Early-life galacto-oligosaccharides supplementation alleviates the small intestinal oxidative stress and dysfunction of lipopolysaccharide-challenged suckling piglets.
Galacto-oligosaccharides (GOS) are non-digestible food ingredients that promote the growth of beneficial bacteria in the gut. This study investigated the protective effect of the early-life GOS supplement on the piglets' gut function against the oxidative stress induced by lipopolysaccharide (LPS)-challenge. Eighteen neonatal piglets were assigned to three groups including CON, LPS and LPS + GOS groups. The piglets in CON group and LPS group received physiological saline, while those in LPS + GOS group received GOS solution for 13 d after birth. On d 14, the piglets in LPS group and LPS + GOS group were injected with LPS solutions, while the piglets in CON group were injected with the same volume of physiological saline. The results showed that the early-life GOS supplement blocked the LPS-induced reactive oxygen species (ROS) secretion, malondialdehyde (MDA) production and the increase of pro-apoptotic factor expression. Meanwhile, the early-life GOS supplement improved the activities of antioxidant enzymes, disaccharidase enzymes activities, and digestive enzymes activities, and increased the mRNA abundance of the gene related to nutrient digestion and absorption and the relative protein expression of tight junction. The study also showed that the early-life GOS supplement improved the expression of Hemeoxygenase-1 (HO-1) and NAD(P)H/quinone acceptor oxidoreductase-1 (NQO-1), and activated the AMP-activated protein kinase (AMPK). These results suggested that GOS enhanced the gut function, reduced the ROS production and pro-apoptotic factors gene expression, and activated the AMPK signaling pathway in LPS-challenged piglets.


Relationship between maladaptive cognitions about sleep and recovery in patients with borderline personality disorder.
Borderline personality disorder (BPD) has been associated with maladaptive cognitive processes including dysfunctional attitudes and a negative attribution style. Comorbid insomnia affects the course of multiple psychiatric disorders, and has been associated with the absence of recovery from BPD. Because dysfunctional beliefs and attitudes are common among patients with insomnia, the purpose of this study was to evaluate the association between maladaptive sleep-related cognitions and recovery status (symptomatic remission plus good concurrent psychosocial functioning) in patients with BPD. Two hundred and twenty three BPD patients participating in the McLean Study of Adult Development (MSAD) were administered the Dysfunctional Beliefs and Attitudes about Sleep questionnaire (DBAS-16) as part of the 16-year follow-up wave. Maladaptive sleep cognitions were compared between recovered (n=105) and non-recovered (n=118) BPD participants, in analyses that adjusted for age, sex, depression, anxiety, and primary sleep disorders. Results demonstrated that non-recovered BPD patients had significantly more severe maladaptive sleep-related cognitions as measured by the overall DBAS-16 score. These results demonstrate an association between dysfunctional beliefs and attitudes about sleep and recovery status among BPD patients. Further research is warranted to evaluate treatments targeted towards maladaptive sleep-related cognitions, and their subsequent effects on the course of BPD.


Nanomechanical characterization of exosomes and concomitant nanoparticles from blood plasma by PeakForce AFM in liquid.
To date, EVs characterization techniques are extremely diverse. The contribution of AFM, in particular, is often confined to size distribution. While AFM provides a unique possibility to carry out measurements in situ, nanomechanical characterization of EVs is still missing. Blood plasma EVs were isolated by ultracentrifugation, analyzed by flow cytometry and NTA. Followed by cryo-EM, we applied PeakForce AFM to assess morphological and nanomechanical properties of EVs in liquid. Nanoparticles were subdivided by their size estimated for their suspended state into sub-sets of small S1-EVs (< 30 nm), S2-EVs (30-50 nm), and sub-set of large ones L-EVs (50-170 nm). Non-membranous S1-EVs were distinguished by higher Young's modulus (10.33(7.36;15.25) MPa) and were less deformed by AFM tip (3.6(2.8;4.4) nm) compared to membrane exosomes S2-EVs (6.25(4.52;8.24) MPa and 4.8(4.3;5.9) nm). L-EVs were identified as large membrane exosomes, heterogeneous by their nanomechanical properties (22.43(8.26;53.11) MPa and 3.57(2.07;7.89) nm). Nanomechanical mapping revealed a few non-deformed L-EVs, of which Young's modulus rose up to 300 MPa. Taken together with cryo-EM, these results lead us to the suggestion that two or more vesicles could be contained inside a large one being a multilayer vesicle. We identified particles similar in morphology and showed differences in nanomechanical properties that could be attributed to the features of their inner structure. Our results further elucidate the identification of EVs and concomitant nanoparticles based on their nanomechanical properties.


2-(2,4-Di-chloro-phen-oxy)-N'-[2-(2,4-di-chloro-phen-oxy)acet-yl]acetohydrazide.
The complete mol-ecule of the title compound, C16H12Cl4N2O4, is generated by a crystallographic centre of symmetry. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into [010] chains featuring R 2 2(10) loops. The chains are cross-linked by short Cl⋯N contacts [3.224 (2) Å].


N-Acetyltransferase 2 (NAT2) genetic variation and the susceptibility to noncardiac gastric adenocarcinoma in Taiwan.
N-Acetyltransferase (NAT) is an important enzyme with the capacity to metabolize carcinogenic aromatic amines. However, it remains controversial whether the encoded functional NAT2 genetic polymorphism is related to the risk of gastric adenocarcinoma (GA). The aim of this study was to evaluate the association between NAT2 genetic variation and gastric adenocarcinoma (GA), with special reference to the gastric noncardiac adenocarcinoma (GNA). Peripheral white blood cell DNA from 368 GA patients and 368 age- and sex-matched controls were genotyped for NAT2 by a polymerase chain reaction method. The lifestyle habits of the participants were assessed using a semiquantitative food-frequency questionnaire. NAT2 genotype, interaction with lifestyle habits, and the risk of GA and GNA were analyzed by logistic regression. GA patients were more likely to have a smoking habit, ate more salted foods, and consumed more well-done meat than the controls. There was no association between the NAT2 genotypes and susceptibility to GA. However, if patients with gastric cardiac adenocarcinoma (GCA; n = 42) were excluded, the NAT2 slow acetylators (without rapid acetylator allele) had a higher risk of GA than intermediate and rapid acetylators (odds ratio = 1.53; 95% confidence interval, 1.05-2.23, p = 0.027). In addition, there was a synergic effect of NAT2 slow acetylator and well-done meat intake to the development of GNA (odds ratio = 3.83; 95% confidence interval, 1.68-8.76, p = 0.001). NAT2 slow acetylators have a higher risk of GNA than intermediate and rapid acetylators have in a Taiwanese population. The intake of well-done meat, an additive to the acetylator status, may contribute to the incidence of gastric carcinogenesis.


Single-Ion-Conducting Hydrogel Electrolytes Based on Slide-Ring Pseudo-Polyrotaxane for Ultralong-Cycling Flexible Zinc-Ion Batteries.
Flexible zinc-ion batteries (ZIBs) with high capacity and long cycle stability are essential for wearable electronic devices. Hydrogel electrolytes have been developed to provide ion-transfer channels while maintaining the integrity of ZIBs under mechanical strain. However, hydrogel matrices are typically swollen with aqueous salt solutions to increase ionic conductivity, which can hinder intimate contact with electrodes and reduce mechanical properties. To address this, a single-Zn-ion-conducting hydrogel electrolyte (SIHE) is developed by integrating polyacrylamide network and pseudo-polyrotaxane structure. The SIHE exhibits a high Zn2+ transference number of 0.923 and a high ionic conductivity of 22.4 mS cm-1 at room temperature. Symmetric batteries with SIHE demonstrate stable Zn plating/stripping performance for over 160 h, with a homogenous and smooth Zn deposition layer. Full cells with La-V2 O5 cathodes exhibit a high capacity of 439 mA h g-1 at 0.1 A g-1 and excellent capacity retention of 90.2% after 3500 cycles at 5 A g-1 . Moreover, the flexible ZIBs display stable electrochemical performance under harsh conditions, such as bending, cutting, puncturing, and soaking. This work provides a simple design strategy for single-ion-conducting hydrogel electrolytes, which could pave the way for long-life aqueous batteries.


Zein-maltodextrin nanocomplex based dissolving microneedle: A promising approach for Paliperidone palmitate delivery.
Researchers are looking at microneedle devices as a possible solution to the problems with poor patient compliance and severe gastrointestinal side effects associated with conventional oral or injectable techniques for treating schizophrenia. Microneedles (MNs) may be an effective approach for transdermal drug delivery of antipsychotic drugs. We fabricated polyvinyl alcohol (PVA) microneedles loaded with paliperidone palmitate (PLDN) nanocomplex and studied their therapeutic potency for schizophrenia. We demonstrated that PLDN nanocomplex-loaded MNs had a pyramidal shape with high mechanical strength, which allowed us to successfully deliver PLDN into the skin and improve permeation behavior ex-vivo. Microneedling enhanced the concentration of PLDN in plasma and brain tissue as compared with the plain drug as observed. In addition, the therapeutic effectiveness was significantly improved by MNs with the capability of extended release. According to the findings of our study, the nanocomplex-loaded microneedle-mediated transdermal delivery of PLDN has the potential to be a novel treatment for schizophrenia.


The Influence of Fasting and Energy Restricting Diets on Blood Pressure in Humans: A Systematic Review and Meta-Analysis.
To the best of our knowledge, no comprehensive meta-analysis has been carried out to investigate the effect of different approaches of fasting and calorie restriction on blood pressure. AIM: Thus, the present systematic review and meta-analysis was designed to examine the effect of fasting and energy restricting diets on blood pressure in adult subjects. We searched PubMed/Medline, Scopus, the Cochrane Library, and Google Scholar up to June 2019. The clinical trials that examined the effects of fasting and energy restricting diets on Blood Pressure was identified using MESH and non-MESH terms. 23 studies, including a total of 1397 participants, reported SBP and DBP as an outcome measure. Overall results from the random-effects model indicated that fasting and energy restricting administration elicited significant changes in SBP (weight mean difference (WMD): - 1.88 mmHg, 95% CI - 2.50, - 1.25) and DBP (WMD - 1.32 mmHg, 95% CI - 1.81, - 0.84, p = 0.000). Subgroup analyses displayed that intervention duration ≤ 12 weeks more effectively reduced SBP (WMD: -3.26 mmHg) and DBP (WMD - 1.32 mmHg). In addition, these analyses showed that fasting regimens (WMD - 3.26 mmHg) more effectively reduced SBP than energy restricting diets (WMD - 1.09 mmHg). The principal finding of this study was that fasting and energy restricting diets elicited, overall, significant reductions in SBP and DBP. Subsequent subgroup analyses revealed that intervention duration ≤ 12 weeks and fasting regimens more effectively reduced SBP and DBP.


