the data gaps. We used a nationwide poisoning database to study all COP patients in Taiwan diagnosed between 1999 and 2012. We conducted descriptive analyses and compared the differences between the two sexes. In addition, we assessed the trends in suicide and mortality rates from 1999 to 2012. We identified 25,912 COP patients with an almost equal female and male distribution (50.6% vs. 49.4%). The mean age was 36.0 years, and most of the patients were between 20 and 50 years old. The highest incidence rate in the year occurred during winter. While female patients were more likely to have mental disorders (35.9% vs. 28.1%, p < 0.001), male patients were more likely to be resulted from suicide attempts (22.9% vs. 17.7%, p < 0.001). In both sexes, the suicidal rate increased from 1999, reached the peak in 2007, and then decreased gradually. Hyperbaric oxygen therapy was performed in 24.2% of the patients. Neurological sequelae developed in 9.1% of the patients, and chronic respiratory failure and requirement of long-term care were observed in 5.0% and 0.1% of the patients. The 1-month and 3-month mortality rates were 1.6% and 5.0%. The 3-month mortality rate did not show significant change between 1999 and 2012. This study showed a whole picture of COP in Taiwan, which could add to the important knowledge of this disastrous problem in public health. Some important findings, including higher percentages of mental disorders in female patients and suicide attempt in male patients, seasonal changes, and trends in mortality and morbidity (suicide) rates, may help developing strategies for prevention and treatment of COP.


Applications of murine and humanized chimaeric monoclonal antibodies for red cell phenotyping.
The limited supply of reagent human polyclonal antibodies to high prevalence antigens, like Js(b), is driving the search for alternative reagents. Murine immunoglobulin G (IgG) monoclonal antibodies (Mabs) and their humanized chimaeric IgM isoforms can now be used for typing patients and screening donors. Antigen typing of red blood cells (RBC) with a positive direct antiglobulin test (DAT) is also possible using these antibodies. Blood from patients with sickle cell disease and African donors were tested with reagent anti-Js(b), murine Mab IgG anti-Js(b) [murine immunochemistry monoclonal antibody-8 (MIMA-8)], and humanized chimaeric IgM anti-Js(b) [human immunochemistry monoclonal antibody-8 (HIMA-8)] by haemagglutination and gel cards. RBC samples that were DAT positive were used to evaluate the humanized chimaeric IgM monoclonal anti-Fy(a) (HIMA-19). RBC samples (n = 243) of known Js(b) type were tested in parallel with MIMA-8 and reagent anti-Js(b), and 132 samples were tested with MIMA-8 in gel cards and HIMA-8 by direct tube testing. No discrepant results were obtained. DAT-positive RBC samples (n = 27) were correctly phenotyped using HIMA-19. We conclude that MIMA-8 is suitable for screening donors and typing patient RBCs. Testing MIMA-8 with gel cards containing anti-mouse IgG enables the screening of donors by automated methods. Humanized chimaeric IgM anti-Js(b) and anti-Fy(a) are suitable as typing reagents by direct agglutination methods.


Social security: does it have a future?
Social Security has been available to Americans since 1937. The current administration is proposing a system overhaul to avoid a predicted bankruptcy by 2017. Nurses are frequently asked to help patients understand benefits or to complete disability paperwork. Nurses can also influence future legislation. This article will review the current Social Security System and attempt to explain the proposed changes.


Identification of frequent novel genetic alterations in small cell lung carcinoma.
We have performed a comprehensive analysis of the DNA copy number changes that occur in 18 small cell lung carcinoma cell lines using comparative genomic hybridization (Kallioniemi et al., Science (Washington DC). 258: 818-821, 1992). DNA copy number abnormalities detected in this study include previously identified increases at 1p22-32 (L-myc), 2p24-25 (N-myc), and 8q24 (c-myc) and decreases at 17p13 (p53), 13q14 (RB), and 3p. In addition, novel DNA copy number increases were detected at 5p, 1q24, and Xq26, and novel decreases were found at 22q12.1-13.1, 10q26, and 16p11.2. Many of the most common DNA copy number changes revealed are at loci not previously recognized to be important in small cell lung cancer. In addition, a number of the DNA copy number changes, including increases at 1p22-32, 2p24-25, and 3q22-25 and a decrease on 18p, were found to occur preferentially in small cell lung carcinoma lines of the "variant" phenotype. This correlation suggests that genes may reside at these loci whose overexpression or inactivation contributes to the radiation resistance or aggressive growth phenotypes characteristic of this subtype of small cell lung carcinoma.


Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease.
Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the "OS hypothesis of AD," including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.


