Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure.
In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. The maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol). Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.


Movements of cross-bridges during and after slow length changes in active frog skeletal muscle.
The cross-bridge movements underlying the tension responses of active muscle to slow length changes were studied by a time-resolved X-ray diffraction method. During an isometric tetanus at 2 degrees C, the meridional reflexion at 1/14.3 nm-1 was 55% more intense than in the resting state, suggesting that the myosin heads maintain the 14.3 nm periodicity of the thick filament. When active muscle was stretched by 7% at a constant speed of 0.03-0.70 muscle lengths s-1, the intensity of the meridional reflexion decreased progressively as the tension increased continuously during the stretch. This suggests that the myosin heads spread out along the thick filament. During stress relaxation after a stretch, the intensity returned gradually toward the active isometric level, suggesting a rearrangement of the myosin heads. The meridional intensity changed in a similar manner when active muscle was released by 7% at the same speeds; it decreased progressively during the release and returned gradually to the isometric level after completion of the release. The intensity decrease during a release was smaller than that during a stretch, provided the speed was low (0.03-0.09 muscle lengths s-1). It was concluded that the tension responses to slow length changes are due to shifts of the myosin heads along the thick filament, and that the elastic element responsible for tension production is located in the myosin molecules.


Benzopyrene induces oxidative stress and increases expression and activities of antioxidant enzymes, and CYP450 and GST metabolizing enzymes in Ulva lactuca (Chlorophyta).
Benzopyrene is rapidly incorporated and metabolized, and induces oxidative stress and activation of antioxidant enzymes, and CYP450 and GST metabolizing enzymes in Ulva lactuca. To analyze absorption and metabolism of benzo[a]pyrene (BaP) in Ulva lactuca, the alga was cultivated with 5 µM of BaP for 72 h. In the culture medium, BaP level rapidly decreased reaching a minimal level at 12 h and, in the alga, BaP level increased until 6 h, remained stable until 24 h, and decreased until 72 h indicating that BaP is being metabolized in U. lactuca. In addition, BaP induced an initial increase in hydrogen peroxide decreasing until 24 h, superoxide anions level that remained high until 72 h, and lipoperoxides that initially increased and decreased until 72 h, showing that BaP induced oxidative stress. Activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (AP), glutathione reductase (GR) and glutathione peroxidase (GP) were increased, whereas dehydroascorbate reductase (DHAR) activity was unchanged. The level of transcripts encoding these antioxidant enzymes was increased, but transcripts encoding DHAR remained unchanged. Interestingly, the activity of glutathione-S-transferase (GST) was also increased, and inhibitors of cytochrome P450 (CYP450) and GST activities enhanced the level of BaP in algal tissue, suggesting that these enzymes participate in BaP metabolism.


Eosinophils in glioblastoma biology.
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review.


Routine skin cultures in predicting sepsis pathogens among hospitalized preterm neonates in Bangladesh.
Few studies from developing countries have examined sensitivity, specificity, positive and negative predictive values of routine surface cultures. The purpose of the study was to determine sensitivity, specificity, and positive predictive value (PPV) of skin cultures among preterm neonates admitted to Dhaka Shishu Hospital, Bangladesh. The study was nested within a prospective, randomized, controlled trial of emollient treatment in Dhaka Shishu Hospital, Bangladesh. A total of 497 preterm infants <33 weeks gestational age and <72 h of chronological age were enrolled, and the sensitivity, specificity, and PPV of skin cultures were analyzed among 3,765 blood-skin culture pairs, wherein the skin culture was obtained within 13 days before the blood culture. Overall sensitivity, specificity, and PPV were 16, 38, and 5%, respectively. PPV during Klebsiella pneumoniae outbreaks was about 9%, and the inguinal site had the highest PPV (6%) among the three skin sites. Acinetobacter spp.- and K. pneumoniae-specific PPVs were 28 and 23%, respectively. PPV was <2% for Candida spp., Enterobacter spp., and Salmonella spp. Routine skin culture is inefficient in predicting the pathogen responsible for sepsis among premature neonates, even in a developing country setting, where the burden of bacterial infection is relatively high. Skin cultures are also of limited utility during K. pneumoniae outbreaks, and are not recommended.


Isothermal decay studies of intermediate energy levels in quartz.
The recent interest in the thermoluminescence of quartz extracted from unfired building materials, such as mortar and concrete for dose reconstruction applications, led to the requirement of an accurate determination of the lifetime of the intermediate glow peaks in this mineral. The prediction of the lifetimes of these peaks is helpful in establishing the likely time range within which retrospective measurements can be carried out. These peaks, corresponding to intermediate energy levels, occur in the glow curve in the temperature range 150-250 degrees C (heating rate 2 degrees C/s). Lifetimes of 720+/-70 days and 580+/-70 years (at a temperature of 15 degrees C) were derived for the two main peaks placed in the glow curve at approximately 150 degrees C and 200 degrees C, respectively, using the isothermal decay technique. These results as well as the estimated values of the trap parameters (thermal activation energy and frequency factor) have been compared with the data already available in the literature.


Associations of systolic blood pressure trajectories during pregnancy and risk of adverse perinatal outcomes.
This study aimed to explore the association of systolic blood pressure (SBP) trajectories of pregnant women with the risk of adverse outcomes of pregnant women and their fetuses. A register-based cohort of 63,724 pregnant women and their fetuses from January 2013 to December 2017 was investigated. Demographic characteristics, history of disease and family history of disease for pregnant women and perinatal outcomes were recorded, and blood pressure was measured during the whole pregnancy. SBP trajectories were estimated with latent mixture modeling by Proc Traj in SAS using SBP data from the first antenatal care appointment (8-14 weeks), the highest SBP before admission, the admission SBP and the SBP at 2 h postpartum. A censored normal model (CNORM) was considered appropriate, and model fit was assessed using the Bayesian information criterion (BIC). A logistic regression model was used to examine the association between SBP trajectories and the risk of adverse perinatal outcomes. Four distinct SBP trajectory patterns over the pregnancy period were identified and were labeled as low-stable, moderate-stable, high-decreasing and moderate-increasing. Three maternal and three fetal adverse outcomes were selected as the main outcome measures. After adjusting for confounding factors, compared with pregnant women with the low-stable pattern, those with the high-decreasing pattern had a higher risk of developing poor growth outcomes of fetuses, while those with the moderate-increasing pattern had higher risks of developing both adverse maternal and fetal outcomes. Our study results suggest that pregnant women should pay attention to the control of blood pressure throughout pregnancy.


Influence of biological matrix and artificial electrospun scaffolds on proliferation, differentiation and trophic factor synthesis of rat embryonic stem cells.
Two-dimensional vs three-dimensional culture conditions, such as the presence of extracellular matrix components, could deeply influence the cell fate and properties. In this paper we investigated proliferation, differentiation, survival, apoptosis, growth and neurotrophic factor synthesis of rat embryonic stem cells (RESCs) cultured in 2D and 3D conditions generated using Cultrex® Basement Membrane Extract (BME) and in poly-(L-lactic acid) (PLLA) electrospun sub-micrometric fibres. It is demonstrated that, in the absence of other instructive stimuli, growth, differentiation and paracrine activity of RESCs are directly affected by the different microenvironment provided by the scaffold. In particular, RESCs grown on an electrospun PLLA scaffolds coated or not with BME have a higher proliferation rate, higher production of bioactive nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) compared to standard 2D conditions, lasting for at least 2 weeks. Due to the high mechanical flexibility of PLLA electrospun scaffolds, the PLLA/stem cell culture system offers an interesting potential for implantable neural repair devices.


A study of the relationship between ABO blood groups, secretor status and infection with Neisseria gonorrhoeae.
The distribution of ABO blood groups and secretor status among 216 male caucasian patients with gonorrhoea was not significantly different from that in 2043 male caucasians who formed a comparison population.


Codon usage in Plasmodium falciparum.
The codon frequencies used in 7874 codons from 17 sequences of Plasmodium falciparum have been examined. The frequency distribution is markedly biased. A and C occur with similar frequency in all positions but G is predominantly in the first base and T is predominantly in the last position. This information can be used to predict the coding strand and reading frame of P. falciparum genes.


Voltammetric sensing of oxacillin by using a screen-printed electrode modified with molecularly imprinted polyaniline, gold nanourchins and graphene oxide.
An imprinted electrochemical sensor was developed for the determination of the antibiotic oxacillin (OXC). A screen-printed carbon electrode (SPCE) was modified with gold nanourchin and graphene oxide, and then aniline was electro-polymerized in the presence of OXC to obtain a molecular imprint on the SPCE. The morphologies in sequential modification processes and the electrochemical behavior of the modified SCPE were characterized by field emission scanning electron microscopy and cyclic voltammetry. The performance of the sensor was evaluated by differential pulse voltammetry. At a typical peak potential of 0.82 mV (vs. Ag/AgCl), response is linear in the 0.7-575 nM OXC concentration range. The electrochemical sensitivity is 97.6 nA nM -1 cm -2, and the detection limit is 0.2 nM. The relative of replicate assays is 2.6% (for n = 6) at an OXC concentration level of 200 nM. The sensor is sensitive and selective. It was successfully applied for the detection of OXC in spiked cow's milk. Schematic presentation of electropolymerization of aniline on sreen-printed carbon electrode (SPCE) modified with graphene oxide (GO) and gold nanouchins (GNU) for voltammetric sensing of oxacillin.


Tank-treading dynamics of red blood cells in shear flow: On the membrane viscosity rheology.
In this article, extensive three-dimensional simulations are conducted for tank-treading (TT) red blood cells (RBCs) in shear flow with different cell viscous properties and flow conditions. Apart from recent numerical studies on TT RBCs, this research considers the uncertainty in cytoplasm viscosity, covers a more complete range of shear flow situations of available experiments, and examines the TT behaviors in more details. Key TT characteristics, including the rotation frequency, deformation index, and inclination angle, are compared with available experimental results of similar shear flow conditions. Fairly good simulation-experiment agreements for these parameters can be obtained by adjusting the membrane viscosity values; however, different rheological relationships between the membrane viscosity and the flow shear rate are noted for these comparisons: shear thinning from the TT frequency, Newtonian from the inclination angle, and shear thickening from the cell deformation. Previous studies claimed a shear-thinning membrane viscosity model based on the TT frequency results; however, such a conclusion seems premature from our results and more carefully designed and better controlled investigations are required for the RBC membrane rheology. In addition, our simulation results reveal complicate RBC TT features and such information could be helpful for a better understanding of in vivo and in vitro RBC dynamics.