Kishenehna prima, a new genus and species of darner dragonfly (Odonata, Aeshnidae, Gomphaeschninae) from the early middle Eocene Kishenehn Formation of Montana, USA.
We describe the darner dragonfly Kishenehna prima n. gen. and sp. (Odonata, Aeshnidae, Gomphaeschninae) based on a well-preserved, nearly complete female hind wing from the Lutetian Coal Creek Member of the Kishenehn Formation, northwestern Montana, USA. Kishenehna is morphologically close to the late Paleocene genus Alloaeschna Wighton Wilson of Alberta, Canada. This is the first dragonfly (Anisoptera) described from the Kishenehn Formation and the first from the Lutetian of the Western Hemisphere.


Relative changes in the cochlear summating potentials to paired-clicks predict speech-in-noise perception and subjective hearing acuity.
Objective assays of human cochlear synaptopathy (CS) have been challenging to develop. It is suspected that relative summating potential (SP) changes are different in listeners with CS. In this proof-of-concept study, young, normal-hearing adults were recruited and assigned to a low/high-risk group for having CS based on their extended audiograms (9-16 kHz). SPs to paired-clicks with varying inter-click intervals isolated non-refractory receptor components of cochlear activity. Abrupt increases in SPs to paired- vs single-clicks were observed in high-risk listeners. Critically, exaggerated SPs predicted speech-in-noise and subjective hearing abilities, suggesting relative SP changes to rapid clicks might help identify putative synaptopathic listeners.


Lung mitochondria in experimental asbestosis.
Alterations in lung mitochondria were followed in guinea pigs at different periods after a single intratracheal injection of chrysotile dust. Cytochrome c oxidase and succinic dehydrogenase activities showed gradual increase after 90 days, whereas monoamine oxidase remained unaffected throughout the study. There was an increase in glutamate dehydrogenase activity in postmitochondrial as well as in mitochondrial fractions, the latter being accompanied by decreased latency of the enzyme. Mitochondria from asbestotic lung appeared to be more swollen than in normal animals at and after 90 days of exposure. There were fluctuations in the contents of different phospholipids as a result of asbestosis. Beyond 90 days, collagen and mucopolysaccharides also increased. The results confirm the contention that pulmonary mitochondria are among the major target sites in asbestosis.


Phylogenetic analysis of Human papillomavirus 16 variants isolated from Indian Breast cancer patients showed difference in genetic diversity with that of cervical cancer isolates.
The genetic variations of HPV16 in Breast Cancer (BC) are not well studied unlike HPV16 in Cervical Cancer (CACX). In this study, the genetic variations of HPV16 in BC were compared with HPV16 in CACX. In sequencing analysis of LCR, E6 and E7 regions of HPV16 in BC and CACX the A lineage was seen to be 64.2% and 66.6% respectively. The other lineages showed differential frequency in BC and CACX. The mutation frequency index of the regions in BC and CACX was in the following order: LCR>E6>E7. However, the inter-patient genetic diversity in LCR and E6/E7 regions was high in BC than CACX. The LCR region showed more variations than the E6/E7 region in BC. Apart from some common variations, some unique tissue specific variants in LCR and E6/E7 region were seen in BC and in CACX. Besides the selection of some common variants in both BC and CACX, some unique variants in BC (D98Y; 395 G>T) and CACX (R48W; 245 G>T) were observed. The 7521 G>A variant of LCR showed association with Luminal B subtype of BC and progression of CACX. Whereas, 145 G>T (Q14H) and 335 C>T (H78Y) variants of E6 showed association with either early invasiveness of BC and/or poor outcome of the patients. Thus, this study indicates that there may be a difference in the genetic variation of HPV16 in BC and in CACX.


Combining climatic and soil properties better predicts covers of Brazilian biomes.
Several techniques have been used to model the area covered by biomes or species. However, most models allow little freedom of choice of response variables and are conditioned to the use of climate predictors. This major restriction of the models has generated distributions of low accuracy or inconsistent with the actual cover. Our objective was to characterize the environmental space of the most representative biomes of Brazil and predict their cover, using climate and soil-related predictors. As sample units, we used 500 cells of 100 km2 for ten biomes, derived from the official vegetation map of Brazil (IBGE 2004). With a total of 38 (climatic and soil-related) predictors, an a priori model was run with the random forest classifier. Each biome was calibrated with 75% of the samples. The final model was based on four climate and six soil-related predictors, the most important variables for the a priori model, without collinearity. The model reached a kappa value of 0.82, generating a highly consistent prediction with the actual cover of the country. We showed here that the richness of biomes should not be underestimated, and that in spite of the complex relationship, highly accurate modeling based on climatic and soil-related predictors is possible. These predictors are complementary, for covering different parts of the multidimensional niche. Thus, a single biome can cover a wide range of climatic space, versus a narrow range of soil types, so that its prediction is best adjusted by soil-related variables, or vice versa.


Microbial indicators in municipal solid waste compost and their fate after land application of compost.
Despite the extensive agricultural use of municipal solid waste (MSW) compost, there is little information about microbial characteristics of the MSW compost and fate of microorganisms following land application. This study was designed to determine the microbial quality and germination index (GI) of the MSW compost as well as fate of indicator microorganisms after application of MSW compost. The results showed a high fraction of samples are immature (GI < 80). In 27% and 16% of samples fecal coliforms and Salmonella were detected in a range exceeding the recommended value for unrestricted application of compost, respectively. HAdV was also detected in 62% of samples. Fecal enterococci were detected with relatively high concentrations in all samples and showed higher survival rate than other indicators in land-applied MSW compost. The results showed that climate condition significantly contributed to the decline of indicator bacteria in land-applied compost. The results highlight the need for further quality monitoring of compost to ensure that its application does not lead to environmental or human health problems. Furthermore, because of the high concentrations and high survival rate of enterococci in compost samples, they can be specifically proposed as an indicator microorganism for MSW compost quality monitoring.


Genetic and environmental mouse models of autism reproduce the spectrum of the disease.
Genetic and environmental factors increase autism spectrum disorder (ASD) incidence, and this has led to the generation of corresponding animal models, with some showing strong construct and face validity. This short review focuses on results we have recently obtained with environmental and genetic mouse models of ASD and that are the valproic acid, the poly I:C and the Shank 3 models. This has allowed us to provide a comparative description of these widely used animal models providing an interesting perspective as to the pros and cons of each one of them, in our experimental settings. In these papers, we focused on motor and gait disorders which are currently not included in the diagnosis criteria, but which may provide new insights to ASD pathophysiology potentially leading to innovative therapies for a disease that currently has none. In all these models, we reported behavioral, cellular and molecular alterations related to the cerebellum. Motor and gait deficits were observed to various degrees in animal models and, when strongly present, they were correlated to the severity of social deficits as well as to the number of cerebellar Purkinje cells. Additionally, we also reported that, like in humans, males are more severely affected than females in these ASD models. These findings, along with an increasing body of literature, open new hopes in the ASD field pointing to brain regions, such the cerebellum, that are at the crossroads between cognitive, social and motor deficits. Targeting these brain regions and their underlying pathways and synaptic connections may prove of significant benefits.


IDO induction in IFN-gamma activated astroglia: a role in improving cell viability during oxidative stress.
In the central nervous system (CNS), astrocytes play an integral role in the maintenance of neuronal viability and function. Inflammation within the CNS increases the concentration of oxidative metabolites and, therefore, the potential for NAD depletion through increased poly-(ADP-ribose) polymerase (PARP) activity. However, the activity of indoleamine 2,3-dioxygenase (IDO), the rate limiting enzyme for de novo NAD synthesis, is also markedly increased in astrocytes during inflammation. This study investigated the role of IDO induction in the maintenance of intracellular NAD and its relationship to improved cell viability under conditions of increased oxidative stress in the human astroglioma cell line, HTB-138. Treatment with the pro-inflammatory cytokine IFN-gamma increased IDO activity in these cells. Intracellular NAD levels also increased significantly after treatment with IFN-gamma in the presence of a PARP inhibitor. Pretreatment of astroglial cells with IFN-gamma significantly moderated both the drop in intracellular NAD concentration and cell death following exposure to hydrogen peroxide. These results suggest that induction of IDO and subsequent de novo NAD synthesis may contribute to the maintenance of intracellular NAD levels and cell viability under conditions of increased oxidative stress.


Comparative modelling of mono- and dinitrophenols sorption on yellow bentonite from aqueous solutions.
Equilibrium removal of three substituted nitrophenols, namely 2-nitrophenol (2-NP), 4-nitrophenol (4-NP), and 2,4-dinitrophenol (2,4-DNP), by adsorption on yellow bentonite was tested. The batch kinetic data are described by the pseudo-first order, pseudo-second order, and intraparticle diffusion models. Results show that chemisorption processes could be rate limiting in the sorption step. The adsorption equilibrium was modelled by the Langmuir and Freundlich equations. The Langmuir model better represents the equilibrium isotherm data for 2-NP, 4-NP, and 2,4-DNP uptake on yellow bentonite. 4-NP is adsorbed in larger amounts than the disubstituted nitrophenol. Uptake of nitrophenols increases in the order 2-NP < 2,4-DNP < 4-NP.