(+)-Angchibangkine, a new type of bisbenzylisoquinoline alkaloid, and other dimers from Pachygone dasycarpa.
Analysis of the alkaloidal fraction of the stem bark extract of Pachygone dasycarpa (Menispermaceae) resulted in the isolation of 10 known bisbenzylisoquinolines, (+)-tetrandrine, (+)-penduline, (+)-fangchinoline, (+)-atherospermoline, (+)-N-methyl-7-O-demethylpeinamine, (+)-daphnoline, (4-)-isotrilobine (1), (+)-cocsuline (2), (+)-tricordatine (3), (+)-2'-norcocsuline, and the new alkaloid (+)-12-O-methyltricordatine (4). The last bisbenzylisoquinoline alkaloid isolated, (+)-angchibangkine (5), is the first member of this alkaloid class found to possess three diphenyl ether bridges in the 7-6',8-7', and 11-12' positions. Structure elucidation of these alkaloids and of (+)-O-methylangchibangkine (6) was achieved by analysis of spectral data. Compounds 4-6 show antiplasmodial activity against Plasmodium falciparum.


Time-resolved multi-mass ion imaging: Femtosecond UV-VUV pump-probe spectroscopy with the PImMS camera.
The Pixel-Imaging Mass Spectrometry (PImMS) camera allows for 3D charged particle imaging measurements, in which the particle time-of-flight is recorded along with (x, y) position. Coupling the PImMS camera to an ultrafast pump-probe velocity-map imaging spectroscopy apparatus therefore provides a route to time-resolved multi-mass ion imaging, with both high count rates and large dynamic range, thus allowing for rapid measurements of complex photofragmentation dynamics. Furthermore, the use of vacuum ultraviolet wavelengths for the probe pulse allows for an enhanced observation window for the study of excited state molecular dynamics in small polyatomic molecules having relatively high ionization potentials. Herein, preliminary time-resolved multi-mass imaging results from C2F3I photolysis are presented. The experiments utilized femtosecond VUV and UV (160.8 nm and 267 nm) pump and probe laser pulses in order to demonstrate and explore this new time-resolved experimental ion imaging configuration. The data indicate the depth and power of this measurement modality, with a range of photofragments readily observed, and many indications of complex underlying wavepacket dynamics on the excited state(s) prepared.


Optical impairment outage computation.
This work details a method to compute a probability of outage of a set of concatenated optical links with respect to multiple simultaneous optical impairments.


Antibody-directed myostatin inhibition improves diaphragm pathology in young but not adult dystrophic mdx mice.
Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle wasting and weakness, leading to premature death from respiratory and/or cardiac failure. A clinically relevant question is whether myostatin inhibition can improve function of the diaphragm, which exhibits a severe and progressive pathology comparable with that in DMD. We hypothesized that antibody-directed myostatin inhibition would improve the pathophysiology of diaphragm muscle strips from young mdx mice (when the pathology is mild) and adult mdx mice (when the pathology is quite marked). Five weeks treatment with a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg/week) increased muscle mass (P < 0.05) and increased diaphragm median fiber cross-sectional area (CSA, P < 0.05) in young C57BL/10 and mdx mice, compared with saline-treated controls. PF-354 had no effect on specific force (sPo, maximum force normalized to muscle CSA) of diaphragm muscle strips from young C57BL/10 mice, but increased sPo by 84% (P < 0.05) in young mdx mice. In contrast, 8 weeks of PF-354 treatment did not improve muscle mass, median fiber CSA, collagen infiltration, or sPo of diaphragm muscle strips from adult mdx mice. PF-354 antibody-directed myostatin inhibition completely restored the functional capacity of diaphragm strips to control levels when treatment was initiated early, but not in the later stages of disease progression, suggesting that such therapies may only have a limited window of efficacy for DMD and related conditions.


A model of autonomous interactions between hippocampus and neocortex driving sleep-dependent memory consolidation.
How do we build up our knowledge of the world over time? Many theories of memory formation and consolidation have posited that the hippocampus stores new information, then "teaches" this information to the neocortex over time, especially during sleep. But it is unclear, mechanistically, how this actually works-How are these systems able to interact during periods with virtually no environmental input to accomplish useful learning and shifts in representation? We provide a framework for thinking about this question, with neural network model simulations serving as demonstrations. The model is composed of hippocampus and neocortical areas, which replay memories and interact with one another completely autonomously during simulated sleep. Oscillations are leveraged to support error-driven learning that leads to useful changes in memory representation and behavior. The model has a non-rapid eye movement (NREM) sleep stage, where dynamics between the hippocampus and neocortex are tightly coupled, with the hippocampus helping neocortex to reinstate high-fidelity versions of new attractors, and a REM sleep stage, where neocortex is able to more freely explore existing attractors. We find that alternating between NREM and REM sleep stages, which alternately focuses the model's replay on recent and remote information, facilitates graceful continual learning. We thus provide an account of how the hippocampus and neocortex can interact without any external input during sleep to drive useful new cortical learning and to protect old knowledge as new information is integrated.