Speciation study of the heavy metals in commercially available recharge cards coatings in Nigeria and the health implication.
This work assessed levels of heavy metals exposure from silver coatings of mobile phones recharge cards of three major companies (designated as A, B and C) with price denominations 100, 200 and 400 from companies A, B and C respectively, which were carefully scratched using a plastic scraper into a glass tube. The coatings were acid digested for total metal concentration, while speciation experiment for Mn, Cu, Cd and Pb was carried out. Total metals and speciation analysis were done using AAS and XRF techniques. The total metal concentration from XRF analysis was in the range: Ca (70-2140 μg/g), K (20-4930 μg/g), Sc (80-270 μg/g), Ti (1530-12,580 μg/g), Fe (50-6660 μg/g), Ni (20-2040 μg/g), Cu (20-850 μg/g) and Zn (40-460 μg/g). Cr had the lowest concentration (10 μg/g) in A ( 400) while Ti had the highest concentration (12,580 μg/g) in C ( 500) for all the coatings analyzed. AAS and XRF results agreed closely except for Fe with higher concentration. A ( 100) contained high concentration of the metals compared with others. Speciation study identified Mn as the most mobile element when present in the environment.


Associations of genetic risk, BMI trajectories, and the risk of non-small cell lung cancer: a population-based cohort study.
Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown. Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk. Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation. Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC. http://www. gov , NCT01696968 .


Safety aspects of ketoconazole, the most commonly used systemic antifungal.
Ketoconazole was first considered as a more or less safe drug. When used on a very large scale, however, it became obvious that this drug, as others mainly metabolized in the liver, can cause liver damage, i.e. chemical hepatitis sometimes even leading to death. Such very rare events seem to be linked to the protracted use of ketoconazole. Taking into account what is now known on the rational use of ketoconazole it still is a drug with a favourable benefit risk ratio.


Cranial computed tomography in acute disseminated encephalomyelitis.
Acute disseminated encephalomyelitis (ADEM) is an uncommon inflammatory disorder of the nervous system. The appearance of ADEM on cranial CT scans has rarely been reported. The author reports seven cases in two institutions during a period of seven years. Only four of the seven patients had hypodense lesions in the white matter and six patients showed spotty, nodular, or gyral enhancement after contrast injections. The enhancement resolved with steroid therapy, leaving some persistent hypoattenuated areas even after 10 months follow-up, these findings support the dual components of the pathogenesis of ADEM. The vasculitic component may be responsive to steroids, nevertheless the demyelinating or necrotic areas may not, and the latter may be responsible for the sequelae of ADEM.


Water quality assessment in the rivers along the water conveyance system of the Middle Route of the South to North Water Transfer Project (China) using multivariate statistical techniques and receptor modeling.
A total of 190 grab water samples were collected from 19 rivers along the water conveyance system of the Middle Route of China's interbasin South to North Water Transfer Project (MRSNWTP). Multivariate statistics including principal component/factor analysis (PCA/FA), analysis of variance (ANOVA), and cluster analysis (CA) were employed to assess water quality, and the receptor model of factor analysis-multiple linear regression (FA-MLR) was used for source identification/apportionment of pollutants from natural processes and anthropogenic activities to river waters. Our results revealed that river waters were primarily polluted by COD(Mn), BOD, NH(4)(+)-N, TN, TP, and Cd with remarkably spatio-temporal variability, and there were increasing industrial effluents in rivers northward. FA/PCA identified four classes of water quality parameters, i.e., mineral composition, toxic metals, nutrients, and organic pollutants. CA classified the selective 19 rivers into three groups reflecting their varying water pollution levels of moderated pollution, high pollution, and very high pollution. The FA-MLR receptor modeling revealed predominantly anthropogenic inputs to river solutes in Beijing and Tianjin, i.e., 77% of nitrogen and 90% of phosphorus from industry, and 80% of COD(Mn) from domestics. This study is critical for water allocation and division in the water-receiving areas using the existing rivers for MRSNWTP.


Regulation of IFN-gamma production in granulocyte-macrophage colony-stimulating factor-deficient mice.
Granulocyte-macrophage colony-stimulating factor-deficient (GM-CSF-/-) mice produce far lower serum levels of IFN-gamma in response to LPS than GM-CSF+/+ mice. CD4+ and CD8+ T cells from LPS-injected GM-CSF-/- mice showed a deficiency in IFN-gamma production and proliferative activity in response to IL-2 and IL-12, whereas IFN-gamma production by NK cells was not compromised. These defects of T cells were reversed by administration of GM-CSF in vivo, but not by supplementation with GM-CSF in vitro. GM-CSF-/- mice do not have an intrinsic defect in IFN-gamma production, because IL-12 injection induces the same high levels of IFN-gamma in GM-CSF-/- and GM-CSF+/+ mice. To investigate the inhibitory effect of LPS on GM-CSF-/- T cells and the indirect restorative activity of GM-CSF, we tested the action of supernatants from cultured dendritic cells (DC). A factor or factors in the DC supernatant normalized serum IFN-gamma levels and T cell responses in LPS-injected GM-CSF-/- mice. IL-18 reproduced some but not all of these in vivo and in vitro effects of DC supernatants. Our results indicate that GM-CSF is important in protecting T cells from inhibitory signals generated during immunization or exposure to LPS, and that this effect of GM-CSF is indirect and mediated by factors produced by DC.


The application of lung ultrasound in acute decompensated heart failure in heart failure with preserved and reduced ejection fraction.
Lung ultrasound detection of B-lines has become a simple, semiquantitative, noninvasive tool for evaluating pulmonary congestion in heart failure (HF) patients. This study compared the correlation of B-lines with E/e', NT-proBNP, and ejection fraction (EF) in acute decompensated heart failure (ADHF). Eighty-two consecutive patients who were diagnosed with acute decompensated HF were divided into two groups: preserved ejection fraction heart failure (HFpEF, EF≥50%, n=32) and reduced ejection fraction heart failure (HFrEF, EF<50%, n=50). Spearman's correlation was used to evaluate associations of B-lines with E/e', NT-proBNP, and EF in the two groups. Receiver operating characteristic (ROC) analysis was performed to compare B-lines with the E/e' ratio. Results revealed no significant differences were observed in the B-lines between the HFpEF and HFrEF groups. However, compared with the control group, B-lines were significantly increased in the HFpEF and HFrEF groups (P<.05). The B-lines were positively correlated with E/e' (r=0.742, r=0.52) and NT-proBNP (r=0.678, r=0.417) but were negatively correlated with EF (r=-0.365, r=-0.337), and the correlation coefficients were higher in the HFpEF group than in the HFrEF group. In ROC analyses, considering E/e' ≥14 as a reference, B-lines yielded a C-statistic value of 0.94 (sensitivity 92%, specificity 83%) in the HFpEF group and 0.84 (sensitivity 86%, specificity 78%) in the HFrEF group. B-lines were significantly correlated with the more established parameters of ADHF. The correlation between B-lines and E/e' was better, especially in the HFpEF group.


Effects of dietary β-glucan on the growth and innate immune response of juvenile Persian sturgeon, Acipenser persicus.
The present study evaluated the effects of different levels of dietary β-glucan (MacroGard(®)) on growth performance and innate immune parameters in juvenile Persian sturgeon (Acipenser persicus). Fish (20.1 ± 0.8 g) were allocated into 12 tanks (15 fish per tank) and triplicate groups were fed a control diet or diets containing 0.1%, 0.2% and 0.3% β-glucan. After six weeks of daily feeding (3.0% body weight day(-1)), humoral innate immune parameters (serum immunoglobulin (Ig) levels, lysozyme activity and alternative complement activity (ACH50)) and growth parameters (final weight, weight gain, specific growth rate (SGR), food conversion ratio (FCR)) were examined. Innate immune responses (lysozyme activity and ACH50) were significantly higher in 0.2% and 0.3% β-glucan fed fish (P < 0.05). Similarly, elevated growth performance (final weight, SGR and FCR) was observed in fish fed 1%, 2% and 3% β-glucan compared to the control group (P < 0.05). However, dietary β-glucan had no significant effect on survival rate of fish (P > 0.05). These results indicate that β-glucan can be considered as a beneficial dietary supplement for improving the immune response and growth performance of Persian sturgeon.


Risk rate neglect in decisions involving invasive diagnostic procedures.
To investigate whether the risk of life-threatening complications influence the decisions involving invasive diagnostic procedures, a study was conducted that focused on the use of coronary angiography and endomyocardial biopsy with risk rates of either 1% or 2%. The participants included 38 physicians from two university-affiliated hospitals. Of their 76 pairs of decisions, 53% were of the "risk-avoidance" type and 26% were of the "risk-taking" type. Only 13% of decisions were of the "risk-conscious" type. The practical implication of these biases can be substantial in real-life decisions regarding events with low-probability, but high-consequence risks.


L-proline catalyzed Michael additions of thiophenols to alpha,beta-unsaturated compounds, particularly alpha-enones, in the ionic liquid [bmim]PF6.
L-proline catalyzed additions of 13 different thiols to 11 different alpha-enone Michael acceptors in [bmim] PF(6 )are reported. Reasonable to high yields of the reaction products were isolated in most cases.