Complement component C1q is an immunological rheostat that regulates Fc:Fc[Formula: see text]R interactions.
Though binding sites for the complement factor C1q and the canonical fragment crystallizable (Fc) gamma receptors (Fc[Formula: see text]Rs) on immunoglobulin G (IgG) molecules overlap, how C1q decoration of immune complexes (ICs) influences their ability to engage Fc[Formula: see text]Rs remains unknown. In this report, we use recombinant human Fc multimers as stable IC mimics to show that C1q engagement of ICs directly and transiently inhibits their interactions with Fc[Formula: see text]RIII (CD16) on human natural killer (NK) cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors. Furthermore, the inhibition of Fc[Formula: see text]RIII engagement mediated by avid binding of C1q to ICs is directly associated with IC size and dependent on the concentrations of both C1q and Fc multimers present. Functionally, C1q-mediated Fc blockade limits the ability of NK cells to induce the upregulation of the cosignaling molecule, 4-1BB (CD137), and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Although C1q is traditionally viewed as a soluble effector molecule, we demonstrate that C1q may also take on the role of an "immunologic rheostat," buffering Fc[Formula: see text]R-mediated activation of immune cells by circulating ICs. These data define a novel role for C1q as a regulator of immune homeostasis and add to our growing understanding that complement factors mediate pleiotropic effects.


Delayed-type hypersensitivity response to crude and fractionated antigens from Fonsecaea pedrosoi CMMI 1 grown in different culture media.
Chromoblastomycosis is a subcutaneous fungal disease caused by dematiaceous fungi, especially by Fonsecaea pedrosoi, regarded as its major causative agent in Brazil. In recent years there has been a decline in the use of skin testing for delayed-type hypersensitivity (DTH) in epidemiological surveys of fungal infections, mainly because of the unpredictability of positive reactions and lack of specificity of the antigens used. The aim of the present study was to assess delayed-type skin tests in guinea pigs experimentally infected with F. pedrosoi using exoantigens prepared from two culture filtrates. Sixteen adult male guinea pigs were inoculated intratesticularly with fungal cells and submitted to sensitivity assays 4 weeks after inoculation. They received an intradermal injection with crude and fractionated antigens from Alviano's and Smith's cultures, and were assessed 24 and 48 h thereafter. Except for one animal, all of them had positive indurations after 48 h. There were no statistical differences between the measurements at 24 and 48 h for each exoantigen used, neither among the induration measurements at 48 h when different preparations were compared. Our results suggest that a delayed-type skin test using antigens produced in synthetic media may be useful for the assessment of primary exposure to chromoblastomycosis.


Impact of the exercise mode on heart rate recovery after maximal exercise.
Heart rate recovery 1 min after exercise termination (HRR-1) is a prognostic predictor. However, the influence of the exercise mode on HRR-1 is incompletely characterised. Twenty-nine young and healthy subjects and 16 elderly patients with chronic heart failure underwent cardiopulmonary exercise testing using cycle ergometer and treadmill ramp protocols in random order. HRR-1 and heart rate recovery 2 and 3 min after exercise (HRR-2, HRR-3) during active recovery and peak oxygen consumption (peak VO(2)) were measured. In both healthy subjects (32 +/- 14 vs. 27 +/- 10 bpm) and HF patients (19 +/- 8 vs. 14 +/- 9 bpm), HRR-1 was faster after cycle exercise (p = 0.029; p for between group difference 0.94). In contrast, HRR-2 and HRR-3 were similar after both tests in both groups. Peak VO(2) was lower during cycle as compared to treadmill exercise in both groups. In conclusion, in both healthy subjects and HF patients, HRR-1 depends on the mode of exercise as peak VO(2) does.


Accumulation of blood platelets in carrageenin rat paw oedema. Possible role in the inflammatory process.
The accumulation of blood platelets in the carrageenin-induced paw oedema in rats was studied, using 51Cr-labeled platelets. A maximum in the accumulation was seen after 4 hours, followed by a decline after 5--6 hours. During the first 6 hours of the oedema formation, change in blood volume were small. A comparison was made with the accumulation of both 125J-albumin as a measure of extravasation and 125J-fibrinogen as an indication of blood clotting. When platelet aggregation was measured during the first 6 hours of the oedema formation, the lag time between the addition of collagen and the beginning of the aggregation was increased. No change in platelet serotonin was seen. These data support the idea that platelets participate in the inflammatory process.


Dipeptidyl aminopeptidase IV, a glycoprotein from pig kidney.
Dipeptidyl aminopeptidase IV was purified 350 fold from pig kidney by chromatographic procedures including affinity chromatography with conjugates of Gly-Pro linked to Sepharose 4.B. Purified enzyme existed in a dimeric form as determined by sodium dodecyl sulfate polyacrylamide-gel electrophoresis using dimethyl suberimidate (a cross-linking reagent). The molecular weight of the subunit was estimated to be 100 000 by gel filtration with 6 M guanidine hydrochloride and to be 94 000 based on analysis of N-terminal residue (dinitrophenyl-serine). The amino acid composition of the purified enzyme was also determined. The enzyme contained 18.3% of carbohydrate consisting of mannose, galactose, fucose, glucosamine and sialic acid. The enzyme desialized with sialidase was found to still possess full enzyme activity.


Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man.
1. The efficacy and tolerability of CV-3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2. The compound, in doses from 750 to 2,000 micrograms kg-1, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 +/- 162% of the basal TAC at the end and 266 +/- 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3. CV-3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4. Our results indicate that, when adequate infusion volumes and infusion rates are used, CV-3988 can safely be administered to man and should be useful in elucidating the role of PAF in disease.


Repurposing of neprilysin inhibitor 'sacubitrilat' as an anti-cancer drug by modulating epigenetic and apoptotic regulators.
Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein-ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7-0.9 fold and at the proteomic level by 0.5-0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2-2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2-0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials.


Study of promoter methylation pattern of 14-3-3 sigma gene in normal and cancerous tissue of breast: A potential biomarker for detection of breast cancer in patients.
In recent years, DNA methylation as a main epigenetic modification in human cancer is found as a promising biomarker in early detection of breast cancer. Possible applications of numerous hypermethylated genes have been reported in diagnosis of breast cancer but there has been a little comprehensive study on the clinical usefulness of these genes in breast cancer. The aim of the present study was to investigate the promoter methylation status of 14-3-3 sigma gene with the goal of developing a diagnostic application in breast cancer. Totally 40 cases of cancerous and noncancerous tissues were studied. DNA was extracted from tissue samples, and promoter methylation pattern was determined by using methylation-specific polymerase chain reaction. Methylation pattern of 14-3-3 sigma promoter significantly differed between control and malignant breast tissues (P = 0.001), and there was no remarkable correlation between methylation and age (P > 0.05). The relationship of promoter methylation of 14-3-3 sigma with development of breast cancer found in this study and confirmed the results of previous reports suggests that we can provide the foundation for possible application of 14-3-3 sigma as a potential biomarker for early detection and monitoring disease status.


The 2756A>G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study.
Elevated plasma homocysteine levels have been associated with increased risk of cardiovascular disease. A 2756A>G polymorphism has been found in the gene (MTR) coding for methionine synthase, an enzyme catalyzing remethylation of homocysteine to methionine. In a Dutch case-control study comprising 123 cases with coronary heart disease (CHD) and 540 controls, we evaluated whether the MTR 2756A>G polymorphism was associated with plasma homocysteine, vitamin B12, folate concentrations, and CHD risk. The polymorphism was not associated with fasting or post-methionine load homocysteine concentrations. Individuals with the GG genotype had 30% lower vitamin B12 concentrations than individuals with AA or AG genotype (P < 0.05). After adjustment for CHD risk factors, the odds ratio (OR) of CHD was 4.0 (95% CI 1.4-11.6) for the GG genotype and 0.7 (95% CI 0.4-1.2) for the AG genotype, when compared to the AA genotype. In conclusion, despite the absence of an association with plasma homocysteine, the GG genotype represented a four-fold increased risk of CHD when compared to the AA genotype. Before putting effort in additional epidemiological studies, it needs to be established first whether this polymorphism has functional consequences for enzyme activity.


Practical Management of Immunosuppressants in Dermatology.
The treatment of inflammatory and autoimmune diseases is challenging because of their frequency and complexity. Treatment of these diseases is based on the suppression of the patient's immune system using corticosteroids, corticosteroid-sparing immunosuppressive agents, and biologic drugs, making an understanding of the management of immunosuppressive therapy essential. Before an immunosuppressive agent is prescribed, a study must be carried out to identify contraindications, detect latent infections, and determine the most appropriate dose. During treatment, regular monitoring is required to detect adverse effects. The clinician must be familiar with the time lag between start of treatment and onset of the immunosuppressive effect as well as the maximum recommended duration of treatment and cumulative dose for each drug. As dermatologists we are accustomed to using these immunosuppressive agents, but we should have a good knowledge of the guidelines for their use and the monitoring required in each case if we are to reduce variability and avoid potentially serious adverse effects.


Extraction, Purification and Primary Characterization of Polysaccharides from Defatted Peanut (Arachis hypogaea) Cakes.
The hot-water extraction, purification and characterization of polysaccharides from defatted peanut cake (PPC) were investigated in this study. A Box-Behnken factorial design (BBD) was used to investigate the effects of three independent variables, namely extraction temperature (X₁), extraction time (X₂) and ratio of water to raw material (X₃). The optimum conditions were 85 °C, 3 h and 20:1 (mL/g) respectively. Regression analysis was done to reveal the experimental results which include 34.97% extraction rate while the value verified under these conditions was 34.49%. The crude PPC was sequentially further purified by Sephadex G-100 chromatography, and one purified fraction was obtained. The PPC purified fraction was characterized by FT-IR, HPAEC; SEC-MALLS. The average molecular weight of the PPC purified fraction was 2.383 × 10⁵ Da. The polysaccharide was mainly composed of glucose, galactose, arabinose and xylose. The PPC have the typical absorption of polysaccharide.


Formation mechanism of a new carbamazepine/malonic acid cocrystal polymorph.
A new 2/1 carbamazepine (CBZ)/malonic acid (MA) cocrystal polymorph form C was formed using a vibrational rod mill, whereas the known cocrystal polymorph form A was prepared using a ball mill. IR measurements showed that the interaction between CBZ and MA in cocrystal form C was formed by amide-carboxylic acid heterosynthons, similar to that in cocrystal form A. However, NMR results showed that the molecular states of CBZ at the dibenzazepine ring appeared to be different, which could be due to variation in either the conjugation of the aromatic rings or the π-π interaction of CBZ. Factors affecting the formation of cocrystal polymorphs, such as heat and force, were investigated to clarify the formation mechanism.