Comparison of different methods for diagnosis of porcine proliferative enteropathy.
The objectives of this study were: (1) to compare 2 methods of serology; (2) to compare 3 histologic techniques; and (3) to compare 2 methods of detecting shedding in pigs experimentally challenged with Lawsonia intracellularis. The sensitivities of these tests were determined by the detection of infection. Forty 5-week-old pigs were inoculated on day 0 with intestinal homogenate from pigs with proliferative enteropathy (PE). Clinical evaluation was done on day 7 and daily from day 14 to 28 postinoculation. Fecal shedding of L. intracellularis was monitored by use of polymerase chain reaction (PCR) analysis and immunoperoxidase staining at 7-day intervals. Serum was obtained on days 0 and 28 for serologic testing by glass slide and tissue culture indirect fluorescent antibody tests. At euthanasia on day 28, gross intestinal lesions were evaluated and ileum samples collected for histologic analyses. Ileal histologic sections from each animal were stained by hematoxylin and eosin, Warthin-Starry silver stain, and immunohistochemistry (IHC). Of the 40 pigs, 36 had gross lesions typical of PE at necropsy. The percentage of agreement between the 2 serologic methods was 94.4%. Immunoperoxidase stain of fecal smears was more sensitive than PCR for detecting fecal shedding, especially on day 21 (89.5% and 60.5%, respectively) and day 28 (59.4% and 37.5%, respectively) post-inoculation. The IHC stain was much more sensitive for detecting infection than the routinely used hematoxylin and eosin and Warthin-Starry silver stains. In conclusion, in experimentally infected pigs, both serologic methods were appropriate techniques for detecting infection. For fecal samples, PCR has low sensitivity. Immunohistochemistry is the best diagnostic tool for formalin-fixed samples.


Genotypic characterization of a nosocomial outbreak of VanA Enterococcus faecalis.
Despite growing concern about vancomycin-resistant enterococci (VRE) as nosocomial pathogens, especially in the United States, in Italy VRE still represent an uncommon and occasional experience for most diagnostic laboratories. We report a genotypic characterization of the first reported nosocomial outbreak of VRE in Italy. Some experiments, including plasmid analysis and pulsed-field gel electrophoresis (PFGE) assays, aimed at investigating the genetic relatedness of the VRE isolates. Other experiments, based on hybridization and polymerase chain reaction (PCR) assays, aimed at characterizing the vancomycin resistance determinants. Over a 6-month period, 21 VRE, all identified as Enterococcus faecalis, were isolated from eight patients (all treated earlier with glycopeptide antibiotics) in a neurosurgical intensive care unit. All isolates had the same biochemical profile and antibiotic susceptibility pattern, including high-level resistance to aminoglycosides and vancomycin and teicoplanin MICs of 256 and 128 micrograms/ml, respectively. Three plasmids, one strongly hybridizing with a vanA probe, were detected in all but the last of the 21 VRE isolates. The last isolate of the cluster lacked the smallest of the three plasmids. Similar restriction profiles were obtained after plasmid DNA digestion with several endonucleases, with minor differences appreciated only in the first and last isolates. Analysis of genomic DNA restriction fragment patterns by PFGE confirmed that the reported cluster of VRE isolations was due to a single nosocomial strain of E. faecalis, despite some modifications in plasmid DNA at the beginning and at the end of the outbreak. Completely different PFGE patterns were yielded by vancomycin-susceptible E. faecalis strains isolated during the same period from inpatients in the same intensive care unit. Hybridization experiments with vanA and vanS-vanH probes and DNA amplification assays using 14 PCR primer pairs specific for vanA cluster genes (vanR, vanS, vanH, vanA, and vanY), orf1, orf2, vanB, and vanC showed identical organization of resistance determinants in all epidemic VRE isolates. This organization appeared to be the same as that described for Tn1546 in VanA prototype strain E. faecium BM4147.


Struma ovarii: US and CT findings.
We describe the ultrasound and CT findings in a case of struma ovarii. Ultrasound showed a multicystic mass with a well-vascularized solid part. CT demonstrated a multilocular cystic mass with calcifications and solid, enhancing components. To prevent radical surgery, struma ovarii should be included in the differential diagnosis when a mixed, multilocular, teratoma-like tumour of the ovary shows a well-vascularized, enhancing, central solid component.