Relationship Between Lateral Tibial Posterior Slope and Tibiofemoral Kinematics During Simulated Jump Landings in Male Cadaveric Knees.
It is not known mechanistically whether a steeper lateral posterior tibial slope (LTS) leads to an increase in anterior tibial translation (ATT) as well as internal tibial rotation (ITR) during a given jump landing. A steeper LTS will result in increased ATT and ITR during simulated jump landings when applying knee compression, flexion, and internal tibial torque of increasing severity. Descriptive laboratory study. Seven pairs of cadaveric knees were harvested from young male adult donors (mean ± SD; age, 25.71 ± 5.53 years; weight, 71.51 ± 4.81 kg). The LTS of each knee was measured by a blinded observer from 3-T magnetic resonance images. Two sets of 25 impact trials of ∼700 N (1× body weight [BW] ±10%) followed by 2 sets of 25 trials of 1400 N (2× BW ±10%) were applied to a randomly selected knee of each pair. Similarly, on the contralateral knee, 2 sets of 25 impact trials of ∼1800 N (2.5× BW ±10%) followed by 2 sets of 25 trials of ∼2100 N (3× BW ±10%) were applied. Three-dimensional knee kinematics, including ATT and ITR, were measured at 400 Hz using optoelectronic motion capture. Two-factor linear mixed effect models were used to determine the relationship of LTS to ATT and ITR as impact loading increased. As LTS increased, so did ATT and ITR during increasingly severe landings. LTS had an increasing effect on ATT (coefficient, 0.50; 95% CI, 0.29-0.71) relative to impact force (coefficient, 0.52; 95% CI, 0.50-0.53). ITR was proportional to LTS (coefficient, 1.36; 95% CI, 0.80-1.93) under increasing impact force (coefficient, 0.49; 95% CI, 0.47-0.52). For steeper LTS, the increase in ITR was proportionally greater than the increase in ATT. In male knee specimens, a steeper LTS significantly increased ATT and ITR during jump landings. Increases in ITR and ATT during jump landings lead to increased strain on the anterior cruciate ligament and are therefore associated with greater risk of ligament failure.


The relationship between mitral regurgitant severity, symptoms, and exercise capacity in primary degenerative mitral regurgitation.
Although it is assumed that more severe MR is associated with a greater burden of symptoms and lower exercise capacity, the relationship between symptoms, exercise capacity, and mitral regurgitant severity has not been well studied. We prospectively studied 67 (63 ± 11 years, 72% male) patients with at least mild degenerative MR and left ventricular ejection fraction ≥ 50% who underwent stress echocardiography, CMR, and evaluation with the Kansas City Cardiomyopathy questionnaire (KCCQ). Symptoms and exercise capacity were evaluated in the context of MR severity. Patients reporting dyspnea had lower KCCQ symptom scores (79 ± 23 vs. 96 ± 9, p = 0.01) and achieved lower percentage of age and gender predicted METs (114 ± 37 vs. 152 ± 43%, p < 0.001) compared to those without dyspnea. There was no significant difference in MR volume between those with vs. without dyspnea by CMR (43 ± 26 ml vs. 51 ± 28 ml, p = 0.3) or echocardiography (64 ± 28 vs. 73 ± 41ml, p = 0.4). Those with severe MR by CMR had similar KCCQ symptom scores (96 ± 10 vs. 89 ± 17, p = 0.04) and percentage of age and gender predicted METs (148 ± 42 vs. 133 ± 47%, p = 0.2) to those without severe MR. Those with severe MR by echocardiography had similar KCCQ symptom score (93 ± 15 vs. 89 ± 16, p = 0.3) and percentage of age and gender predicted METs (138 ± 43 vs. 153 ± 46%, p = 0.2) to those without severe MR. Patients with degenerative MR assessed by CMR and stress echocardiography, there was no relationship between MR severity and either symptoms or exercise capacity. These findings highlight the disconnect between symptoms and the severity of MR and challenge the assumption that correcting MR can be counted on to improve symptom status in patients with degenerative MR.


Induction and repression of peroxisome proliferator-activated receptor alpha transcription by coregulator ARA70.
In an effort to understand transcriptional regulation by the peroxisome proliferator-activated receptor alpha (PPARalpha), we investigated the ability of a number of transcriptional coactivators to enhance PPARalpha:retinoic acid receptor (RXR) mediated transcription. We identified ARA70, a coactivator of the androgen receptor and PPARgamma, as a ligand-enhanced coactivator of PPARalpha in the prostate cancer cell line DU145. In prostate cancer cells, ARA70 demonstrated the strongest enhancement of PPARalpha transcription among the coactivators examined. Mutation of the N-terminal of the PPARalpha ligandbinding domain dramatically reduced the ability of ARA70 to enhance PPARalpha:RXR transcription. ARA70 was able to physically interact with both the wild-type and mutant PPARalpha as determined by coimmunoprecipitation. However, in the adrenal cell line Y1, ARA70 behaved as a repressor of PPARalpha while still able to coactivate PPARgamma.


Treatment of lateral ankle instability with transfer of the extensor digitorum brevis muscle.
Ankle sprains are the most common injuries sustained during sports and physical exercise. Treatment is usually conservative because most of these injuries heal without consequence. However, some injuries may be followed by chronic lateral pain and instability, and surgical stabilization is sometimes necessary. In select cases, there is little or no residual ligament or scar tissue remaining for late reconstruction. Proximal transfer of the origin of the extensor digitorum brevis muscle as a substitute for deficient ligament tissue can be used in these difficult cases. During the years 1971 to 1992, 13 ankles in 10 patients underwent surgery using the proximal extensor digitorum brevis muscle transfer method. At follow-up, all the ankles manifested functional stability and were stable with no clinical drawer sign. All had a normal range of motion in the ankle joint but showed a desired decreased supination range of motion throughout the hindfoot and ankle. The functional Karlsson scores were 84.5 +/- 18.8 before injury, 26.4 +/- 18.7 before surgery, and 83.6 +/- 18.7 at follow-up. Thus, the extensor digitorum brevis muscle transfer seems to be a useful alternative method of long-term ankle stabilization in these difficult chronic case; the results correlate well with a few other studies using this method.


Urinary protein excretion pattern and renal expression of megalin and cubilin in nephropathic cystinosis.
Nephropathic cystinosis is the most common cause of inherited renal Fanconi syndrome, caused by mutations in lysosomal cystine carrier cystinosin that result in lysosomal cystine accumulation throughout the body. How defects in cystinosin cause proximal tubular dysfunction is not known. We hypothesized that cystine accumulation could cause disturbed proximal tubular endocytosis by megalin and cubilin. Megalin, cubilin, and their ligands were studied in kidney tissue by means of immunohistochemistry. Urinary protein excretion pattern was evaluated. Kidney tissue from a patient with cystinosis was compared with minimal change nephrotic syndrome tissue, end-stage renal disease tissue, and control renal tissue. Urine from 7 patients with cystinosis was compared with 6 control samples. Expression of megalin, cubilin, and ligands (transferrin, albumin, vitamin D-binding protein, alpha(1)-microglobulin, retinol-binding protein, and beta(2)-microglobulin) in convoluted proximal tubules of cystinotic kidney was similar to that in other kidney specimens. In straight tubules, low-molecular-weight proteins were present in only cystinotic kidney samples. Next to low-molecular-weight proteins and albumin, urinary excretion of immunoglobulin G was increased in patients with cystinosis with Fanconi syndrome compared with controls. This was already observed at an early age, suggesting enhanced glomerular permeability in patients with cystinosis. This study is essentially observational, and immunohistochemical data are based on 1 cystinotic kidney. Our findings indicate that low-molecular-weight proteinuria in patients with cystinosis is not caused by decreased megalin and cubilin expression, and glomerular damage might already be present at early stages of the disease.


(Auto)immunity to cartilage matrix proteins - a time bomb?
Geng and colleagues consolidate and detail the role of cartilage oligomeric matrix protein (COMP) as a (potential) autoantigen in experimental and human arthritis, a finding also supported by the detection of COMP fragments and anti-COMP antibodies in rheumatoid arthritis serum and/or synovial fluid and by synovial B-cell responses against COMP. The reactivity to COMP is yet another example of how, in addition to collagen II and the large aggregating proteoglycan, cartilage-specific proteins can induce arthritis and contribute to autoimmunity. Progression of cartilage damage and degradation in disease is believed to promote the autoimmune reaction to cartilage components. However, Geng and colleagues show that anti-COMP mAbs bind in vivo to undamaged cartilage, as previously also observed for anti-collagen II antibodies. Whether this autoimmunity also involves modifications of cartilage matrix proteins, such as citrullination, remains to be further investigated. Latent, subpathogenic (auto)immune reactions directed against cartilage matrix proteins may thus eventually contribute to the outbreak of human arthritis.


Role of histidine 373 in the catalytic activity of coagulation factor XIII.
Factor XIII catalysis proceeds via formation of thioester acyl enzyme intermediate involving an active site cysteine residue at position 314. The contribution of other residues to catalysis has not been established. Earlier studies of the pH dependence of factor XIII activity suggested the existence of a putative active site histidine. We used chemical modification and oligonucleotide directed site-specific mutagenesis to investigate the role of histidines. Photo-oxidation with methylene blue resulted in a complete loss of catalytic activity under conditions that oxidized histidine but did not affect the essential cysteine. Single substitution of each of the 14 histidine residues in the a-subunit of factor XIII by asparagine or alanine led to mutants with catalytic activities generally not significantly different from the wild-type recombinant enzyme. The only exceptions were the H373N and H373A mutants that were poorly expressed, had no detectable rate of [14C]putrescine incorporation into dimethylcasein, and failed to cross-link fibrin gamma-chains. Thus, the a-subunit His-373 may function in the active site of factor XIII, by analogy with papain's mechanism, as a histidinium cation that increases the nucleophilicity of the essential Cys-314. Decreased expression levels of His-373 mutants also indicate that this residue may be critical for enzyme stability.


Carbon dioxide absorber as a cause of high airway pressures.
We investigate an incident in which a carbon dioxide absorber caused difficulty with ventilation. The problem as it developed throughout the anesthetic, and clues that led to the determination that the carbon dioxide canister was the problem, is discussed.