Effect of Toremifene on Endometrium and Neurocognitive Function in Patients with Breast Cancer Based on Resting-State Functional Magnetic Resonance Imaging.
In this study, the characteristics of hemodynamic changes with use of toremifene before and after neoadjuvant chemotherapy in breast cancer treatment were analyzed using resting-state functional magnetic resonance imaging. Also, the effect of toremifene on the quality of life of patients with advanced breast cancer was analyzed. The study population comprised 100 patients who received endocrine therapy after breast cancer surgery in our hospital from January 2016 to January 2019. Patients were randomly divided into an observation group and a control group, with 50 cases in each group. The observation group was treated with tamoxifen combined with toremifene treatment; the control group was treated with toremifene. Before and after chemotherapy, the same scheme was used to perform dynamic contrast-enhanced imaging of the breast using a 1.5T superconducting scanner with 3 mL/second bolus injection of adiphenine meglumine 0.2 mmol/kg. Semiquantitative blood flow measurement was completed on the workstation and before and after chemotherapy to compare results. The patient's quality of life, progesterone and estrogen levels, social function, physical function, mental function, and material function were analyzed. The mean values of the early enhancement parameters Efirst, Vfirst, Ee, and Ve before chemotherapy were greater than in the residual lesions after chemotherapy (P < 0.5). The semiquantitative study of resting brain function before and after breast cancer neoadjuvant chemotherapy showed that the hemodynamics of the residual lesions were significantly reduced, and the blood flow rate was significantly reduced. Compared with the clinical effect of tamoxifen in the treatment of breast cancer after surgery, tamoxifen combined with toremifene has more advantages in improving quality of life, improving progesterone levels, and reducing estrogen levels, and it has no detrimental effects on the endometrium.


Impaired gastrointestinal transit and its associated morbidity in the intensive care unit.
To determine the proportion of critically ill adults developing impaired gastrointestinal transit (IGT) using a clinically pragmatic definition, its associated morbidity and risk factors. Critically ill adult patients receiving enteral nutrition for ≥ 72 hours and mechanically ventilated for ≥ 48 hours were prospectively identified. IGT was defined as absence of a bowel movement for ≥ 3 days, treatment for constipation, and one of the following: (1) radiologic confirmed ileus, (2) feed intolerance, (3) abdominal distention, or (4) gastric decompression. One thousand patients were screened, and 248 were included for analysis. Fifty patients (20.1%; 95% confidence interval, 15.1-25.6%) developed IGT persisting for 6.5 ± 2.5 days. Patients with IGT had longer lengths of intensive care unit stay and were less likely to reach nutrition targets compared to patients without IGT or traditional definitions of constipation. Daily opioid use and pharmacological constipation prophylaxis were identified risk factors for IGT. Traditional definitions of constipation or ileus in intensive care unit patients are simplistic and lack clinical relevance. Pragmatically defined IGT is a common complication of critical illness and is associated with significant morbidity. Future interventional studies for IGT in critically ill adults should use a more clinically relevant definition and evaluate energy deficits and lengths of stay as clinically relevant outcomes.


The association between tree planting and mortality: A natural experiment and cost-benefit analysis.
Several recent longitudinal studies have found that exposure to the natural environment is associated with lower non-accidental mortality. However, most of these studies used the normalized difference vegetation index (NDVI) as an exposure metric; and because NDVI might not be sensitive enough to adequately capture changes in urban vegetation, these studies might lack true longitudinal variation in exposure. Therefore, we used a natural experiment to assess the impact of 30 years of tree planting by the nonprofit Friends of Trees on non-accidental, cardiovascular, lower-respiratory, and accidental mortality in Portland, Oregon (mortality data were provided by the Oregon Health Authority). We estimated autoregressive mixed models of Census-tract level mortality rate (deaths per 100,000 population) associated with trees planted, including a tract-level random effect. All models used data from the American Community Survey to control for year, race, education, income, and age. Each tree planted in the preceding 15 years was associated with significant reductions in non-accidental (-0.21, 95 % CI: -0.30, -0.12) and cardiovascular mortality (-0.066, 95 % CI: -0.11, -0.027). Furthermore, the dose-response association between tree planting and non-accidental mortality increased in magnitude as trees aged and grew. Each tree planted in the preceding 1-5 years was associated with a reduction in mortality rate of -0.154 (95 % CI: -0.323, 0.0146), whereas each tree planted in the last 6-10 and 11-15 years was associated with a reduction in mortality rate of -0.262 (95 % CI: -0.413, -0.110) and -0.306 (95 % CI: -0.527, -0.0841) respectively. Using US EPA estimates of a value of a statistical life, we estimated that planting a tree in each of Portland's 140 Census tracts would generate $14.2 million in annual benefits (95 % CI: $8.0 million to $20.4 million). In contrast, the annual cost of maintaining 140 trees would be $2,716-$13,720.


Effect of cyclo-oxygenase blockade on the renal actions of vasopressin and SK&F 105494 in the rhesus monkey.
1. Vasopressin administration to pentobarbitone-anaesthetized, hydrated female rhesus monkeys resulted in dose-dependent increases in urine osmolality and decreases in urine flow. Treatment with indomethacin at a dose (5 mg kg-1, i.v.) that reduced urinary prostaglandin E2 (PGE2) excretion by at least 70% did not alter these responses. 2. The vasopressin antagonist, SK&F 105494 (Pas1,6D-Tyr(Et)2Val4Arg7D-Arg8desGly9 arginine vasopressin; 10 micrograms kg-1), caused significant rightward shifts (P less than 0.05) of both the vasopressin-urine osmolality and the vasopressin-urine flow dose-response curves. Treatment with indomethacin did not alter these responses. 3. SK&F 105494 alone or after indomethacin treatment had minimal effects on urine osmolality and urine flow. 4. The data indicate that indomethacin does not alter the antidiuretic activity of vasopressin in the rhesus monkey and that SK&F 105494 is a potent antagonist of exogenous vasopressin with minimal agonist activity.


[Impact of patient testimony in the education of medicine and pharmacy students].
The initiative from patients suffering from cancer or having had the disease in speaking about their illness to medical students during an internship in a cancer control center of the faculty of medicine and to pharmacy students at the university of Strasbourg was implemented in 2014. This action was coordinated by the French Cancer League as part of the National French cancer plan 3. After training, ten patients teachers were able to freely and spontaneously explain their diagnostic and therapeutic journey as well as their feelings about the disease and their relationship with their oncologists in front of 187 medical students and 131 pharmacy students. A moderator, often a former cancer teacher, helped coordinate the discussions. Questionnaires were given to students, patients teachers and moderators in order to assess the merits of the action and the expected benefits at the end of the training. A second questionnaire was sent to the students six months after the interviews. The assessment was made by an independent firm. The students' responses were very favorable and this training met their expectations in almost 98% of the cases and 1/3 of the students were destabilized by this training. Patients teacher were very satisfied with their intervention and felt that they were able to convey a message. Six months later, the 30% of student respondents said that these testimonies had or could have an impact on their practices. This is the first assessment of the interest of resource patients in teaching cancer patients about medical and pharmacy students.


Strategies for controlling sleep-related intrusive thoughts, and subjective and objective sleep quality: how self-reported poor and good sleepers differ.
Along with changes in subjective and objective sleep patterns, metacognitive control of intrusive and unwanted thoughts at bedtime has been shown to significantly influence sleep quality. The present study examined individual differences between self-reported poor and good sleepers' thought control strategies, as well as their subjective and objective sleep quality, considering adults in a broad range of ages. The study involved 147 individuals aged 18-79 years, divided into self-reported poor and good sleepers using the Pittsburgh Sleep Quality Index (PSQI). Participants' thought control strategies were assessed using the Thought Control Questionnaire for Insomnia - Revised (TCQI-r). Subjective sleep parameters were recorded in a sleep diary, and objective sleep parameters were measured over 7 days using actigraphy. Self-reported poor sleepers employed aggressive suppression, reappraisal and worry strategies more than self-reported good sleepers. On logistic regression, the use of reappraisal and worry strategies distinguished between poor and good sleepers, while age did not. Self-reported poor sleepers objectively had a much longer sleep onset latency, a shorter total sleeping time, and a lower sleep efficiency, as well as subjectively longer times awake again after sleep onset, and a lower sleep efficiency than self-reported good sleepers. Together with some subjective and objective sleep parameters, the use of certain thought control strategies (reappraisal and worry, in particular) seems to be one of the crucial aspects accounting for individual differences between self-reported poor and good sleepers.


Mycobacterium tuberculosis H37Rv comparative gene-expression analysis in synthetic medium and human macrophage.
Mycobacteria are intracellular pathogens that survive and grow in host macrophages. Following phagocytosis, sustained intracellular bacterial growth depends on its ability to avoid destruction by macrophage-mediated host defences such as lysosomal enzymes, reactive oxygen and the reactive nitrogen intermediates. This suggests that the interaction between host cell and microbe is delicately balanced, and can be tipped in favour of either organism. The identification of Mycobacterium tuberculosis H37Rv (MTB) genes expressed within host cells would contribute greatly to the development of new strategies to fight tuberculosis. In the present study, we compared MTB gene expression in the course of intra- (human macrophages) and extracellular growth (Sauton's medium) to ascertain whether differences might occur between gene-expression patterns in the two habitats of replication. Using reverse-transcriptase polymerase chain reaction (RT-PCR) on a group of 14 MTB-Complex-specific genes, we found that MT10Sa (a small stable RNA), 35 kDa (unknown), ahpC (alkyl hydroperoxide reductase, AhpC), sigF (alternative RNA Polymerase sigma factor), and katG (catalase-peroxidase, HPI) genes are expressed in both the environments, while Ag85B, Ag85C (members of the Antigen 85 Complex), rpoV (RNA Polymerase sigma factor) and ESAT6 (early secretory antigen, 6 kDa) are expressed only in the in vitro culture; on the other hand, Ag85A (Antigen 85 Complex), rpoB (RNA Polymerase beta sub-unit), pab (Protein antigen b), invA and invB genes (encoding proteins that show homologies with p60 of Listeria monocytogenes) are expressed only inside the macrophage. Positive RT-PCR products on cDNAs for these genomic regions were not obtained from approximately 1000-fold more bacteria grown in Laboratory Broth. Identification of M. tuberculosis genes expressed in response to phagocytosis by human macrophages increases our basic understanding of the host-pathogen interaction, and helps to identify bacterial factors necessary for in vivo survival and growth.