Examination of membrane rupture as a mechanism for mammalian cell detachment from fibronectin-coated biomaterials.
Synthetic biomaterials intended for the reconstruction of tissues and organs must be capable of sustaining adhesive contact with adjacent cells and tissues under mechanical and hydrodynamic stresses. To facilitate this adhesion, extracellular matrix proteins or peptide sequences are frequently immobilized to the biomaterial interface. These ligands enhance cell attachment by raising the number of cell receptor/ligand interactions, but consequently they may alter the mechanism of cell detachment. In particular, as the cell membrane is more strongly immobilized to the substratum, the tendency for cell detachment to involve membrane rupture may increase. To test this hypothesis, cells were fluorescent stained with a membrane dye, allowed to attach to fibronectin-coated model substrates for 30 min, and then subjected to a spatially dependent range of shear stress for 5 min (28-220 dyn/cm2) using a radial-flow chamber. Phase-contrast and fluorescent images were analyzed to determine the probability for cell detachment and the area of fluorescent debris left by detaching cells as a function of fibronectin concentration, magnitude of shear stress, and time. It was found at all concentrations of fibronectin that the majority of detaching cells left membrane fragments, the mean size of these fragments was independent of shear stress, and the shape independent of the direction of flow. However, mean fragment area increased with concentration of fibronectin and decreased with duration of shearing flow. We postulate that the area of debris reflects the extent of cell attachment prior to the application of shear and that adhesive complexes can disassemble at the onset of flow.


Association of Pasteurella haemolytica, Pasteurella multocida and Haemophilus somnus with pneumonia in calves.
Pathological and bacteriological observations were made on 100 (0.98%) pneumonic lungs of 10140 slaughtered beef calves during March 1995-June 1996 period. Gross lesions were mainly lobular and occasionally lobar pattern and, were frequently observed in the pars cranialis of lobus cranialis dexter. In histological examination, proliferative-exudative pneumonia was observed in 79 cases, and proliferative pneumonia alone in 21 cases. In bacteriological examination, Pasteurella haemolytica. Pasteurella multocida and Haemophilus somnus were isolated from 42.8 and 10 of pneumonic lungs respectively. In 7 cases, P. haemolytica and H. somnus were isolated from the same sample P. haemolytica and P. multocida were also found in the same sample in 2 cases. There was a close relation among these organisms and exudative inflammation (P < 0.01).


Long-term follow-up of two siblings with adult-onset neuronal ceroid lipofuscinosis, Kufs type A.
Reports on the clinical presentation of adult-onset neuronal ceroid lipofuscinoses (NCL) are scarce compared to infantile- and childhood-onset forms. Here, we aimed to present detailed temporal evolution of clinical and electrophysiological features of two siblings with adult-onset NCL and homozygous mutation in the CLN6 gene. We retrospectively analysed medical records and electrophysiological data in order to delineate evolution of clinical and electrophysiological findings. Electrophysiological studies included routine EEG and video-EEG, as well as polymyographic analysis of myoclonus and brainstem reflex studies. Both patients had seizures and cerebellar signs. Despite the slow progression of ataxia, they developed no mental deterioration, but had severe obsessive compulsive disorder and depression. EEG revealed frequent generalized spikes, polyspikes, and waves, prominent on awakening and during photic stimulation without significant change throughout the clinical course. Abnormalities concerning the blink reflex, auditory startle response, and startle response to somatosensory inputs manifested within four years. The patients underwent transient and mild improvement with valproate, whereas ataxia and seizures were dramatically ameliorated following high-dose piracetam. Patients with adult-onset NCL may present with slowly progressive ataxia, persistent photosensitivity, and seizures without dementia or extrapyramidal findings. Brainstem abnormalities become more evident with time, in line with ataxia. Piracetam is effective for both seizures and ataxia.


Recommendations for pneumococcal immunization outside routine childhood immunization programs in Western Europe.
The global burden of pneumococcal diseases is high, with young children and adults≥50 years of age at highest risk of infection. Two types of vaccine are available for the prevention of pneumococcal diseases caused by specific Streptococcus pneumoniae serotypes: the pneumococcal polysaccharide vaccine (PPV23) and the pneumococcal conjugate vaccine (PCV7, PCV10, and PCV13). Despite pneumococcal immunization programs in adults and children, the burden in adults has remained high. Most European countries have national or local/regional vaccination recommendations. The objective of this review was to provide an overview of the government recommendations for pneumococcal vaccination outside routine childhood vaccination programs for 16 Western European countries as of August 2014. We found that recommendations for pneumococcal immunization across Europe are complex and vary greatly among countries in terms of age groups and risk groups recommended for vaccination, as well as which vaccine should be administered. Clarifying or simplifying these recommendations and improving their dissemination could help to increase pneumococcal vaccine uptake and decrease the high burden of pneumococcal diseases in adults, both through a direct effect of the vaccine and via a herd effect in unvaccinated individuals.