[Effects of serum and decidual tissue fluid in early pregnant women on natural killer cells activity and lymphocyte proliferation].
To study the effects of serum and decidual tissue fluid in early pregnant women on natural killer cells (NK cells) activity and lymphocyte proliferation. The effects of the serum and decidual tissue fluid obtained from 32 normal early pregnant women on NK cells activity and lymphocyte proliferation were tested by isotope incorporation methods. Sera of 25 nonpregnant women were chosen as controls. The NK cells activity and lymphocyte proliferation of sera and decidual tissue fluids from early pregnant women were lower than those of sera from nonpregnant women (P < 0.01). So were those of decidual tissue fluid as compared with sera during early pregnancy (P < 0.005). Serum and decidual tissue fluid from early pregnant women expressed immunosuppressive effects. It is possible that these effects of decidual tissue fluid play an important role in regulating local immune status of pregnant uterus.


Bilateral metal stents for hilar biliary obstruction using a 6Fr delivery system: outcomes following bilateral and side-by-side stent deployment.
Controversy exists on optimal endoscopic management for palliation of malignant hilar obstruction, with advocates for metal "side-by-side" (SBS) and "stent-in-stent" (SIS) techniques. We sought to evaluate the technical feasibility, efficacy, and outcomes of bilateral biliary self-expanding metal stents (SEMS) for treatment of malignant hilar obstruction using a stent with a 6Fr delivery system. This was a single-center, retrospective review of all patients who underwent bilateral placement of Zilver® biliary SEMS for malignant hilar obstruction from January 2010 to August 2012. Patients underwent endoscopic retrograde cholangiopancreatography with placement of stents using either the SIS or SBS stent techniques. Twenty-four patients (19 men, mean age 63 years) underwent bilateral stenting for malignant hilar obstruction during the study period. Seventeen and seven patients underwent the SBS and SIS technique, respectively. Cholangiocarcinoma (n=14) was the most common cause of hilar obstruction. Initial technical success was achieved in 24/24 (100%) of patients; however, 12 (50%) patients required re-intervention during the study period (median 98 days). Comparison of the SBS and SIS groups revealed no statistical difference with respect to need for re-intervention (P=0.31), successful re-intervention (P=0.60), or procedural length (P=0.89). Use of bilateral Zilver® SEMS in either the SBS or SIS configuration is safe, technically feasible, and effective for drainage of malignant hilar obstruction; however, duration of stent patency and procedure-free survival remain variable.


Z-scheme cobalt-iron oxide/perylene diimide supermolecule heterojunction for high-efficiency ciprofloxacin removal in a photocatalysis-self-Fenton system.
Fenton technology has been famous on antibiotics removal, but seriously restricted by the extra addition of H2O2 and low mineralization efficiency. Herein, we develop a novel cobalt-iron oxide/perylene diimide organic supermolecule (CoFeO/PDIsm) Z-scheme heterojunction under photocatalysis-self-Fenton system, in which the holes (h+) of photocatalyst can mineralize organic pollutants and the photo-generated electrons (e-) are used to in-situ H2O2 production with high efficiency. The CoFeO/PDIsm exhibits superior in-situ H2O2 production at a rate of 281.7 µmol g-1 h-1 in contaminating solution, correspondingly of total organic carbon (TOC) removal rate of ciprofloxacin (CIP) is 63.7 %, far exceeding current photocatalysts. The high H2O2 production rate and remarkable mineralization ability are ascribed to great charge separation in Z-scheme heterojunction. This work provides a novel Z-scheme heterojunction with photocatalysis-self-Fenton system for environmental-friendly removing the organic containment.


Managing side effects of tyrosine kinase inhibitor therapy to optimize adherence in patients with chronic myeloid leukemia: the role of the midlevel practitioner.
In the last decade, the development of imatinib, a tyrosine kinase inhibitor, has brought about unprecedented change in the way newly diagnosed, chronic-phase chronic myeloid leukemia patients are treated. Two next-generation tyrosine kinase inhibitors, nilotinib and dasatinib, were initially indicated for imatinib-resistant or imatinib-intolerant chronic myeloid leukemia patients and recently received approval from the Food and Drug Administration for treatment of newly diagnosed, chronic-phase chronic myeloid leukemia patients. In comparison with the previous standards of care, benefits with these three tyrosine kinase inhibitors have included more rapid response rates, increased survival, and fewer side effects. The improved long-term outcomes have altered the approach to management of chronic myeloid leukemia from a progressive fatal disease with a poor prognosis to a chronic condition similar to diabetes or hypertension. Prolonged survival increases the need for patient education, support, monitoring, and assistance with adverse event management. Even low-grade side effects can adversely affect patients' quality of life and, therefore, require prompt attention to prevent long-term complications or suboptimal outcomes. New evidence has indicated that patient adherence to tyrosine kinase inhibitor therapy is essential to successful treatment. Midlevel practitioners can help to optimize outcomes by educating patients regarding the importance of adherence, performing regular monitoring, helping patients to understand their test results, and aggressively managing treatment-related side effects.


Mutations in the MCFD2 gene and a novel mutation in the LMAN1 gene in Indian families with combined deficiency of factor V and VIII.
Combined deficiency of factors V (FV) and factor VIII (FVIII) (F5F8D) is an autosomal recessive bleeding disorder caused by simultaneous moderate-to-mild decrease of both clotting proteins. Mutations in two components of the ER-Golgi intermediate compartment (ERGIC-53), i.e., lectin mannose binding protein (LMAN1) and multiple coagulation factor deficiency 2 (MCFD2), have been found to be responsible for this dual deficiency in most of the cases reported in literature. Three Indian families with F5F8D were analyzed for the presence of mutations in their LMAN1 and MCFD2 genes. One of the three families showed the presence of a G to A substitution in exon 2 of the MCFD2 gene, whereas another family showed a nonsense mutation, i.e., G to T substitution, in exon 2 of the LMAN1 gene, the latter being a novel mutation not previously reported. The third family did not show mutations in either of the two genes, suggesting that a significant subset of F5F8D cases may be due to additional genes resulting in a similar phenotype.


Defining treatment margins for six field conformal irradiation of localized prostate cancer.
To define the "ideal margins" to be used for the delivery of six-field conformal radiotherapy for localized prostate cancer. For a typical patient, 3-D based 6-field conformal treatment plans were generated using uniform margins ranging from 0.5-2.5 cm (in 0.25 cm increments). In a step-wise fashion the minimum margins required to encompass the gross tumor volume within the 90% isodose shell were identified. Additional margins were then added to account for extracapsular penetration, setup and patients movement error as well as for organ movement. Assumptions about the relative tolerance of surrounding normal tissues were also incorporated into the final decisions regarding margins. For the various areas of interface, between the prostate and surrounding normal tissues "ideal margins" varied from 0.75-2.25 cm. The use of nonuniform "ideal margins" appears to insure adequate coverage of the tumor, while minimizing the volume of surrounding dose limiting normal tissues irradiated. This approach should in theory improve the tumor control and complication probabilities compared to using conventional treatment techniques and to using a 6-field conformal technique with uniform margins.


Biphasic surface amorphous layer lubrication of articular cartilage.
The biphasic nature of articular cartilage has been acknowledged for some time and is known to play an important role in many of the biomechanical functions performed by this unique tissue. From the lubrication point of view however, a simple biphasic model is unable to account for the extremely low friction coefficients that have been recorded experimentally, particularly during start-up. In addition, research over the last decade has indicated the presence of a surface amorphous layer on top of articular cartilage. Here, we present results from a finite element model of articular cartilage that includes a thin, soft, biphasic surface amorphous layer (BSAL). The results of this study show that a thin BSAL, with lower elastic modulus, dramatically altered the load sharing between the solid and liquid phases of articular cartilage, particularly in the near-surface regions of the underlying bulk cartilage and within the surface amorphous layer itself where the fluid load support exceeded 85%. By transferring the load from the solid phase to the fluid phase, the biphasic surface layer improves lubrication and reduces friction, whilst also protecting the underlying cartilage surface by 'shielding' the solid phase from elevated stresses. The increase in lubrication effectiveness is shown to be greatest during short duration loading scenarios, such as shock loads.


Fusarium mycotoxins in forage maize - occurrence, risk assessment, minimization.
The deoxynivalenol contents of forage maize in this study ranged between 0.22 and 12.9 mg/kg DM, but seldom exceeded critical concentrations suggested for ruminant diets. Zearalenone was found in considerably lower concentrations than DON and rarely reached critical levels. Therefore risk to the health and performance of ruminants is regarded as low. Fusarium toxin occurrence in forage maize can be minimized by choosing maize varieties less susceptible to stem rot, harvesting at optimal maturity (dry matter content 30-35%) and elevating the cutting height to at least 40 cm above ground.


A sector-disaggregated cross-regional emission analysis for carbon mitigation policies from production and consumption perspectives.
As one of the most challenging environment issues worldwide, climate change has posed a serious threat to habitat, species, and people's livelihoods. In this study, a sector-disaggregated cross-regional emission analysis model is developed to systematically analyze enviro-economic effects of sector-level carbon mitigation efforts from both production and consumption perspectives for supporting climate change-related policymaking. A special case study of Hubei Province, China, is conducted to demonstrate the potential benefits of its use in the climate change related policymaking field. The power generation sector has been disaggregated into five subsectors based on different power generation technologies to help investigate the potential of such technologies to carbon emission mitigations. The carbon mitigation policy scenarios from both industry optimization and demand substitute perspectives will further be explored to provide bases for decision makers to formulate the desired carbon mitigation policy aimed at different regions and sectors. Results indicate that dominant direct and indirect CO2 emissions in Hubei Province are from the Production and supply of fossil-fuel power sector and Construction sector, respectively. When industry optimization policies on the fossil-fuel power sector (in Hubei), there are significant effects on the CO2 emission mitigation whichever regions. Therefore, industry optimization policies are suggested for implementation in specific sectors with close intersectoral/interprovince trade contacts and significant emissions to achieve joint carbon emission mitigations.