Temperature-sensitive phenotype caused by natural mutation in Capsicum latescent in two tropical regions.
Plants in tropical regions experience temperature fluctuation only in non-extreme ambient temperatures. Thus, moderate changes in temperatures, which they never experience in their local environments, might be sufficient to manifest the locally hidden phenotype caused by natural mutation. To validate this hypothesis, temperature-treating experiments were performed on Capsicum accessions collected from tropical regions. Thirty-six Capsicum accessions, collected from Caribbean countries, were screened for temperature sensitivity. Similarities in their temperature sensitivities were compared with Sy-2 (C. chinense) from Seychelles, which was previously found to be a temperature-sensitive accession. Tr-13 from Trinidad & Tobago exhibited developmental abnormalities at temperatures below 24 °C. Expression of defense-related genes was induced, and salicylic acid, which is a key molecule in the plant's defense response, accumulated in Tr-13 at temperatures below 24 °C. Tr-13 and Sy-2 appeared normal when they were grown at temperatures simulating those in Trinidad and Seychelles, respectively. Crossing Tr-13 with No. 3341 or Sy-2 revealed that the temperature-sensitive phenotype of Tr-13 was caused by a genetic mutation in the same locus as Sy-2. Plants having a temperature-sensitive phenotype that is caused by natural mutations evade artificial selection and exist as crops in specific environments, such as tropical regions.


Norcantharidin modulates miR-655-regulated SENP6 protein translation to suppresses invasion of glioblastoma cells.
Norcantharidin (NCTD) is currently used as an anticancer drug for the treatment of some malignant cancers. However, whether it may have therapeutic effects on glioblastoma multiforme (GBM) remains unknown. Moreover, the underlying mechanisms have not been completely elucidated. Recently, SUMO-specific protease 6 (SENP6) has been shown as a tumor suppressor in some cancers. Nevertheless, whether it is involved in the pathogenesis of GBM has not been examined. Here, we studied the effects of NCTD on GBM cells. We found that NCTD dose-dependently increased SENP6 protein, but not messenger RNA (mRNA), in GBM cells, resulting in the suppression of cell invasion. Depletion of SENP6 in GBM cells significantly attenuated the NCTD-induced suppression of GBM cell invasion, while overexpression of SENP6 in GBM cells mimicked the effects of NCTD on cell invasion. Moreover, NCTD dose-dependently decreased the levels of microRNA-655 (miR-655), which bound to 3'-UTR of SENP6 mRNA to inhibit its translation. Overexpression of miR-655 decreased SENP6 in GBM cells, while depletion of miR-655 increased SENP6 protein in GBM cells. Taken together, our data demonstrates a previously unappreciated control of NCTD to suppress GBM cell invasion through modulation of miR-655-regulated SENP6 protein translation.


Serum Metabolomic Indicates Potential Biomarkers and Metabolic Pathways of Pediatric Kashin-Beck Disease.
To explore potential serum biomarkers of children with Kashin-Beck Disease (KBD) and the metabolic pathways to which the biomarkers belong. A two-stage metabolomic study was employed. The discovery cohort included 56 patients, 51 internal controls, and 50 external controls. The metabolites were determined by HPLC-(Q-TOF)-MS and confirmed by Human Metabolome Databases (HMDB) and Metlin databases. MetaboAnalyst 3.0 and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used to analyze the metabolic pathways of the candidate metabolites. The use of HPLC-(Q-TRAP)-MS enabled quantitative detection of the target metabolites which were chosen using the discovery study and verified in another independent verification cohort of 31 patients, 41 internal controls, and 50 external controls. Eight candidate metabolites were identified out in the discovery study, namely kynurenic acid, N-α-acetylarginine, 6-hydroxymelatonin, sphinganine, ceramide, sphingosine-1P, spermidine, and glycine. These metabolites exist in sphingolipid, glutathione, and tryptophan metabolic pathways. In the second-stage study, five candidate metabolites were validated, including kynurenic acid, N-α-acetylarginine, sphinganine, spermidine, and sphingosine-1P. Except for spermidine, all substances exhibited low expression in the case group compared with the external control group, and the difference in levels of sphinganine, spermidine, and sphingosine-1P was statistically significant. The direction of change of levels of sphinganine, spermidine, and sphingosine-1P in the two-stage study cohorts was completely consistent, and the differences were statistically significant. Therefore, these substances can be used as potential biomarkers of KBD. Furthermore, these results raise the possibility that sphingolipid metabolic pathways may be closely related to KBD.


Kidney Dysfunction After Traumatic Brain Injury: Pathophysiology and General Management.
Traumatic brain injury (TBI) remains a major cause of mortality and morbidity, and almost half of these patients are admitted to the intensive care unit. Of those, 10% develop acute kidney injury (AKI) and 2% even need kidney replacement therapy (KRT). Although clinical trials in patients with TBI who have AKI are lacking, some general principles in this population may apply. The present review is an overview on the epidemiology and pathophysiology of AKI in patients with TBI admitted to the intensive care unit who are at risk for or who have developed AKI. A cornerstone in severe TBI management is preventing secondary brain damage, in which reducing the intracranial pressure (ICP) and optimizing the cerebral perfusion pressure (CPP) remain important therapeutic targets. To treat episodes of elevated ICP, osmolar agents such as mannitol and hypertonic saline are frequently administered. Although we are currently awaiting the results of a prospective randomized controlled trial that compares both agents, it is important to realize that both agents have been associated with an increased risk of developing AKI which is probably higher for mannitol compared with hypertonic saline. For the brain, as well as for the kidney, targeting an adequate perfusion pressure is important. Hemodynamic management based on the combined use of intravascular fluids and vasopressors is ideally guided by hemodynamic monitoring. Hypotonic albumin or crystalloid resuscitation solutions may increase the risk of brain edema, and saline-based solutions are frequently used but have a risk of hyperchloremia, which might jeopardize kidney function. In patients at risk, frequent assessment of serum chloride might be advised. Maintenance of an adequate CPP involves the optimization of circulating blood volume, often combined with vasopressor agents. Whether individualized CPP targets based on cerebrovascular autoregulation monitoring are beneficial need to be further investigated. Interestingly, such individualized perfusion targets are also under investigation in patients as a strategy to mitigate the risk for AKI in patients with chronic hypertension. In the small proportion of patients with TBI who need KRT, continuous techniques are advised based on pathophysiology and expert opinion. The need for KRT is associated with a higher risk of intracranial hypertension, especially if osmolar clearance occurs fast, which can even occur in continuous techniques. Precise ICP and CPP monitoring is mandatory, especially at the initiation of KRT.


Effect of surface chemistry of silica nanoparticles on contact angle of oil on calcite surfaces in concentrated brine with divalent ions.
For an oil droplet on calcite with an intervening brine film, the water contact angle θw may be reduced markedly (greater water wetness) with surface modified silica nanoparticles (NP). Modification with cationic, anionic, and nonionic ligands may be used to control the nanoparticle adsorption and interactions at the oil-brine and brine-calcite interfaces to influence the rate and degree of reduction in θw. The colloidal stability at 25 °C was determined in concentrated divalent brine (8 wt% NaCl and 2 wt% CaCl2) with dynamic light scattering, and the NP adsorption was determined on calcite. The NP adsorption at the oil-brine interface was characterized with the elastic dilational modulus. θw was measured for model decane-stearic acid droplets and crude oil droplets on calcite from 25 to 80 °C. The fastest rate and greatest extent of reduction in θw for grafted ligands followed the order: cationic quaternary trimethylamine > sulfonate > methyl phosphonate > gluconamide. New mechanisms for reduction in θw were demonstrated on the basis of changes in interactions from NP adsorption at each interface. The greatest efficacy for the cationic NPs results from the weakest adsorption on calcite, steric repulsion at the three-phase contact line and the greatest desorption of carboxylate surfactants from the calcite.


Editorial: Beta-blockers and the prevention of decompensation in cirrhosis: worth the trouble.
Non-selective beta-blockers have been a cornerstone of therapy for prevention of esophageal variceal bleeding in cirrhosis patients for more than two decades. When lowering the hepatic vein portal pressure gradient (HVPG) below 12 mm Hg or decreasing the pressure by 20% from baseline, these drugs are of proven benefit in reducing variceal bleeding and improving survival in this patient population. The recent work by Hendández-Gea et al., suggests that initiation of the beta-blocker nadolol in cirrhosis patients with high-risk varices can delay or prevent the first occurrence of clinically evident ascites. This finding comes with some caveats, however. The beneficial effect was only seen in patients who had an improvement by 10% or more from baseline HVPG pressure (only 51% of the treated patients in this study). This class of medications has some risk and tolerance issues, and many patients do not respond, even when the heart rate is optimally decreased. Despite this, the use of beta-blockers may be beneficial in the primary prevention of the formation of ascites and further decompensation of cirrhosis.


Deriving Schwann cells from hPSCs enables disease modeling and drug discovery for diabetic peripheral neuropathy.
Schwann cells (SCs) are the primary glia of the peripheral nervous system. SCs are involved in many debilitating disorders, including diabetic peripheral neuropathy (DPN). Here, we present a strategy for deriving SCs from human pluripotent stem cells (hPSCs) that enables comprehensive studies of SC development, physiology, and disease. hPSC-derived SCs recapitulate the molecular features of primary SCs and are capable of in vitro and in vivo myelination. We established a model of DPN that revealed the selective vulnerability of SCs to high glucose. We performed a high-throughput screen and found that an antidepressant drug, bupropion, counteracts glucotoxicity in SCs. Treatment of hyperglycemic mice with bupropion prevents their sensory dysfunction, SC death, and myelin damage. Further, our retrospective analysis of health records revealed that bupropion treatment is associated with a lower incidence of neuropathy among diabetic patients. These results highlight the power of this approach for identifying therapeutic candidates for DPN.