Enumerating immunoglobulin-secreting cells among peripheral human lymphocytes. A hemolytic plaque assay for a B cell function.
Cells bearing immunoglobulin (Ig) can be enumerated by current methods, but cells secreting Ig (with unknown antibody specificity) can not. By using a reverse plaque-forming cell assay, we counted the Ig-secreting cells in the blood of nonimmunized individuals. Isolated human lymphocytes were plated in gels together with erythrocytes coated with purified antibody to human Ig. After treatment with anti-Ig antibody and complement, the Ig-secreting cells formed hemolytic plaques. In 10 normal individuals, 1.2 +/- 0.4% of the plated mononuclear cells formed plaques; in an individual tested on 7 different days during 3 months, 1.1 +/- 0.2% of the cells formed plaques. From the number of mononuclear cells in the blood, we calculated 22 +/- 8 Ig-secreting cells per mm3 of blood. Enumerating Ig-secreting cells is a new direct assay for a B cell function and need not correlate with quantitating serum Ig. Thus, this assay should be useful for studying Ig-secretion in normal and altered states.


Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum.
Sphingosine 1-phosphate (S1P) is the natural ligand for a specific G protein-coupled receptors. In endothelial cells, S1P has been shown to modulate the activity of the endothelial nitric-oxide synthase (eNOS) through phosphorylation operated by Akt. Nitric oxide (NO) produced by neuronal nitric-oxide synthase and eNOS plays a central role in triggering and maintaining penile erection. This study has assessed the possibility of a similar cross-talk between eNOS and S1P in human corpus cavernosum and whether this interaction is connected to penile vascular response. Quantitative reverse transcription-polymerase chain reaction demonstrated the presence of S1P(1), S1P(2), and S1P(3) receptors in both the human corpus cavernosum (HCC) and the penile artery. S1P on its own did not relax or contract HCC strips, but on the other hand, incubation with S1P (0.1 microM) caused a 6-fold increase in relaxation induced by a subliminal dose of acetylcholine. This effect is dependent upon eNOS activation through an Akt-dependent phosphorylation, as demonstrated by pharmacological modulation with l-nitroarginine methyl ester and wortmannin and by Western blot studies. In human tissue, S1P seems to be the possible candidate for the activation of the eNOS calcium-independent pathway. This pathway may represent a new therapeutic area of intervention in erectile dysfunction (ED) to develop a way to selectively promote NO production at the endothelial level. This approach could also be used to enhance phosphodiesterase 5 therapy in patients with ED that are poor responders, such as in the case of diabetes.


Body cell mass: model development and validation at the cellular level of body composition.
Existing models to estimate the metabolically active body cell mass (BCM) component in vivo remain incompletely developed. The classic Moore model is based on an assumed BCM potassium content of 120 mmol/kg. Our objectives were to develop an improved total body potassium (TBK)-independent BCM prediction model on the basis of an earlier model (Cohn SH, Vaswani AN, Yasumura S, Yuen K, and Ellis KJ. J Lab Clin Med 105: 305-311, 1985), to apply this improved model in subjects to explore the sex and age dependence of the TBK/BCM ratio, to develop a new TBK/BCM model on the basis of physiological associations between TBK and total body water (TBW) at the cellular level of body composition, and to fit this new model with available reference data. Subjects were 112 healthy adults who had the following components measured: TBW by 2H2O or 3H2O, extracellular water by NaBr, total body nitrogen by in vivo neutron activation, bone mineral by dual-energy X-ray absorptiometry, and TBK by whole body counting. Human reference data were collected from earlier published reports. The improved Cohn model-derived TBK/BCM ratio was (mean +/- SD) 109.0 +/- 10.9 mmol/kg and was not significantly related to sex and age. A simplified version of the new TBK-TBW model provided a TBK/BCM ratio almost identical (109.1 mmol/kg) to that derived by the improved Cohn model. The TBK-BCM prediction formula derived from the improved and new models [BCM (kg) = 1/109 x TBK (mmol); or BCM = 0.0092 x TBK] gives BCM estimates approximately 11% higher than the classic Moore model (BCM = 0.0083 x TBK) formulated on rough tissue composition estimates. The present analyses provide a physiologically based, improved, and validated TBK-BCM prediction formula that should prove useful in body composition and metabolism research.


Observations on the distribution and ecology of Clostridium botulinum type E in Alaska.
Environmental samples collected along the coastline and from the interior of Alaska were examined for the presence of Clostridium botulinum. Clostridium botulinum type E was detected in soils from 5 of 12 beaches; in 7 of 115 non-coastal soil samples; in sediments from six of eight locales; in gills of salmon from two fishing areas; and in the feces of 1 of 44 colonic samples from marine mammals. The basic biochemical characteristics of the isolates were determined. Tube tests for demonstrating gelatin liquefaction proved insensitive with these strains, whereas a plate test detected gelatinase in all isolates. The presence of multiple nidi and the continual discharge of organic materials into the environment may contribute to the perpetuation of botulinum spores by which foods prepared form marine animals become contaminated. An emphasis should be placed upon the need for measures to reduce environmental contamination, to reduce contamination during food preparation, and to alert continually the population of the hazard wherever botulism is endemic.