NRIP1 is activated by C-JUN/C-FOS and activates the expression of PGR, ESR1 and CCND1 in luminal A breast cancer.
Using chip array assays, we identified differentially expressed genes via a comparison between luminal A breast cancer subtype and normal mammary ductal cells from healthy donors. In silico analysis confirmed by western blot and immunohistochemistry revealed that C-JUN and C-FOS transcription factors are activated in luminal A patients as potential upstream regulators of these differentially expressed genes. Using a chip-on-chip assay, we identified potential C-JUN and C-FOS targets. Among these genes, the NRIP1 gene was revealed to be targeted by C-JUN and C-FOS. This was confirmed after identification and validation with transfection assays specific binding of C-JUN and C-FOS at consensus binding sites. NRIP1 is not only upregulated in luminal A patients and cell lines but also regulates breast cancer-related genes, including PR, ESR1 and CCND1. These results were confirmed by NRIP1 siRNA knockdown and chip array assays, thus highlighting the putative role of NRIP1 in PGR, ESR1 and CCND1 transcriptional regulation and suggesting that NRIP1 could play an important role in breast cancer ductal cell initiation.


Combination of genetic variants in cyclin D1 and retinoblastoma genes predict clinical outcome in oral cancer patients.
Oral cancer is a dreadful disease with a wide variation in geographical distribution. In order to identify some useful biomarkers for the disease prognosis, the present study assessed the influence of single nucleotide polymorphisms (SNPs) in cell cycle genes on survival in a well-annotated set of patients with oral squamous cell carcinoma (OSCC). The study examined 12 sequence variants or SNPs in selected cell cycle genes, with prognostic outcomes in 311 oral cancer patients. Our analysis showed that SNPs in cyclin D1:rs9344 and retinoblastoma:rs427686 genes showed a strong correlation with disease-free survival. In addition, the cumulative effect of these SNPs significantly and independently predicts the survival. Thus, the current study identified genotypes (SNP signature), which can be used as novel prognostic biomarkers to stratify patients based on disease-free survival and therefore maybe helpful in therapeutic decision-making.


Efficient low redundancy large-scale DNA sequencing at EMBL.
An efficient low redundancy DNA sequencing strategy should allow high accuracy determination of the consensus sequence on both strands of a DNA fragment from a minimal number of sequencing reactions with minimal overlap. At EMBL we developed a directed strategy for cosmid-scale sequencing based on primer walking, whereas most other sequencing projects of this scale rely on the random 'shotgun' strategy. In our strategy, highly accurate raw data are obtained from automated double-stranded Sanger dideoxy sequencing with inexpensive walking primers (8 to 10 $ per primer), T7 DNA polymerase and internal labelling by fluorescein-15- dATP on A.L.F. DNA sequencers (Pharmacia Biotech). The use of 60-cm long glass plates enables reading length of up to 1000 bases. Comparing various random and directed sequencing strategies in the course of the European Community yeast genome sequencing project on cosmids from chromosomes IX, XI and XV, primer walking was found to be the strategy resulting in the lowest possible redundancy of 2.6 to 2.8. Future development of the sequencing strategy is based on the new EMBL 2-dye sequencing device for simultaneous sequencing on both strands, and implementation of an initial limited random sequencing phase to reduce the number of walking primers required by a factor of 3, while still maintaining a low redundancy of approx. 3.


The remediation of di-(2-ethylhexyl) phthalate-contaminated sediments by water hyacinth biochar activation of calcium peroxide and its effect on cytotoxicity.
The presence of di-(2-ethylhexyl) phthalate (DEHP) in the aquatic systems, specifically marine sediments has attracted considerable attention worldwide, as it enters the food chain and adversely affects the aquatic environment and subsequently human health. This study reports an efficient carbocatalytic activation of calcium peroxide (CP) using water hyacinth biochar (WHBC) toward the efficient remediation of DEHP-contaminated sediments and offer insights into biochar-mediated cellular cytotoxicity, using a combination of chemical and bioanalytical methods. The pyrolysis temperature (300-900 °C) for WHBC preparation significantly controlled catalytic capacity. Under the experimental conditions studied, the carbocatalyst exhibited 94% of DEHP removal. Singlet oxygen (1O2), the major active species in the WHBC/CP system and electron-rich carbonyl functional groups of carbocatalyst, played crucial roles in the non-radical activation of CP. Furthermore, cellular toxicity evaluation indicated lower cytotoxicity in hepatocarcinoma cells (HepG2) after exposure to WHBC (25-1000 μg mL-1) for 24 h and that WHBC induced cell cycle arrest at the G2/M phase. Findings clearly indicated the feasibility of the WHBC/CP process for the restoration of contaminated sediment and contributing to understanding the mechanisms of cytotoxic effects and apoptotic of carbocatalyst on HepG2.


A model-based method for the prediction of the isotopic distribution of peptides.
The process of monoisotopic mass determination, i.e., nomination of the correct peak of an isotopically resolved group of peptide peaks as a monoisotopic peak, requires prior information about the isotopic distribution of the peptide. This points immediately to the difficulty of monoisotopic mass determination, whereas a single mass spectrum does not contain information about the atomic composition of a peptide and therefore the isotopic distribution of the peptide remains unknown. To solve this problem a technique is required, which is able to estimate the isotopic distribution given the information of a single mass spectrum. Senko et al. calculated the average isotopic distribution for any mass peptide via the multinomial expansion (Yergey 1983), using a scaled version of the average amino acid Averagine (Senko et al. 1995). Another method, introduced by Breen et al., approximates the result of the multinomial expansion by a Poisson model (Breen et al. 2000). Although both methods perform well, they have their specific limitations. In this manuscript, we propose an alternative method for the prediction of the isotopic distribution based on a model for consecutive ratios of peaks from the isotopic distribution, similar in spirit to the approach introduced by Gay et al. (1999). The presented method is computationally simple and accurate in predicting the expected isotopic distribution. Further, we extend our method to estimate the isotopic distribution of sulphur-containing peptides. This is important because the naturally occurring isotopes of sulphur have an impact on the isotopic distribution of a peptide.


Petit-High Pressure Carbon Dioxide stress increases synthesis of S-Adenosylmethionine and phosphatidylcholine in yeast Saccharomyces cerevisiae.
Petit-High Pressure Carbon Dioxide (p-HPCD) is a promising nonthermal technology for foods pasteurization. Cluster analysis of gene expression profiles of Saccharomyces cerevisiae exposed to various stresses exhibited that gene expression profile for p-HPCD stress (0.5MPa, 25°C) was grouped into a cluster including profiles for Sodium Dodecyl Sulfate and Roundup herbicide. Both are detergents that can disorder membrane structurally and functionally, which suggests that cell membrane may be a target of p-HPCD stress to cause cell growth inhibition. Through metabolomic analysis, amount of S-Adenosylmethionine (AdoMet) that is used as methyl donor to participate in phosphatidylcholine synthesis via phosphatidylethanolamine (PE) methylation pathway, was increased after p-HPCD treatment for 2h. The key gene OPI3 encoding phospholipid methyltransferase that catalyzes the last two steps in PE methylation pathway was confirmed significantly induced by RT-PCR. Transcriptional expression of genes (MET13, MET16, MET10, MET17, MET6 and SAM2) related to AdoMet biosynthesis was also significantly induced. Choline as the PC precursor and ethanolamine as PE precursor in Kennedy pathway were also found increased under p-HPCD condition. We also found that amounts of most of amino acids involving protein synthesis were found decreased after p-HPCD treatment for 2h. Moreover, morphological changes on cell surface were observed by scanning electron microscope. In conclusion, the effects of p-HPCD stress on cell membrane appear to be a very likely cause of yeast growth inhibition and the enhancement of PC synthesis could contribute to maintain optimum structure and functions of cell membrane and improve cell resistance to inactivation.


CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data.
The CluePedia Cytoscape plugin is a search tool for new markers potentially associated to pathways. CluePedia calculates linear and non-linear statistical dependencies from experimental data. Genes, proteins and miRNAs can be connected based on in silico and/or experimental information and integrated into a ClueGO network of terms/pathways. Interrelations within each pathway can be investigated, and new potential associations may be revealed through gene/protein/miRNA enrichments. A pathway-like visualization can be created using the Cerebral plugin layout. Combining all these features is essential for data interpretation and the generation of new hypotheses. The CluePedia Cytoscape plugin is user-friendly and has an expressive and intuitive visualization. http://www.ici.upmc.fr/cluepedia/ and via the Cytoscape plugin manager. The user manual is available at the CluePedia website.


Allopregnanolone inhibits learning in the Morris water maze.
The progesterone metabolite allopregnanolone (3alpha-OH-5alpha-pregnane-20-one) inhibits neural functions, enhancing the GABA induced GABA(A) receptor activation. This effect is benzodiazepine like and benzodiazepines are known to impair memory. Acute effects of allopregnanolone on the hippocampus dependent spatial learning in the Morris water maze have not been studied. Adult male Wistar rats where injected (i.v.) with allopregnanolone (2 mg/kg), or vehicle, daily for 11 days. At 8 or 20 min after each injection, studies of place navigation were performed in the Morris water maze. Allopregnanolone concentrations in plasma and in nine different brain areas where analyzed by radioimmunoassay. The latency to find the platform was increased 8 min after the allopregnanolone injection, while normal learning was seen after 20 min. Swim speed did not differ between groups. A higher number of rats were swimming close to the pool wall (thigmotaxis) in the 8 min allopregnanolone group compared to the other groups. Allopregnanolone concentrations in the brain tissue at 8 min were 1.5 to 2.5 times higher then at 20 min after the allopregnanolone injections. After vehicle injections the brain concentrations of allopregnanolone were at control levels. Plasma concentrations of allopregnanolone followed the same pattern as in the brain, with the exception of an increase 8 min after vehicle injections. The natural progesterone metabolite allopregnanolone can inhibit learning in the Morris water maze, an effect not caused by motor impairment. The learning impairment might be due to a combination of changed swimming behavior and difficulties in navigation.


Arbuscular mycorrhizal fungi favor invasive Echinops sphaerocephalus when grown in competition with native Inula conyzae.
In a globalized world, plant invasions are common challenges for native ecosystems. Although a considerable number of invasive plants form arbuscular mycorrhizae, interactions between arbuscular mycorrhizal (AM) fungi and invasive and native plants are not well understood. In this study, we conducted a greenhouse experiment examining how AM fungi affect interactions of co-occurring plant species in the family Asteracea, invasive Echinops sphaerocephalus and native forb of central Europe Inula conyzae. The effects of initial soil disturbance, including the effect of intact or disturbed arbuscular mycorrhizal networks (CMNs), were examined. AM fungi supported the success of invasive E. sphaerocephalus in competition with native I. conyzae, regardless of the initial disturbance of CMNs. The presence of invasive E. sphaerocephalus decreased mycorrhizal colonization in I. conyzae, with a concomitant loss in mycorrhizal benefits. Our results confirm AM fungi represent one important mechanism of plant invasion for E. sphaerocephalus in semi-natural European grasslands.