Health Care Provider Barriers to Patient Referral to Palliative Care.
The purpose of this study was to explore healthcare provider-perceived challenges to HBPC patient referral and elicited providers' feedback for overcoming these challenges. We conducted a qualitative study using semi-structured interviews with 25 Medicaid managed care providers (primary care physicians, nurse practitioners, and care managers) working in the greater Los Angeles area. Our interview protocol elicited providers' knowledge and awareness of palliative care; perceived barriers to HBPC referral; and suggestions for overcoming these barriers. We analyzed verbatim transcripts using a grounded theory approach. Themes related to referral barriers included providers' lack of palliative care knowledge and clarity regarding referral processes, provider reluctance to refer to HBPC, and provider culture. Providers also identified patient-level barriers, including financial barriers, reluctance to have home visits, health literacy, cultural barriers, and challenges related to living situations. Themes related to methods for overcoming challenges included increased HBPC education and outreach to providers, specifically by HBPC agency staff. Findings from this study underscore the need for additional palliative care education for Medicaid healthcare providers. They point to the need for novel strategies and approaches to address the myriad barriers to patient identification and referral to HBPC.


The microenvironments of multistage carcinogenesis.
Overt neoplasia is often the result of a chronic disease process encompassing an extended segment of the lifespan of any species. A common pathway in the natural history of the disease is the appearance of focal proliferative lesions that are known to act as precursors for cancer development. It is becoming increasingly apparent that the emergence of such lesions is not a cell-autonomous phenomenon, but is heavily dependent on microenvironmental cues derived from the surrounding tissue. Specific alterations in the tissue microenvironment that can foster the selective growth of focal lesions are discussed herein. Furthermore, we argue that a fundamental property of focal lesions as it relates to their precancerous nature lies in their altered growth pattern as compared to the tissue where they reside. The resulting altered tissue architecture translates into the emergence of a unique tumor microenvironment inside these lesions, associated with altered blood vessels and/or blood supply which in turn can trigger biochemical and metabolic changes fueling tumor progression. A deeper understanding of the role(s) of tissue and tumor microenvironments in the pathogenesis of cancer is essential to design more effective strategies for the management of this disease.


Salsalate improves glycemia and inflammatory parameters in obese young adults.
Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes. In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo. Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05). This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.


Costs of hospitalization for stroke patients aged 18-64 years in the United States.
Estimates for the average cost of stroke have varied 20-fold in the United States. To provide a robust cost estimate, we conducted a comprehensive analysis of the hospitalization costs for stroke patients by diagnosis status and event type. Using the 2006-2008 MarketScan inpatient database, we identified 97,374 hospitalizations with a primary or secondary diagnosis of stroke. We analyzed the costs after stratifying the hospitalizations by stroke type (hemorrhagic, ischemic, and other strokes) and diagnosis status (primary and secondary). We employed regressions to estimate the impact of event type and diagnosis status on costs while controlling for major potential confounders. Among the 97,374 hospitalizations (average cost: $20,396 ± $23,256), the number with ischemic, hemorrhagic, or other strokes was 62,637, 16,331, and 48,208, respectively, with these types having average costs, in turn, of $18,963 ± $21,454, $32,035 ± $32,046, and $19,248 ± $21,703. A majority (62%) of the hospitalizations had stroke listed as a secondary diagnosis only. Regression analysis found that, overall, hemorrhagic stroke cost $14,499 more than ischemic stroke (P < .001). For hospitalizations with a primary diagnosis of ischemic stroke, those with a secondary diagnosis of ischemic heart disease (IHD) had costs that were $9836 higher (P < .001) than those without IHD. The costs of hospitalizations involving stroke are high and vary greatly by type of stroke, diagnosis status, and comorbidities. These findings should be incorporated into cost-effective strategies to reduce the impact of stroke.


Intermediate-risk pulmonary embolism: echocardiography predictors of clinical deterioration.
We determine the predictive value of transthoracic echocardiographic (TTE) metrics for clinical deterioration within 5 days in adults with intermediate-risk pulmonary embolism (PE). This was a prospective observational study of intermediate-risk PE patients. To determine associations of TTE and clinical predictors with clinical deterioration, we used univariable analysis, Youden's index for optimal thresholds, and multivariable analyses to report odds ratios (ORs) or area under the curve (AUC). Of 306 intermediate-risk PE patients, 115 (37.6%) experienced clinical deterioration. PE patients who had clinical deterioration within 5 days had greater baseline right ventricle (RV) dilatation and worse systolic function than the group without clinical deterioration as indicated by the following: RV basal diameter 4.46 ± 0.77 versus 4.20 ± 0.77 cm; RV/LV basal width ratio 1.14 ± 0.29 versus 1.02 ± 0.24; tricuspid annular plane systolic excursion (TAPSE) 1.56 ± 0.55 versus 1.80 ± 0.52 cm; and RV systolic excursion velocity 10.40 ± 3.58 versus 12.1 ± 12.5 cm/s, respectively. Optimal thresholds for predicting clinical deterioration were: RV basal width 3.9 cm (OR 2.85 [1.64, 4.97]), RV-to-left ventricle (RV/LV) ratio 1.08 (OR 3.32 [2.07, 5.33]), TAPSE 1.98 cm (OR 3.3 [2.06, 5.3]), systolic excursion velocity 10.10 cm/s (OR 2.85 [1.75, 4.63]), and natriuretic peptide 190 pg/mL (OR 2.89 [1.81, 4.62]). Significant independent predictors were: transient hypotension 6.1 (2.2, 18.9), highest heart rate 1.02 (1.00, 1.03), highest respiratory rate 1.02 (1.00, 1.04), and RV/LV ratio 1.29 (1.14, 1.47). By logistic regression and random forest analyses, AUCs were 0.80 (0.73, 0.87) and 0.78 (0.70, 0.85), respectively. Basal RV, RV/LV ratio, and RV systolic function measurements were significantly different between intermediate-risk PE patients grouped by subsequent clinical deterioration.


Demonstration of two distinct antigenic determinants on human alpha-foetoprotein by monoclonal antibodies.
Mice were immunized with a purified preparation of human alpha-foetoprotein (AFP) and their spleen cells were hybridized with mouse myeloma cells. Eleven hybridoma cell lines secreting antibody to AFP were obtained. These antibodies were classified into two groups on the basis of different antigenic determinants they recognized. Seven cell lines produced antibodies directed to one determinant of AFP (determinant a), while the remaining 4 produced antibodies to another determinant (determinant b). A native AFP molecule bore one each of a and b determinants which were accessible by monoclonal antibodies; it was detected by a sandwich-type solid-phase radioimmunoassay only when antibody to a was used for coating wells of the microtitre plate and antibody to b as radiolabelled reagent, or vice versa. The presence of two different antigenic determinants on AFP was further confirmed by a chemical modification. When AFP was reduced in the presence of 2 mM dithiothreitol and then alkylated, determinant b was completely destroyed, but the determinant a remained unaffected. Furthermore, reduced and alkylated AFP was detected by the radioimmunoassay employing antibody to a both for coating wells and as radiolabelled reagent, thereby indicating that it bore two determinant as, one of which had been unaccessible in the native AFP.


First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis.
Inhibition of the mitogen-activated protein kinase (MAPK) pathway as well as programmed death 1 receptor (PD-1) blockade was shown to prolong overall survival (OS) in patients with advanced B-Raf proto-oncogene (BRAF)-mutant melanoma. However, due to the lack of head-to-head trials, it remains unclear if one of these therapeutic approaches should be preferred in first-line therapy. Here, we present a retrospective analysis comparing anti-PD-1 monotherapy with BRAF/MAPK/ERK kinase (MEK) combined inhibition used as first-line agents in a real-world clinical setting. Clinical data, routine blood counts and lactate dehydrogenase (LDH) levels of 301 patients with unresectable or metastatic melanoma harboring an activating mutation in BRAF (V600E/K) were included. Of these, 106 received anti-PD-1 antibodies, while 195 patients were treated with a selective BRAF inhibitor combined with an MEK inhibitor as palliative first-line therapy. Patients were sub-grouped according to previously described predictive and prognostic markers. OS was significantly longer in patients receiving anti-PD-1 monotherapy compared to patients receiving combined MAPK inhibitors. Subsequent therapies were comparable among these groups. The difference in OS was less pronounced in patients with high LDH levels and visceral metastatic spread. First-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials.


Distributed multi-UAV cooperation for dynamic target tracking optimized by an SAQPSO algorithm.
Real-time tracking of the dynamic intrusion targets consists of two crucial factors: the path forecast of the target and real-time path optimization of multi-UAV target tracking. For the first one, the uncertainty of the target trajectory is an obstacle to realizing real-time tracking. Thus a trajectory prediction method is proposed in this paper to ensure the sampling period of the target. Owing to the poor prediction accuracy of the single-step trajectory, a multi-step Unscented Kalman Filter (MUKF) is proposed to forecast its multi-step trajectory further in different regions. For the second one, there are two problems: poor optimization accuracy of the tracking trajectory and larger local optimization deviation, which will cause failure of the regional tracking. Under this circumstance, a hybrid algorithm called SAQPSO is proposed, combining the specific mechanism of two intelligence algorithms. The annealing mechanism in the Simulated Annealing (SA) algorithm is used to modify the Quantum Particle Swarm Optimization (QPSO) algorithm. Then the characteristic of quantum particles is used to update the population and enhance global searchability. Furthermore, to testify the effectiveness of the trajectory optimization algorithm and related target prediction method, a specific simulation environment is given as an example, in which the tracking trajectories of eight different algorithms are compared. Simulation results show the effectiveness of the proposed algorithm.


Application of the solvent perturbation technique to the study of protein systems by luminescence and light-scattering spectrophotometry.
The solvent perturbation technique was applied to the study of a membrane model consisting of lysozyme and sodium dodecyl sulfate (SDS) micelles, in comparison with erythrocyte ghosts, in aqueous solutions supplemented with dimethyl-sulfoxide. By correlated fluorescence and light-scattering spectrophotometric determinations it was possible to demonstrate a nonmonotonous variation suggesting a phenomenon equivalent to a conformation transition. Such a transition was made evident by the direct action of the cis-[PtCl2(HN3)2]complex on the lysozyme--SDS system at concentrations higher than the critical micelle concentration and at a temperature of 40 degrees C.


Significance of Hageman factor (coagulation factor XII) for neutrophil locomotion and chemotaxis.
Neutrophils separated from Hageman factor-deficient blood exhibit normal random and directional locomotion. No defect in cytotaxin formation could be demonstrated in Hageman factor-deficient plasma, nor did kallikrein inhibitor interfere with the chemotactic activity of normal immune complex-activated human plasma. The results suggest that the chemotactic activity which is detectable in unfractionated human plasma is not derived from Hageman factor-dependent pathways.