[Primary hypertrophic osteoarthropathy without cutaneous involvement (Currarino's disease)].
Hypertrophic osteoarthropathy (HOA) is a syndrome associating hippocratic fingers, arthropathy and periostosis of long bones. Currarino's disease, considered at present as a clinical form of primary HOA, is characterized by the absence of pachydermia. A 24-year-old Caucasian man, consulted for a painful swelling of both ankles that had developed over the past year. Clinical examination revealed hippocratic fingers without pachydermia. The ankles were swollen. The X-rays showed periosteal apposition and an acro-osteolysis. In view of this triad: arthropathy, hippocratic fingers and periostosis, primary HOA without cutaneous involvement or Currarino's disease was diagnosed. The search for a secondary cause remained negative. Clinical improvement was obtained after 15 months with non-steroidal anti-inflammatory drugs (NSAID) and colchicine. Although exceptional, primary HOA without cutaneous involvement is a genetic disease which must not be ignored.


Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial.
To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days. Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258. The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR ≤ 3 hours = 0.78, 0.68 to 0.90; HR > 3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise. Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.


Regulation of nausea and vomiting in cancer chemotherapy. A review with emphasis on opiate mediators.
Chemotherapy-induced nausea and vomiting are primarily regulated by chemoreceptor trigger zone (CTZ)-vomiting center (VC) pathways. Dopaminergic (D2), histaminic (H1), and muscarinic cholinergic (Ach) receptors are present in these sites, and specific receptor antagonists are potent but not "universal" antiemetics when used alone or in combination. Recently, neurons containing the endogenous opiate enkephalin were also identified near the CTZ and the VC. Furthermore, opiates stimulate vomiting at the CTZ and inhibit vomiting at the VC in dogs and in cats. A dose-related increase in nausea and vomiting in response to the opiate antagonist naloxone has also been demonstrated in patients receiving cancer chemotherapy. These observations support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting; further, they suggest that narcotic agents may be effective antiemetics in this setting.


Insights into binding of cholera toxin to GM1 containing membrane.
Interactions of cholera toxin (CT) with membrane are associated with the massive secretory diarrhea seen in Asiatic cholera. Ganglioside GM1 has been shown to be responsible for the binding of the B subunit of cholera toxin (CT-B), which then helps CT to pass through the membrane, but the exact mechanism remains to be explored. In this work, we have carried out atomistic scale molecular dynamics simulation to investigate the structural changes of CT upon membrane binding and alteration in membrane structure and dynamics. Starting from the initial structure where the five units of B subunit bind with five GM1, only three of five units remain bound and the whole CT is tilted such that the three binding units are deeper in the membrane. The lipids that are in contact with those units of the CT-B behave differently from the rest of the lipids. Altogether, our results demonstrate the atomistic interaction of CT with GM1 containing lipid membrane and provide a probable mechanism of the early stage alteration of lipid structure and dynamics, which can make a passage for penetration of CT on membrane surface.


Laparoscopic sacral colpopexy for vaginal vault prolapse.
Laparoscopic sacral colpopexy can be used to treat vaginal vault and genital prolapse. After preparation, the vaginal apex is attached to the sacrum over the third and fourth sacral vertebrae using mesh.


Degradation of amyloid beta species by multi-copper oxidases.
Reduction of the production of amyloid beta (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. In this study, we discovered that ceruloplasmin (CP), an important multi-copper oxidase (MCO) in human blood, could degrade Aβ peptides. We also found that the presence of Vitamin C could enhance the degrading effect in a concentration-dependent manner. We then validated the CP-Aβ interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer, and fluorescence polarization measurement. Based on the above discovery, we hypothesized that other MCOs had similar Aβ-degrading functions. Indeed, we found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect among the tested MCOs. Using induced pluripotent stem (iPS) neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Ab-induced deficit in synaptic transmission in the hippocampus. To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.


Production of aflatoxin on wheat and oats: measurement with a recording densitometer.
A method has been developed for the production of aflatoxin by growing Aspergillus flavus NRRL 3145 on solid substrate wheat. Optimal yields of 900 mug of aflatoxin G(1) and 900 mug of aflatoxin B(1) per g of substrate were obtained in 4 to 5 days at 28 C. A study of aflatoxin production on hulls and groats of oats and on whole oats by A. flavus strains NRRL 2999, NRRL 3000, and NRRL 3145 revealed that aflatoxin was produced on all three substrates, although production was very slight on hulls. Strain NRRL 3145 grown on solid substrate groats produced the largest amounts of aflatoxin: 580 mug of B(1) and 450 mug of G(1) per g of substrate. A densitometric method for reading thin-layer chromatographic plates is described; this is more objective and more accurate than the visual methods previously used for the determination of all four aflatoxins.