The use of a resuscitation room: a review of current trends.
One hundred consecutive patients treated in the resuscitation room of the Accident and Emergency Department at the Royal Infirmary of Edinburgh were studied and the results were compared with earlier surveys. Half the cases were medical emergencies, which suggests that this should be reflected in the training for specialists in accident and emergency medicine.


Phosphorylation of platelet actin binding protein protects against proteolysis by calcium dependent sulfhydryl protease.
When Actin Binding Protein (ABP) isolated from human blood platelets is phosphorylated in vitro with a cyclic AMP dependent kinase it becomes resistant to proteolysis by the Calcium Dependent Sulfhydryl Protease (CDSP). This protection against proteolytic cleavage is specific for CDSP since phosphorylation of ABP does not protect against proteolysis by trypsin, papain and thermolysin. Thus, there appears to be a distinct phosphorylation site on the ABP molecule which is essential for regulating the initial proteolytic degradation of ABP by CDSP.


Auditory-driven phase reset in visual cortex: human electrocorticography reveals mechanisms of early multisensory integration.
Findings in animal models demonstrate that activity within hierarchically early sensory cortical regions can be modulated by cross-sensory inputs through resetting of the phase of ongoing intrinsic neural oscillations. Here, subdural recordings evaluated whether phase resetting by auditory inputs would impact multisensory integration processes in human visual cortex. Results clearly showed auditory-driven phase reset in visual cortices and, in some cases, frank auditory event-related potentials (ERP) were also observed over these regions. Further, when audiovisual bisensory stimuli were presented, this led to robust multisensory integration effects which were observed in both the ERP and in measures of phase concentration. These results extend findings from animal models to human visual cortices, and highlight the impact of cross-sensory phase resetting by a non-primary stimulus on multisensory integration in ostensibly unisensory cortices.


Clinical implications and optimal extent of lymphadenectomy for intrahepatic cholangiocarcinoma: A multicenter analysis of the therapeutic index.
Lymph node metastases (LNM) are associated with lethal prognosis in intrahepatic cholangiocarcinoma (ICC). Lymphadenectomy is crucial for accurate staging and hopes of possible oncological treatment. However, the therapeutic implications and optimal extent of lymphadenectomy remain contentious. To clarify the prognostic value and optimal extent of lymphadenectomy, the therapeutic index (TI) for each lymph node was analyzed for 279 cases that had undergone lymphadenectomy in a multi-institutional database. Tumor localization was divided into hilar lesions (n = 130), right peripheral lesions (n = 60), and left peripheral lesions (n = 89). In addition, the lymph node station was classified as Level 1 (LV1: hepatoduodenal ligament node), Level 2 (LV2: postpancreatic or common hepatic artery nodes), or Level 3 (LV3: gastrocardiac, left gastric artery, or celiac artery nodes). Lymph node metastases were confirmed in 109 patients (39%). Five-y survival rates were 45.3% for N0 disease, 27.1% for LV1-LNM, 22.9% for LV2-LNM, and 7.3% for LV3-LNM (P < 0.001). LV3-LNM were the most frequent and earliest recurrence outcome, including multisite recurrence, followed by LV2, LV1, and N0 disease. The 5-year TI (5year-TI) for lymphadenectomy was 7.2 for LV1, 5.5 for LV2, and 1.9 for LV3. Regarding tumor location, hilar lesions showed 5-year TI >5.0 in LV1 and LV2, whereas bilateral peripheral lesions showed 5-year TI > 5.0 in LV1. The implications and extent of lymphadenectomy for ICC appear to rely on tumor location. In the peripheral type, the benefit of lymphadenectomy would be limited and dissection beyond LV1 should be avoided, while in the hilar type, lymphadenectomy up to LV2 could be recommended.


Homologous human macrophage hybridomas that produce a novel cytotoxic factor in their culture supernatants.
Homologous human macrophage hybridoma cell lines were obtained by somatic cell fusion between peripheral blood monocyte-derived macrophages and a subclone of the myelomonocytic cell line, U937-F9. The hybridoma cell lines grown in vitro for more than a year were confirmed by manifestations of phagocytosis, adherence, nonspecific esterase, acid phosphatase, chromosome numbers and other cell surface antigens. Cell surface antigens on hybridomas were detected by flow cytometry analysis with monoclonal antibodies. With interclonal differences, a typical phenotype of hybridoma cells was CDw14+, OKM5+, Mac-1+ (equivalent to OKM1 and Mol), OKT9+, HLA-DR- and CD20+. After stimulation with lipopolysaccharide and calcium ionophore A23187, culture supernatants of clones c18A and c29A showed cytotoxic activity against human melanoma A375 Met-Mix and other cell lines which were resistant to the tumor necrosis factor, lymphotoxin and interleukin 1. This cytotoxic factor was found to be distinct from the tumor necrosis factor, lymphotoxin and interleukin 1 using the anti-tumor necrosis factor, anti-lymphotoxin and anti-interleukin 1 antisera.


Innate Immune Molecule Surfactant Protein D Attenuates Sepsis-induced Acute Pancreatic Injury through Modulating Apoptosis and NF-κB-mediated Inflammation.
Sepsis causes multiple-organ dysfunction including pancreatic injury, thus resulting in high mortality. Innate immune molecule surfactant protein D (SP-D) plays a critical role in host defense and regulating inflammation of infectious diseases. In this study we investigated SP-D functions in the acute pancreatic injury (API) with C57BL/6 Wild-type (WT) and SP-D knockout (KO) mice in cecal ligation and puncture (CLP) model. Our results confirm SP-D expression in pancreatic islets and intercalated ducts and are the first to explore the role of pancreatic SP-D in sepsis. CLP decreased pancreatic SP-D levels and caused severe pancreatic injury with higher serum amylase 24 h after CLP. Apoptosis and neutrophil infiltration were increased in the pancreas of septic KO mice (p < 0.05, vs septic WT mice), with lower Bcl-2 and higher caspase-3 levels in septic KO mice (p < 0.05). Molecular analysis revealed increased NF-κB-p65 and phosphorylated IκB-α levels along with higher serum levels of TNF-α and IL-6 in septic KO mice compared to septic WT mice (p < 0.01). Furthermore, in vitro islet cultures stimulated with LPS produced higher TNF-α and IL-6 (p < 0.05) from KO mice compared to WT mice. Collectively, these results demonstrate SP-D plays protective roles by inhibiting apoptosis and modulating NF-κB-mediated inflammation in CLP-induced API.


Thermodynamics of protein-ligand interactions as a reference for computational analysis: how to assess accuracy, reliability and relevance of experimental data.
For a conscientious interpretation of thermodynamic parameters (Gibbs free energy, enthalpy and entropy) obtained by isothermal titration calorimetry (ITC), it is necessary to first evaluate the experimental setup and conditions at which the data were measured. The data quality must be assessed and the precision and accuracy of the measured parameters must be estimated. This information provides the basis at which level discussion of the data is appropriate, and allows insight into the significance of comparisons with other data. The aim of this article is to provide the reader with basic understanding of the ITC technique and the experimental practices commonly applied, in order to foster an appreciation for how much measured thermodynamic parameters can deviate from ideal, error-free values. Particular attention is paid to the shape of the recorded isotherm (c-value), the influence of the applied buffer used for the reaction (protonation reactions, pH), the chosen experimental settings (temperature), impurities of protein and ligand, sources of systematic errors (solution concentration, solution activity, and device calibration) and to the applied analysis software. Furthermore, we comment on enthalpy-entropy compensation, heat capacities and van't Hoff enthalpies.


Non-enzymic post-translational modification of proteins in aging. A review.
Various non-enzymic post-translational changes to proteins occur in vivo and some of these progress with aging. These changes are reviewed and linked to a number of age-related diseases, and to alterations in the charge distribution on protein surfaces. Modification by cyanate and by glucose 6-phosphate causes a partial unfolding of proteins, with loss of tertiary structure but retention of secondary structure. These products are reminiscent of the intermediate state observed during folding and unfolding of some proteins.


[The effect of plasm radiofrequency at low temperature in treatment of chronic rhinitis on nasal airway resistance].
The main purpose of the study is to observe the effect of plasm radiofrequency at low temperature in treatment of chronic rhinitis on nasal airway resistance (NAR). Using active anterior rhinomanometry, NAR were measured in eighty two patients who suffered from chronic rhinitis before and postoperation. The subjective impression of their nasal patency was assessed using a 10-pointscale. The NAR was (0.665 +/- 0.21) kPa /(s x L) before operation and (0.301 +/- 0.16) kPa/(s x L) three months after operation. The NAR was (0.391 +/- 0.24) ten months after operation. The differences were statistically significant (P < 0.01) between the NAR before and postoperation. There were significant differences in the subjective impression of patients' nasal patency as well (P < 0.01). Plasm radiofrequency at low temperature in treatment of chronic rhinitis is effective in decreasing NAR and improving the subjective impression of their nasal patency.


Serum TSH is positively associated with BMI.
To investigate whether there is an association between serum thyroid-stimulating hormone (TSH) within the normal range and body mass index (BMI). The study was performed in 6164 subjects (2813 males) who attended the fifth Tromsø study in 2001, and in 1867 subjects (873 males) that attended both the fourth Tromsø study in 1994/1995 as well as the fifth Tromsø study. Height, weight, and serum TSH were measured in all subjects, and smoking status was recorded. Smokers and nonsmokers were analyzed separately. In the fifth Tromsø study, serum TSH was positively and significantly associated with BMI in the nonsmokers. Within the normal TSH range (defined as the 2.5-97.5 percentile), nonsmoking males in the highest TSH quartile had a mean BMI 0.4 kg/m(2) higher compared to those in the lower quartile, whereas the difference for nonsmoking women was 1.4 kg/m(2). Similarly, in nonsmokers in the longitudinal study, there was a significant and positive association between delta serum TSH (serum TSH in 2001 minus serum TSH in 1994) and delta BMI in those with serum TSH within the normal range both in 1994 and 2001. In these subjects, the quartile with the highest delta serum TSH had a mean increase in BMI from 1994 to 2001 that was 0.3 kg/m(2) higher compared to those in the quartile with the lowest delta serum TSH. For the smokers, relations between serum TSH and BMI were not statistically significant. In nonsmokers there is a positive association between serum TSH within the normal range and BMI.