The effect of Helicobacter pylori on the expression of FRA-1 in gastric epithelial cells and its mechanism.
Gastric cancer is a major global health threat and is often related with Helicobacter pylori (H. pylori) infection. FRA-1 is a subunit of the activator protein-1 transcription factor complex, which played a central role in cell proliferation and migration. It has also been implicated in stomach inflammation and malignancy. The present study aimed to clarify the relationship between H. pylori infection and production of FRA-1 in controlling cell proliferation and migration and its molecular mechanisms. Cell proliferation was measured by colony formation assay. Cell migration was monitored by transwell migration assay. Gastric mucosal epithelial cells were treated with FRA-1-specific siRNA with or without H. pylori infection in vitro, and RNA and proteins were extracted. The expression of FRA-1 and indicators in cells was determined by RT-PCR and western blot analysis. β-Catenin and TGF-β activities were then assessed by western blotting and immunofluorescence. The expression of FRA-1 increased after H. pylori infection. Additional analysis identified that knockdown of FRA-1 attenuated the H. pylori-induced proliferative activity and migration of gastric cancer cells. Furthermore, upregulation of FRA-1 by H. pylori led to increase in Wnt/β-Catenin levels and TGF-β dependent signaling events. These results demonstrate that the upregulation of FRA-1 in H. pylori-infected gastric epithelial cells plays a key role in the carcinogenic process.


Predictors of poor treatment outcomes in multidrug-resistant tuberculosis patients: a retrospective cohort study.
We aimed to determine the characteristics, treatment outcomes and risk factors for poor treatment outcomes among multidrug-resistant (MDR) tuberculosis (TB) patients in Khyber Pakhtunkhwa province, Pakistan. A retrospective cohort study including all patients with MDR-TB who sought care at the MDR-TB unit in Peshawar was conducted between January 2012 and April 2014. Patients were followed until an outcome of TB treatment was recorded as successful (cured or completed) or unsuccessful. Binary logistic regression was used to identify predictors of poor outcome, i.e. unsuccessful treatment outcomes. Overall, 535 patients were included. The proportion of female subjects was relatively higher (n = 300, 56.1%) than male subjects. The mean (standard deviation) age of patients was 30.37 (14.09) years. Of 535 patients for whom treatment outcomes were available, 402 (75.1%) were cured, 4 (0.7%) completed therapy, 34 (6.4%) had disease that failed to respond to therapy, 93 (17.4%) died and two (0.4%) defaulted; in total, 129 (24.1%) had an unsuccessful outcome. We found three significant predictors of unsuccessful treatment during multivariate logistic regression: being married (odds ratio (OR) = 2.17, 95% confidence interval (CI) 1.01, 4.66), resistance to second-line drugs (OR = 2.61, 95% CI 1.61, 4.21) and presence of extensively drug-resistant TB (OR = 7.82, 95% CI 2.90, 21.07). Approximately 75% of the treatment success rate set by the Global Plan to Stop TB was achieved. Resistance to second-line drugs and presence of extensively drug-resistant TB are the main risk factors for poor treatment outcomes.


Hyaline membrane disease: prognostic factors and medium-term follow-up.
One hundred and twenty two cases of severe hyaline membrane disease are reported. 68 of them survived (57%). Adverse clinical, radiological and laboratory factors, and their effects on the early mortality rate, are analysed with particular reference to the referring centers, delay in admission, transport and the critical state of most infants on admission. The follow-up of 29 survivors treated before 1974 has been examined with reference to birthweight and assisted respiration. Four (30%) of the twelve infants with birthweights below 2000 g had major neurological sequelae. Only two out of the 17 babies with a birthweight over 2000 g had minor mental disturbances.


Extending the tissue penetration capability of conventional photosensitisers: a carbon quantum dot-protoporphyrin IX conjugate for use in two-photon excited photodynamic therapy.
A carbon quantum dot (CQD)-protoporphyrin (IX) sensitisier conjugate was designed to exploit the large two-photon absorption cross section of CQDs and enable the indirect excitation of the sensitiser with 800 nm irradiation via FRET.


Influence of monosaccharide derivatives on liver cell glycosaminoglycan synthesis: 3-deoxy-D-xylo-hexose (3-deoxy-D-galactose) and methyl (methyl 4-chloro-4-deoxy-beta-D-galactopyranosid) uronate.
An improved, convenient synthesis of 3-deoxy-D-xylo-hexose (3-deoxy-D-galactose) has been developed, and the chemical synthesis of a novel monosaccharide derivative, methyl (methyl 4-chloro-4-deoxy-beta-D-galactopyranosid)uronate (compound 10), is described. Using primary hepatocytes in culture, each was used to explore its effect on glycosaminoglycan (GAG) synthesis. In the absence of analogues hepatocytes synthesize primarily (92-95%) heparan sulphate. At 1 mM, 3-deoxy-D-galactose had little observable effect on either liver cell GAG or protein synthesis. At 10 mM and 20 mM, 3-deoxy-D-galactose reduced [3H]glucosamine and 35SO4 incorporation into hepatocyte cellular GAGs to, respectively, 75% and 60% of the control cells. This inhibition of GAG synthesis occurred without any effect on hepatocyte protein synthesis, indicating that 3-deoxy-D-galactose's effect on GAG synthesis is not mediated through an inhibition of proteoglycan core protein synthesis. Furthermore, GAGs in the presence of 20 mM of the analogue were significantly reduced in size, 17 kDa vs. 66 kDa in untreated cells. These results reflect either impaired cellular GAG chain elongation, and/or altered GAG chain degradation. Compound 10 exhibited a concentration-dependent inhibition of both hepatocyte cellular GAG and protein synthesis. At concentrations of 5, 10 and 20 mM, compound 10 inhibited GAG and protein synthesis by 20, 65 and 90%, respectively. Exogenous uridine was able to restore partially the inhibition of protein synthesis, but was unable to reverse the effect of compound 10 on GAG synthesis. These results show that part of the effect of compound 10 on GAG synthesis is not mediated by an inhibition of proteoglycan core protein synthesis. GAGs in the presence of compound 10 are half as large as those in the absence of this compound (33 and 66 kDa, respectively). These results again may reflect either impaired cellular GAG chain elongation and/or altered GAG chain degradation. Potential metabolic routes for each analogue's effect are presented.


Document-level medical relation extraction via edge-oriented graph neural network based on document structure and external knowledge.
Relation extraction (RE) is a fundamental task of natural language processing, which always draws plenty of attention from researchers, especially RE at the document-level. We aim to explore an effective novel method for document-level medical relation extraction. We propose a novel edge-oriented graph neural network based on document structure and external knowledge for document-level medical RE, called SKEoG. This network has the ability to take full advantage of document structure and external knowledge. We evaluate SKEoG on two public datasets, that is, Chemical-Disease Relation (CDR) dataset and Chemical Reactions dataset (CHR) dataset, by comparing it with other state-of-the-art methods. SKEoG achieves the highest F1-score of 70.7 on the CDR dataset and F1-score of 91.4 on the CHR dataset. The proposed SKEoG method achieves new state-of-the-art performance. Both document structure and external knowledge can bring performance improvement in the EoG framework. Selecting proper methods for knowledge node representation is also very important.


Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy.
Patients with frequent premature ventricular complexes (PVCs) are at risk of developing reversible PVC-induced cardiomyopathy (rPVC-CMP). Not all determinants of rPVC-CMP are known. To assess the impact of the QRS duration of PVCs on the development of rPVC-CMP. In a consecutive series of 294 patients with frequent idiopathic PVCs referred for PVC ablation, the width of the PVC-QRS complex was assessed. The QRS width was correlated with the presence of rPVC-CMP. The PVC-QRS width was significantly greater in patients with rPVC-CMP than in patients without rPVC-CMP (164 ± 20 ms vs 149 ± 17 ms; P < .0001). The site of origin of the PVC had an impact on the PVC-QRS width, with epicardial PVCs having the broadest QRS complexes. Patients with PVCs originating from the right ventricular outflow tract or the fascicles had the narrowest QRS complexes. After adjusting for PVC burden, symptom duration, and PVC site of origin, PVC-QRS width and an epicardial PVC origin were independently associated with rPVC-CMP. Based on receiver operator characteristics analysis, a QRS duration of >150 ms best differentiated patients with and without rPVC-CMP (area under the curve 0.66; sensitivity 80%; specificity 52%). The PVC burden for developing rPVC-CMP is significantly lower in patients with a PVC-QRS width of ≥150 ms than in patients with a narrower PVC-QRS complex (22% ± 13% vs 28% ± 12%; P < .0001). Broader PVCs and an epicardial PVC origin are associated with the development of rPVC-CMP independent of the PVC burden.


Adrenoceptors in the control of human nasal mucosal blood flow.
The blood flow in the human nasal mucosa is controlled by the functional state of the resistance vessels. This blood flow was studied by means of the 133Xe washout method. Using topical application of drugs that stimulate or block adrenoceptors, including clinical doses of nasal decongestants, we classified the adrenoceptors of the resistance vessels in the mucosa. The results suggest that stimulation of alpha2-adrenoceptors causes a reduction of nasal mucosal blood flow; stimulation of alpha1- and beta2-adrenoceptors seems to have no significant effects. Drugs that selectively stimulate alpha2-adrenoceptors, as well as those with preference for alpha1-adrenoceptors, cause nasal decongestion. To avoid the negative effects of a nasal mucosal blood flow reduction, it is suggested that a nasal decongestant with an alpha1-adrenoceptor stimulating effect should be preferable to a drug acting mainly on alpha2-adrenoceptors, provided that the decongestive effects are equal.