[Mammography after breast-preserving therapy of breast cancer].
Follow-up after tumorectomy and intensive irradiation for carcinoma of the breast creates new diagnostic problems. In particular, more experience is necessary about the value of mammography. We have therefore analysed the mammograms of 104 patients intensively followed over one to eight years after primary treatment. Changes in the appearances of the breast due to irradiation are compared with mammographic changes caused by recurrence of tumor. It can be shown that definite structural patterns can be recognised regularly. Optimal diagnosis of recurrencies, however, is only possible by comparing all follow-up mammograms, and additionally the pre-operative films. Close cooperation between the surgeon, radiotherapist and diagnostic radiologist is essential.


Nitric oxide in CsA-induced hypertension: role of beta-adrenoceptor antagonist and thromboxane A2.
Cyclosporine A (CsA) is an immunosuppressive agent, which also causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and rat aortic rings. Male rats weighing 250-300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by intraperitoneal (ip) injection for 7 days. CsA administration produced a 42% increase (P < 0.001) in mean arterial pressure (MAP) which reached a plateau after 3 days. The level of both nitrate/nitrite (NO2/NO3), metabolites of nitric oxide (NO), decreased by 50% (P < 0.001), but the level of thromboxane A2 (TBXA2) increased by 75% (P < 0.001), in the urine. When 10(-9) M of CsAwas added acutely to intact aortic rings from untreated rats, NO2/NO3 production decreased by 83% (P < 0.011), but TBXA2 production increased by 86% (P < 0.001). The effects of CsA were reversed both in vivo and in vitro by pretreatment with propranolol (15 mg/kg/day ip), beta-adrenoceptor antagonist. There were no changes in MAP and tension in rats treated with prop alone. In addition, in aorta of rats that were treated with CsA ip for 7 days, CsA significantly activated protein kinase C (PKC) translocation. This suggests that PKC mediate, in part, CsA-induced hypertension. In summary, CsA inhibits endothelial NO formation, activate PKC, and increaseTBXA2 production, with resulting increase in MAP, and this changes can be overcome by pretreatment with propranolol.


Reduced expression of P120 catenin in cholangiocarcinoma correlated with tumor clinicopathologic parameters.
To investigate the relationship between the expression of P120 and the clinicopathologic parameters in intrahepatic cholangiocarcinoma (ICC). An immunohistochemical study of E-cadherin and P120 catenin was performed on 42 specimens of ICC with a Dako Envision kit. The expression of E-cadherin and P120 was reduced in 27 cases (64.3%) and 31 cases (73.8%), respectively. Both E-cadherin and P120 expressions were significantly correlated with the tumor histological grade (chi2 = 9.333, P = 009 and chi2 = 11.71, P = 0.003), TNM stage (chi2= 8.627, P = 0.035 and chi2 = 13.123, P = 0.004), intrahepatic metastasis (chi2= 7.292, P = 0.007 and chi2 = 4.657, P = 0.041, respectively) and patients' survival (chi2= 6.351, P = 0.002 and chi2 = 4.023, P = 0.000, respectively). In addition, the expression of P120 was in concordance with that of E-cadherin (chi2 = 13.797, P = 0.000), indicating that the expression of P120 may be dependent on that of E-cadherin. Finally, only P120 expression was found to be an independent prognostic factor in Cox regression model (r = 0.088, P = 0.049). Down-regulated expression of E-cadherin and P120 occurs frequently in ICC and contributes to the progression and development of tumor. Both of them may be valuable biologic markers for predicting tumor invasion, metastasis and patients' survival, but only P120 is an independent prognostic factor for ICC.


Manifestations of carcinoma of the uncinate process by means of superior mesenteric arteriography.
Identification of carcinoma arising in the uncinate region of the pancreas is difficult because of the peculiar topographic relationship of this lesion with adjacent structures. Among the various diagnostic procedures performed upon ten patients with this malignant lesion, superior mesenteric arteriography provided the most helpful information, including signs of invasion in the main trunk of the superior mesenteric artery and vein and in the proximal portion of the jejunal arteries. A clearer visualization of these vascular involvements was attained in the right posterior oblique projection rather than in the anteroposterior projection. On the contrary, the arterial and portal vessels belonging to the celiac territory, such as superior pancreaticoduodenal arteries, dorsal pancreatic artery, gastroduodenal artery, splenic vein and portal vein, were almost free of involvement. At laparotomy, almost all of the patients had direct extension of the tumor to the superior mesenteric vessels, forming a cancerous core in the root of mesentery. All died of cachexia within six months after a palliative surgical procedure. Serial roentgenograms of superior mesenteric artery, especially taken in the oblique projection, are the best means of confirming carcinoma of the uncinate process, for which only a few available methods have been established to evaluate the clinical aspects.