Care for infants born at 23 weeks gestational age: 5 years' experience from a large medical center.
Assessing parental choice regarding care of infants born at 23 weeks' gestation. Neonatal records review. During 2010-2014, of 26 births (33 infants), 13 families (17 newborns) conceded comfort care only with no survivors, while 13 families (16 babies) requested full medical care and three survived. With birth year, gender, multi-fetal pregnancy, assisted reproductive technology, religious background and specialization of physician counseling at delivery as independent variables, none significantly affected parental decision; yet, that decision impacted outcome. Parental choice regarding infants born at 23 weeks' gestation cannot be predicted from demographics; counseling should concentrate on local experience/outcome.


Carbon Dioxide Blower Facilitates Visceral Pleurectomy in Malignant Pleural Mesothelioma.
Pleurectomy and decortication serves as a major component of therapy for malignant pleural mesothelioma (MPM), but the procedure is time consuming. We tentatively applied a carbon dioxide (CO2) blower into pleurectomy and decortication for a patient with local relapse of MPM. The blower can help increase the potential subpleural place thanks to the positive pressure by CO2, while the mist of saline could clean the potential bleeding to increase visibility. Thereby, the procedure was greatly facilitated in a more precise manner, with blood loss of 100 mL and acceptable postoperative air leak and thorax drainage. Therefore, a CO2 blower may be considered in pleurectomy and decortication for MPM.


Nuclear medicine in the assessment of differentiated thyroid cancer.
Despite modern multi-modality treatment, 10-30% of patients treated for differentiated thyroid cancer (DTC) ultimately develop local recurrence or metastatic disease. These malignancies are frequently slow-growing and secondary surgical resection is often undertaken along with radioactive iodine treatment. Correlation of radiological imaging with nuclear medicine studies is essential for individualized treatment planning, and to optimize this management. Radiologists should be familiar with the interpretation of various nuclear medicine studies used to image differentiated thyroid neoplasms.


Merging base-promoted C-C bond cleavage and iron-catalyzed skeletal rearrangement involving C-C/C-H bond activation: synthesis of highly functionalized carbazoles.
An efficient and atom-economical methodology for the synthesis of multi-substituted carbazoles starting from α-aryl ketones and ynones under mild reaction conditions has been developed. This process goes through Cs2CO3 promoted C-C σ-bond activation of α-aryl ketones followed by highly selective C-H bond activations and C-C bond fragmentations in a one-pot operation.


Integrating HIS-RIS-PACS: the Freiburg experience.
With the integration of different formerly isolated information systems, such as Hospital Information System (HIS). Radiology Information System (RIS), Picture Archiving and Communication System (PACS) and modalities, we evolve towards an architecture of distributed information processing in radiology, the data being stored in distributed databases. The frontier between the cooperative information systems becomes more subtle than in the past, and it seems more convenient to distinguish the different computer functionalities or services used in radiology than to detail the functions of RIS and PACS. This paper opens with a description of the different computer services used in radiology and how they relate one to another. It also shows how these functionalities could be integrated within a global Radiology Information and Archiving System. Finally, it shows the degree of systems interconnection that can be achieved presently, using the PACS-RIS installation at the University Hospital of Freiburg as an example.


PEDOT-AuNPs-based impedimetric immunosensor for the detection of SARS-CoV-2 antibodies.
Electrochemical sensors and biosensors are useful techniques for fast, inexpensive, sensitive, and easy detection of innumerous specimen. In face of COVID-19 pandemic, it became evident the necessity of a rapid and accurate diagnostic test, so the impedimetric immunosensor approach can be a good alternative to replace the conventional tests due to the specific antibody-antigen binding interaction and the fast response in comparison to traditional methods. In this work, a modified electrode with electrosynthesized PEDOT and gold nanoparticles followed by the immobilization of truncated nucleoprotein (N aa160-406aa) was used for a fast and reliable detection of antibodies against COVID-19 in human serum sample. The method consists in analyzing the charge-transfer resistance (RCT) variation before and after the modified electrode comes into contact with the positive and negative serum sample for COVID-19, using [Fe(CN)6]3-/4- as a probe. The results show a linear and selective response for serum samples diluted in a range of 2.5 × 103 to 20 × 103. Also, the electrode material was fully characterized by Raman spectroscopy, transmission electron microscopy and scanning electron microscopy coupled with EDS, indicating that the gold nanoparticles were well distributed around the polymer matrix and the presence of the biological sample was confirmed by EDS analysis. EIS measurements allowed to differentiate the negative and positive samples by the difference in the RCT magnitude, proving that the material developed here has potential properties to be applied in impedimetric immunosensors for the detection of SARS-CoV-2 antibodies in about 30 min.


Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness.
Healthy adults carrying the short (S) allele of the human serotonin transporter gene linked polymorphism (5-HTTLPR) show increased amygdala activation during visual processing of emotionally negative stimuli compared to healthy adults homozygous for the long (L) allele. To determine whether abnormal brain responses during negative emotion appear early in life in S allele carriers, functional magnetic resonance imaging (fMRI) was used to measure brain activity during a transient state of sadness in children carrying the S allele (S group) or homozygous for the L allele (L group). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and sad film excerpts. During the sad condition (relative to the neutral condition), there was significantly greater activation in the S group compared to the L group in brain regions known to be involved in normal sadness and major depression. Given that the 5-HTTLPR polymorphism has been associated with mood disorders, it is plausible that the abnormal pattern of regional brain activity detected here, in children carrying the S allele, increases susceptibility to emotional dysregulation and depressive symptoms.


Systematic pan-cancer analysis identifies RBM39 as an immunological and prognostic biomarker.
RNA-binding Motif Protein39 (RBM39) is identified as a splicing factor and transcription coactivator. Despite mounting evidence that RBM39 plays a critical role in the development of specific malignancies, no systematic pan-cancer investigation of RBM39 has been conducted. As a result, we set out to investigate RBM39's prognostic significance and putative immunological activities in 33 different cancers. Based on TCGA and CCLE, GTEx, cBioportal and HPA, we used a series of bioinformatics approaches to explore the potential oncogenic role of RBM39, including analysis of the expression of the pan-cancer species RBM39, the prognostic relationship between RBM39 expression and overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI), the relationship between RBM39 expression and clinical phenotype, analysis of the relationship between RBM39 expression and tumour mutational burden (TMB), microsatellite instability (MSI), DNA methylation and immune cell infiltration. Our results showed that RBM39 is overexpressed in most cancers. RBM39 was positively or negatively correlated with the prognosis of different tumours. RBM39 expression was associated with TMB and MSI in 9 and 12 cancer types. In addition, RBM39 expression was associated with DNA methylation in almost all tumours. There are eight tumours were screened for further study, including BRCA, COAD, HNSC, LIHC, LUSC, SKCM, STAD, UCEC. In the screed tumours, RBM39 was found to be negatively correlated with the infiltration of most immune cells. In addition, the correlation with RBM39 expression varied by immune cell subtype. Based on RBM39's role in tumorigenesis and tumour immunity, we suggest it can serve as a surrogate prognostic marker.


Source apportionment and risk assessment of polycyclic aromatic hydrocarbons in the atmospheric environment of Alexandria, Egypt.
In this study, three receptor models [factor analysis/multiple linear regression (FA/MLR), positive matrix factorization (PMF) and UNMIX] were applied seasonally to investigate the source apportionment of PAHs in the atmospheric environment of Alexandria, and a lifetime cancer risk was assessed. ∑44 (gas+particle) PAH concentrations varied from 330 to 1770ngm(-3) and 170-1290ngm(-3) in the summer and winter seasons respectively. PAH concentrations at the industrial sites were significantly higher than at the traffic and residential sites during the winter season (p<0.001). Summer PAH concentrations were significantly higher than the winter season at the traffic sites (p=0.027). Results obtained from the three receptor models were comparable. Vehicle emissions, both diesel and gasoline contributed on average 36.0-49.0% and 19.0-34.0% respectively, natural gas combustion 11.0-27.0% and, during the summer only, also evaporative/uncombusted petroleum sources 8.00-18.0%. Seasonal trends were found for the gasoline emission source. Overall, PMF and UNMIX models afforded better source identification than did FA/MLR. The lifetime cancer risk assessment showed that incremental lifetime cancer risks (ILTCRs) were greater than the acceptable level of 10(-6) through dermal and ingestion routes at all the investigated sites and through the inhalation route at the industrial and traffic sites only. Total ILTCRs (6.64×10(-3)-4.42×10(-2)) indicated high potential risks to the local residents.


Vasculitis in 2011: the renaissance of granulomatous inflammation in AAV.
In 2011, the year that subtypes of ANCA-associated vasculitis (AAV) were officially renamed according to key pathological characteristics, important progress was made not only in differentiating these subtypes, but also in understanding—and treating—their eponymous manifestations.


Developmental differences in the neural oscillations underlying auditory sentence processing in children and adults.
Although very young children seem to process ongoing language quickly and effortlessly, neuroimaging and behavioral studies reveal that children continue to mature in their language skills through adolescence. During this prolonged development, children likely engage the same basic cognitive processes and neural mechanisms to perform language tasks as adults, but in somewhat different ways. In this study we used time frequency analysis of EEG to identify developmental differences in the engagement of neural oscillations between children (ages 10-12) and adults while listening to naturally-paced sentences. Adults displayed consistent beta changes throughout the sentence compared to children, thought to be related to efficient syntactic integration, and children displayed more broadly distributed theta changes than adults, thought to be related to more effortful semantic integration. Few differences in alpha, related to verbal working memory, existed between groups. These findings shed new light on developmental changes in the neuronal processes underlying language comprehension.