The potential of organic substrates based on mushroom substrate and straw to dissipate fungicides contained in effluents from the fruit-packaging industry - Is there a role for Pleurotus ostreatus?
Citrus fruit-packaging plants (FPP) produce large wastewater volumes with high loads of fungicides like ortho-phenylphenol (OPP) and imazalil (IMZ). No methods are in place for the treatment of those effluents and biobeds appear as a viable alternative. We employed a column study to investigate the potential of spent mushroom substrate (SMS) of Pleurotus ostreatus, either alone or in mixture with straw and soil plus a mixture of straw /soil to retain and dissipate IMZ and OPP. The role of P. ostreatus on fungicides dissipation was also investigated by studying in parallel the performance of fresh mushroom substrate of P. ostreatus (FMS) and measuring lignolytic enzymatic activity in the leachates. All substrates effectively reduced the leaching of OPP and IMZ which corresponded to 0.014-1.1% and 0.120-0.420% of their initial amounts respectively. Mass balance analysis revealed that FMS and SMS/Straw/Soil (50/25/25 by vol) offered the most efficient removal of OPP and IMZ from wastewaters respectively. Regardless of the substrate, OPP was restricted in the top 0-20cm of the columns and was bioavailable (extractable with water), compared to IMZ which was less bioavailable (extractable with acetonitrile) but diffused at deeper layers (20-50, 50-80cm) in the SMS- and Straw/Soil-columns. PLFAs showed that fungal abundance was significantly lower in the top layer of all substrates from where the highest pesticide amounts were recovered suggesting an inhibitory effect of fungicides on total fungi in the substrates tested. Our data suggest that biobeds packed with SMS-rich substrates could ensure the efficient removal of IMZ and OPP from wastewaters of citrus FPP.


Raccoons (Procyon lotor) as Sentinels of Trace Element Contamination and Physiological Effects of Exposure to Coal Fly Ash.
Anthropogenic pollutants disrupt global biodiversity, and terrestrial sentinels of pollution can provide a warning system for ecosystem-wide contamination. This study sought to assess whether raccoons (Procyon lotor) are sentinels of local exposure to trace element contaminants at a coal fly ash site and whether exposure resulted in health impairment or changes in the intestinal helminth communities. We compared trace element accumulation and the impact on health responses and intestinal helminth communities of raccoons inhabiting contaminated and reference sites of the U.S. Department of Energy's Savannah River Site (South Carolina, USA). Data on morphometry, hematology, histopathology, helminth community and abundance, and liver trace element burdens were collected from 15 raccoons captured adjacent to a coal fly ash basin and 11 raccoons from a comparable uncontaminated site nearby. Of eight trace elements analyzed, Cu, As, Se, and Pb were elevated in raccoons from the contaminated site. Raccoons from the contaminated site harbored higher helminth abundance than animals from the reference site and that abundance was positively associated with increased Cu concentrations. While we found changes in hematology associated with increased Se exposure, we did not find physiological or histological changes associated with higher levels of contaminants. Our results suggest that raccoons and their intestinal helminths act as sentinels of trace elements in the environment associated with coal fly ash contamination.


Differential effects of various skin tumor-promoting agents on prostaglandin E2 release from primary cultures of mouse epidermal cells.
Prostaglandin E2 (PGE2) release from primary cultures of mouse epidermal cells was markedly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and 1-oleoyl-2-acetyl-glycerol but not by 4 alpha-phorbol-12,13-di-decanoate in low Ca2+ (50 microM) medium. TPA-evoked PGE2 release was inhibited by mepacrine, indomethacin and H-7 but not by HA1004. These findings suggest that TPA stimulates PGE2 release through activation of protein kinase C, phospholipase A2 and the cyclooxygenase pathway. Of the non-TPA type of tumor promoting agents, i.e. anthralin, chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, only anthralin stimulated PGE2 release. Anthralin-evoked PGE2 release was not inhibited by H-7. In normal Ca2+ (1.8 mM) medium, PGE2 release increased markedly compared to the release in low Ca2+ medium. In normal Ca2+ medium, PGE2 release was stimulated by TPA, anthralin and okadaic acid but not by other tumor promoting agents. In mouse peritoneal macrophages, TPA, palytoxin and okadaic acid stimulated PGE2 release, but other tumor-promoting agents failed to stimulate it. These results suggest that skin tumor promoting agents are not necessarily effective stimulators of prostaglandin production either in macrophages or in epidermal cells, the target cells of skin tumor promotion.


[Approaches to the correction of auditory tube dysfunction in children with allergic rhinitis].
Allergic diseases are a global public health problem. One of the most common among them is allergic rhinitis (AR), which affects up to 40% of adults and 2-25% of children. To assess the state of ventilation of the middle ear in various forms of AR in children and the effectiveness of drug correction. We conducted a comprehensive examination of 100 children with various forms of AR. The examination complex included the analysis of anamnestic data, the clinical picture of the disease, subjective otological symptoms, data from otoscopy, acoustic impedansometry and tonal threshold audiometry. There are 3 groups of children. Group 1 - 40 children suffering from intermittent allergic rhinitis with pollen sensitization. Group 2 - 20 children with persistent allergic rhinitis with household sensitization. Group 3 - 40 children suffering from persistent allergic rhinitis in combination with an allergic form of bronchial asthma. 1. Regardless of the form of AR, every third patient has auditory tube dysfunction, which develops mainly on both sides, is asymptomatic and is not accompanied by otoscopic changes. 2. As a result of combination therapy, including irrigation agents, montelukast and cetirizine, an improvement in the ventilation of the tympanic cavity was noted with a decrease in the number of recording tympanograms of type «B» and «C» from 30.5 to 22.0%.


Vascularized os pisiform for reinforcement of the lunate in Kienböck's Disease: an average of 12 years of follow-up study.
Little is known about the long-term results of vascularized bone transplantation for Kienböck's disease. This retrospective study investigated the long-term results of vascularized pisiform transfer. We reviewed 23 patients to analyze results after vascularized pisiform transposition to a cored-out lunate for Lichtman stages II and III. Patients with ulnar-minus variance received additional radial shortening. Pain improved in 20 of 23 patients. Range of motion increased significantly relative to preoperative values but was only 80% that of opposite side. Grip power was 84% of the contralateral hand. At follow-up evaluation the mean Disabilities of the Arm, Shoulder, and Hand questionnaire score was 15.3 +/- 17.9 and the mean Cooney score was 82.4 +/- 10.0. Radiologically, out of 20 patients with preoperative x-rays Lichtman stage was unchanged in 11, improved in 3, and progressed in 6 patients. No patient showed radiologic signs of arthritis before surgery. At follow-up evaluation osteoarthritis was found in 7 of 22 patients. The majority of degenerative changes were of low grade and were seen at the radiocarpal joint. The results show high patient satisfaction and good function after vascularized bone transplantation for Kienböck's disease. In the long term vascularized pisiform transfer prevented lunate collapse in 16 of 22 patients.


Impact of mitigation strategies on acid sulfate soil chemistry and microbial community.
Potential acid sulfate soils contain reduced iron sulfides that if oxidized, can cause significant environmental damage by releasing large amounts of acid and metals. This study examines metal and acid release as well as the microbial community capable of catalyzing metal sulfide oxidation after treating acid sulfate soil with calcium carbonate (CaCO3) or calcium hydroxide (Ca(OH)2). Leaching tests of acid sulfate soil samples were carried out in the laboratory. The pH of the leachate during the initial flushing with water lay between 3.8 and 4.4 suggesting that the jarosite/schwertmannite equilibrium controls the solution chemistry. However, the pH increased to circa 6 after treatment with CaCO3 suspension and circa 12 after introducing Ca(OH)2 solution. 16S rRNA gene sequences amplified from community DNA extracted from the untreated and both CaCO3 and Ca(OH)2 treated acid sulfate soils were most similar to bacteria (69.1% to 85.7%) and archaea (95.4% to 100%) previously identified from acid and metal contaminated environments. These species included a Thiomonas cuprina-like and an Acidocella-like bacteria as well as a Ferroplasma acidiphilum-like archeon. Although the CaCO3 and Ca(OH)2 treatments did not decrease the proportion of microorganisms capable of accelerating acid and metal release, the chemical effects of the treatments suggested their reduced activity.


A comparison study on environmental policies for expressway construction projects between China and the US: A tiered analysis approach.
The development of expressway construction projects (ECPs) poses overwhelming challenges to the physical environment around the world. The challenges are supposed to be addressed with the enforcement of environmental policies (EPs). In this regard, developed countries have gained rich experience in EP formulation while developing countries are making efforts to improve policy decision-making on environmental sustainability. This study compares ECP-related EPs (EREPs) between China and the US by conducting a historical analysis with materials from 1960 to 2018 and text mining-based evaluation with materials from 2009 to 2019. The comparison results indicate that (1) an EREP framework is composed of two systems, namely outer factors and inner EPs; (2) the upper-level EPs exhibit a periodic and plan-dominating trend in China and an explanatory tendency in the US; (3) Chinese EPs are focused on pollution mitigation, whereas US EPs highlight the impacts on human health; (4) Both attach less importance to environmental protection measures at the project-level EPs. This paper provides a longitudinal comparison and analysis of EREPs in two huge countries, implying that EREPs are a snapshot of national rules and backgrounds. The findings lay a foundation for future research to examine the innovation of environmental policies, especially for those countries with massive expressway construction projects and the related environmental issues.


Vibrational spectra and structure of CH3Cl:H2O, CH3Cl:HDO, and CH3Cl:D2O complexes. IR matrix isolation and ab initio calculations.
The infrared spectra of CH3Cl + H2O isolated in solid neon at low temperatures have been investigated. The CH3Cl + H2O system is remarkable because of its propensity to form CH3Cl:H2O and CH3Cl:(H2O)n (n > or = 2) complexes. We focus here on the CH3Cl:H2O species. Low concentration studies (0.01-0.5%) and subsequent annealing lead to formation of the 1:1 CH3Cl:H2O complex with O-H. . .Cl-C or O. . .H-C intermolecular hydrogen bonds. Vibrational modes of this complex have been detected. In addition, spectra of D2O + CH3Cl and HDO + CH3Cl have also been recorded. A detailed vibrational analysis of partially deuterated species shows that HDO is exclusively D bonded to CH3Cl. This is a consequence of the preference for HDO to form a deuterium bonding complex rather than a hydrogen bonding one.


Use of CT scans in selection of patients for pectus excavatum surgery: a preliminary report.
A pectus index can be derived from dividing the transverse diameter of the chest by the anterior-posterior diameter on a simple CT scan. In a preliminary report, all patients who required operative correction for pectus excavatum had a pectus index greater than 3.25 while matched normal controls were all less than 3.25. A simple CT scan may be a useful adjunct in objective evaluation of children and teenagers for surgery of pectus excavatum.