Effect of Pyrazosulfuron-Methyl on the Photosynthetic Characteristics and Antioxidant Systems of Foxtail Millet.
Foxtail millet (Setaria Italica L.) plays a principal role in food security in Africa and Asia, but it is sensitive to a variety of herbicides. This study was performed to clarify whether pyrazosulfuron-methyl can be used in foxtail millet fields and the effect of pyrazosulfuron-methyl on the photosynthetic performance of foxtail millet. Two foxtail millet varieties (Jingu 21 and Zhangzagu 10) were subjected to five doses (0, 15, 30, 60, and 120 g ai ha-1) of pyrazosulfuron-methyl in pot and field experiments. The plant height, leaf area, stem diameter, photosynthetic pigment contents, gas exchange parameters, chlorophyll fluorescence parameters, antioxidant enzyme activities, and antioxidant contents at 7 and 15 days after pyrazosulfuron-methyl application, and the yield of foxtail millet were measured. The results suggested that pyrazosulfuron-methyl inhibited the growth of foxtail millet and reduced the photosynthetic pigment contents, photosynthetic rate, and photosynthetic system II activity. Similarly, pyrazosulfuron-methyl decreased the antioxidant enzyme activities and antioxidant contents. These results also indicated that the toxicity of pyrazosulfuron-methyl to foxtail millet was decreased gradually with the extension of time after application; however, the foxtail millet yield was still significantly reduced. Therefore, pyrazosulfuron-methyl is not recommended for application in foxtail millet fields.


Constructing public and political discourse on alcohol issues: towards a framework for analysis.
To examine the possibilities for research into news reporting and its role in reflecting and informing public and political beliefs and action in relation to alcohol and drinking practices. Studies on media and alcohol, focusing on the role of media in relation to alcohol consumption and drinking-related practices, policies and beliefs. Most research on alcohol and media has focused on either advertising or entertainment media content, rather than on news reporting and its wider social implications. The role of news reporting could usefully be widened. We offer a framework for analysing the role of news media in relation to public debate and practice with regard to alcohol and drinking.


The Relation Between Light-Induced Lacrimation and the Melanopsin-Driven Postillumination Pupil Response.
To investigate the chromatic characteristics and intensity-response function of light-induced reflex lacrimation and its correlation with the melanopsin-driven postillumination pupil response (PIPR). Eleven visually normal participants completed the experiment. Lacrimation was measured in one eye by placing a calibrated filter paper strip in the conjunctival sac over a 1 minute-interval (Schirmer's test) during which participants received either no light stimulation (baseline trial) or one flash of blue or red light stimuli presented binocularly with a Ganzfeld stimulator, while the pupil response was recorded simultaneously from the fellow eye by using an eye tracker. Light stimulation trials were presented in alternating fashion at seven incremental intensity steps (0.1, 1, 3.16, 10, 31.6, 100, and 400 cd/m2). Postillumination pupil response was defined as the mean pupil constriction from 10 to 30 seconds post illumination. The amount of lacrimation in response to 10 to 400 cd/m2 blue light was significantly greater than baseline and increased monotonically with increasing light intensity. Red light did not induce significant reflex lacrimation until the brightest stimulation at 400 cd/m2. There was a positive linear correlation between PIPR and lacrimation in response to blue light (r = 0.74, P < 0.001) but not to red light (r = 0.13, P = 0.25). The chromatic characteristics and intensity-response of light-induced lacrimation are highly consistent with the features of melanopsin phototransduction. This finding is the first in vivo evidence in humans, supporting the hypothesis that light-induced reflex lacrimation is mediated primarily by melanopsin photoactivity, and provides new insight into the putative mechanisms of photophobia.


[A rare tumour of the right hypochondrium in the child (author's transl)].
Pancreatic pathology in the child is rare and usually limited to necrotic or traumatic pseudo-cysts. The authors report a case of multicystic dysplasis localised in the pancreas in a one-year old infant. The preoperative diagnosis of a traumatic cyst was made in error as the result of the discovery of a fracture of the skull. At operation, the "tumour" was seen to be a multicystic mass within the duodenal loop but pediculated under the inferior surface of the pancreas. Histological examination confirmed its dysplasic nature. The presence, as a result of vascular compression, together with the post-operative resolution of hypertension lend further originality to this case.