Identification of diarrheagenic Escherichia coli by a new multiplex PCR assay and capillary electrophoresis.
Diarrheagenic Escherichia coli (DEC) is a set of the most common pathogens causing diarrhea. DEC strains are classified into five pathotypes based on the possession of different virulence genes: enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC) or Shiga toxin-producing E. coli (STEC), enteroaggregative E. coli (EAEC), enterotoxigenic E. coli (ETEC), and enteroinvasive E. coli (EIEC). The development of an easy-to-use method to detect the specific virulence genes and distinguish the pathotypes is essential for the diagnosis and surveillance of DEC infections. In this study, a multiplex PCR assay (mPCR) specific to nine virulence genes and an internal control was designed for the identification of five DEC pathotypes. A temperature switch PCR (TSP) strategy was used in the PCR amplification. The PCR products were detected by capillary electrophoresis. The limit of detection (LOD) of the 10-plex reaction was 5 × 103 copies/reaction for stx2 and 5 × 102 copies/reaction for the other targets. The mPCR showed very high specificity, and inclusivity and exclusivity were both 100%. When the mPCR assay was used for the detection of 221 cryopreserved diarrhea specimens, DEC colonies were detected from 49 specimens, and the positive rate was 22.2%. The mPCR assay was sensitive and specific, and the amplified product could be analyzed easily. Thus, this method could be used effectively to identify the suspected colonies of DEC in the primary culture of the specimen.


Surgical complications of pars plana vitreous surgery.
Evaluation of 200 consecutive pars plana vitrectomies shows delayed corneal epithelial healing after intentional scraping and formation of a posterior subcapsular cataract, presumably due to exposure to inadequate infusion fluids. Posterior retinal holes occur frequently, whereas entrance site complications have been reduced to an acceptable minimum. Temporary rise in intraocular pressure is common.


Prompt and delayed NAA techniques for the characterization of specimen bank materials.
The combined application of instrumental-, radiochemical- and prompt gamma neutron activation analysis to two spruce shoot materials from the German Environmental Specimen Bank (ESB) resulted in information on 50 elements, covering more than 50% of the total mass. Comparison of the element concentrations in the 'fingerprint' mode clearly indicated a different status of heavy metal pollution at the two distinct collecting sites.


Photosynthetic characteristic of South African sclerophylls.
Sclerophyll shrubs of the South African mountain fynbos have leaves similar in structural and physiological properties to leaves from evergreen shrubs of other mediterranean-climate regions. These leaves have relatively low photosynthetic capacities (<14 μmol CO2 m-2 s-1), and are light saturated at relatively low photon irradiances (<1.0 mmol m-2 s-1). They have broad temperature responses of photosynthesis, moderate water-use efficiencies (∼0.003 mol CO2/mol H2O), high specific weights (∼200 g m-2) and low nitrogen contents (∼10 mg g-1).


Exposure to2,2',4,4'-tetrabromodiphenyl ether (BDE-47) alters thyroid hormone levels and thyroid hormone-regulated gene transcription in manila clam Ruditapes philippinarum.
Polybrominated diphenyl ethers (PBDEs) have the potential to disturb the thyroid endocrine system in vertebrates, but little is known about the disruptive effects of PBDEs on marine bivalves. In this study, we first examined the effects of BDE-47 exposure on growth of juvenile manila clams Ruditapes philippinarum. The result showed that 1.0 and 10 μg L(-1) BDE-47 had adverse effects on 14-d shell-length growth of juvenile clams. Then, one-year-old adult clams were exposed to 0, 0.1 and 1 μg L(-1) BDE-47 for 15 d. BDE-47 (1 μg L(-1)) exposure caused significant decreases of total T4 (thyroxine) by 40% and T3 (3,5,3'-triiodothyronine) by 75% concentrations in haemolymph of the clams. Transcription of genes involved in thyroid hormone synthesis and metabolism were also studied by quantitative RT-PCR. Gene expression levels of sodium iodide symporter (rp-NIS), iodothyronine deiodinase (rp-Deio) and thyroid peroxidase (rp-TPO) were increased in a dose-dependent manner at day 5 and day 10, while monocarboxylate transporter 8 (rp-Mct8) was downregulated at day 5, day 10 and day 15. The effect and preliminary mechanism observed in the present study were consistent with the results from previous studies on rodent and fish, implying that exposure to BDE-47 may pose threat to thyroid hormone homeostasis in bivalves through thyroid synthesis and metabolism pathways. This study may provide a first step towards understanding of the thyroid function disruptive effects of PBDEs on marine bivalves and the underlying mechanism across taxonomic groups and phyla.


The effects of anesthesia methods and anesthetics on postoperative delirium in the elderly patients: A systematic review and network meta-analysis.
Postoperative delirium (POD) is one of the serious postoperative complications in elderly patients, which is always related to long-term mortality. Anesthesia is often considered a risk factor for POD. This systematic review and network meta-analysis (NMA) aimed to assess the impact of different anesthesia methods and anesthetics on POD. We searched for studies published in PubMed, Embase, Web of Science, Scopus, and Cochrane Library (CENTRAL) from inception to 18 March 2022. RevMan 5.3 and CINeMA 2.0.0 were used to assess the risk of bias and confidence. Data analysis using STATA 17.0 and R 4.1.2. STATA 17.0 was used to calculate the surface under the cumulative ranking curve (SUCRA) and provide network plots with CINeMA 2.0.0. NMA was performed with R 4.1.2 software gemtc packages in RStudio. This NMA included 19 RCTs with 5,406 patients. In the pairwise meta-analysis results, only regional anesthesia (RA) with general anesthesia (GA) vs. GA (Log OR: -1.08; 95% CI: -1.54, -0.63) were statistically different in POD incidence. In the NMA results, there was no statistical difference between anesthesia methods, and psoas compartment block (PCB) with bupivacaine was superior to the desflurane, propofol, sevoflurane, and spinal anesthesia with bupivacaine of POD occurrence. Our study indicated that RA and GA had no significant effect on POD, and there was no difference between anesthesia methods. Pairwise meta-analysis showed that, except for RA with GA vs. GA, the rest of the results were not statistically different. Besides, PCB with bupivacaine may benefit to reduce POD incidence. https://www.crd.york.ac.uk/prospero/dis play_record.php?ID=CRD42022319499, identifier PROSPERO 2022 CRD42022319499.


Thrombolysis in acute lower limb ischaemia.
For the past three decades balloon embolectomy has been the treatment of choice for acute lower limb occlusion. However, although usually successful in emboli, results are often disappointing in thrombotic atherosclerotic vessels. Attempted dissolution of the clot is accordingly attractive, and has theoretically been possible since the introduction of streptokinase in 1933. This was initially used intravenously, with variable success rates, although intraarterial administration is currently the method of choice. Later thrombolytic drugs such as tissue plasminogen activator, urokinase and anistreplase have been introduced. Lysis time has also been increased by using pharmaco-mechanical methods of administration such as pulsed spray catheters, which could increase the usefulness of thrombolysis in patients with rapidly progressive neurological signs where currently surgical embolectomy would be advocated. Several newer drugs with theoretical advantages over older drugs such as single-chain urokinase-type plasminogen activator or K1K2PU are currently undergoing trials. The role of thrombolysis as an adjunct to surgical embolectomy is also promising, though again requires further trials. There is still no consensus as to which patients are best suited to thrombolysis, nor an optimum drug or method of administration. However, there seems no doubt that thrombolysis will be increasingly used in the management of peripheral limb ischaemia, though requiring a team approach between surgeons, radiologists and haematologists.


Revisiting the concept of 'chronic disease' from the perspective of the episode of care model. Does the ratio of incidence to prevalence rate help us to define a problem as chronic?
This is a study of the epidemiology of acute and chronic episodes of care (EoCs) in the Transition Project in three countries. We studied the duration of EoCs for acute and chronic health problems and the relationship of incidence to prevalence rates for these EoCs. The Transition Project databases collect data on all elements of the doctor-patient encounter in family medicine. Family doctors code these elements using the International Classification of Primary Care. We used the data from three practice populations to study the duration of EoCs and the ratio of incidence to prevalence for common health problems. We found that chronic health problems tended to have proportionately longer duration EoCs, as expected, but also a lower incidence to prevalence rate ratio than acute health problems. Thus, the incidence to prevalence index could be used to define a chronic condition as one with a low ratio, below a defined threshold. Chronic health problems tend to have longer duration EoCs, proportionately, across populations. This result is expected, but we found important similarities and differences which make defining a problem as chronic on the basis of time rather difficult. The ratio of incidence to prevalence rates has potential to categorise health problems into acute or chronic categories, at different ratio thresholds (such as 20, 30 or 50%). It seems to perform well in this study of three family practice populations, and is proposed to the scientific community for further evaluation.


Serum soluble α-Klotho levels in patients with diabetic nephropathy.
The study aimed to determine the variability in the stages of diabetic nephropathy by examining specific biochemical functions associated with the target organ. As a result, various biochemical parameters were assessed in all of the groups under investigation. These parameters encompassed soluble α-Klotho and serum insulin, which were determined through ELISA. Additionally, spectrophotometric methods were employed to assess other parameters such as blood levels of urea in all groups. Instead of using HPLC method, HbA1c levels were determined. Blood and urine samples were obtained from a total of 90 participants, who were aged between 37 and 70 years. A total of 70 patients were categorized into three groups according to their ACR. The first group consisted of patients with an ACR value of less than 30 mg/g. The second group included patients with an ACR value ranging from 30 to 300 mg/g. The third group comprised patients with an ACR value greater than 300 mg. Additionally, the study also involved 20 healthy individuals. The serum soluble α-Klotho in the patient group was significantly lower than that of the healthy subjects. There were strong negative correlations between serum soluble α-Klotho and both ACR and HOMA-IR. The AUC value was excellent, measuring at 0.93 with a p < 0.0001. Soluble α-Klotho levels in the sera of diabetic patients were shown to be lower and significantly linked to patients with diabetic nephropathy. This implies that klotho levels may be influenced by ACR in addition to playing a significant role in insulin resistance.