TXNIP loss expands Myc-dependent transcriptional programs by increasing Myc genomic binding.
The c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To meet this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters, glycolytic enzymes, and represses the expression of thioredoxin interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. A Mychigh/TXNIPlow gene signature is clinically significant as it correlates with poor clinical prognosis in triple-negative breast cancer (TNBC) but not in other subtypes of breast cancer, suggesting a functional relationship between Myc and TXNIP. To better understand how TXNIP contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc's intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the nutrient and progrowth signals that control TXNIP expression.


Irreversible Electroporation for Locally Advanced Pancreatic Cancer.
Several minimally invasive image guided tumor ablation techniques have been added to the treatment spectrum for locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) might have a significant additive value in the management of this difficult-to-treat disease. As opposed to thermal ablative techniques, IRE induces cell death by the delivery of high-voltage electrical pulses. The electrical energy disrupts the cellular membrane integrity, causes loss of cellular homeostasis and ultimately results in cell death. The extracellular matrix of connective tissue in surrounding delicate structures such as bile ducts, bowel wall, and larger blood vessels is spared. The preservation of these structures makes IRE attractive for the treatment of pancreatic cancers that are unresectable due to their anatomical location (ie, LAPC and local recurrence after surgical resection). In addition to its cytoreductive abilities, evidence is emerging on IRE's capability to induce systemic immunomodulation through active in vivo vaccination against pancreatic cancer cells. These effects in combination with immunotherapy may offer a new treatment paradigm for tumors with low immunogenic potential like pancreatic ductal adenocarcinoma (PDAC). This review discusses several practical and technical issues of IRE for LAPC: clinical evaluation, indications, patient preparations, procedural steps, imaging characteristics, clinical results, and "tricks of the trade" used to improve the safety and efficacy of the treatment. Future directions such as the combination of IRE with immunotherapy will be shortly addressed.


Gypenosides regulate farnesoid X receptor-mediated bile acid and lipid metabolism in a mouse model of non-alcoholic steatohepatitis.
Gypenosides (Gyp) are the main ingredient of the Chinese medicine, Gynostemma pentaphyllum. They are widely used in Asia as a hepatoprotective agent. Here, we elucidated the mechanism of Gyp in non-alcoholic steatohepatitis (NASH) with a focus on farnesoid X receptor (FXR)-mediated bile acid and lipid metabolic pathways. NASH was induced in mice by high-fat diet (HFD) feeding, while mice in the control group were given a normal diet. At the end of week 10, HFD-fed mice were randomly divided into HFD, HFD plus Gyp, and HFD plus obeticholic acid (OCA, FXR agonist) groups and were given the corresponding treatments for 4 weeks. Next, we analyzed the histopathological changes as well as the liver triglyceride (TG) level and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG), fasting insulin (FINS), TG, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels as well as the bile acid profile. We carried out RT-PCR and western blotting to detect HFD-induced alterations in gene/protein expression related to bile acid and lipid metabolism. The HFD group had histopathological signs of hepatic steatosis and vacuolar degeneration. The liver TG and serum ALT, AST, FBG, FINS, TC, and LDL-C levels as well as the total bile acid level were significantly higher in the HFD group than in the control group (P < 0.01). In addition, we observed significant changes in the expression of proteins involved in bile acid or lipid metabolism (P < 0.05). Upon treatment with Gyp or OCA, signs of hepatic steatosis and alterations in different biochemical parameters were significantly improved (P < 0.05). Further, HFD-induced alterations in the expression genes involved in bile acid and lipid metabolism, such as CYP7A1, BSEP, SREBP1, and FASN, were significantly alleviated. Gyp can improve liver lipid and bile acid metabolism in a mouse model of NASH, and these effects may be related to activation of the FXR signaling pathway.


Influence of Me2SO and incubation time on papain activity studied using fluorogenic substrates.
Papain activity in a buffer containing Me2SO was studied using fluorogenic substrates. It was found that the number of active sites of papain decreases with increasing Me2SO concentration whereas the incubation time, in a buffer containing 3% Me2SO does not affect the number of active sites. However, an increase of papain incubation time in the buffer with 3% Me2SO decreased the initial rate of hydrolysis of Z-Phe-Arg-Amc as well as Dabcyl-Lys-Phe-Gly-Gly-Ala-Ala-Edans. Moreover, an increase of Me2SO concentration in working buffer decreased the initial rate of papain-catalysed hydrolysis of both substrates. A rapid decrease of the initial rate (by up to 30%) was observed between 1 and 2% Me2SO. Application of the Michaelis-Menten equation revealed that at the higher Me2SO concentrations the apparent values of k(cat)/Km decreased as a result of Km increase and kcat decrease. However, Me2SO changed the substrate binding process more effectively (Km) than the rate of catalysis k(cat).


Evaluation of the proximate composition, antioxidant potential, and antimicrobial activity of mango seed kernel extracts.
After pulp extraction in fruit processing industry, a significant quantity of mango seed kernels are discarded as solid wastes. These seed kernels can be ideal raw materials for obtaining extracts rich in bioactive compounds with good antioxidant properties. The conversion of these wastes into utilizable food ingredients would help in reducing environmental problems associated with processing waste disposal. In order to determine their potential use, this study evaluated some of the biochemical characteristics and antimicrobial potential of mango seed kernel extracts on medically important human bacterial and fungal pathogens. Four mango varieties (Apple, Ngowe, Kent and Sabine) from Makueni and Embu counties in Kenya were used for this study. The analyzed mango seed kernel powders were found to contain on average, 6.74-9.20% protein content. Apple and Ngowe mango seed kernels had significantly higher fat content of 13.04 and 13.08, respectively, while Sabine from Makueni had the least fat content of 9.84%. The ash, fiber, and carbohydrate contents ranged from 1.78 to 2.87%, 2.64 to 3.71% and 72.86 to 75.92%, respectively. The mean percentage scavenging ability of mango kernel extracts at the concentration of 20 mg/mL was 92.22%. Apple and Sabine mango kernel extracts had significantly high inhibition zones of 1.93 and 1.73 compared to Kent and Ngowe with 1.13 and 1.10, respectively, against E. coli. For C. albicans, the inhibition of Kent mango kernel extract, 1.63, was significantly lower than that of Ngowe, Apple, and Sabine with 2.23, 2.13, and 1.83, respectively. This study demonstrates that mango seed powder is an abundant and cost-effective potential natural antibiotic and antifungal that can be utilized in addressing the challenge of food poisoning and infections caused by pathogenic microorganisms in the food industry.


Biomechanical testing of a unique built-in expandable anterior spinal internal fixation system.
Expandable screws have greater pullout strength than conventional screws. The purpose of this study was to compare the biomechanical stability provided by a new built-in expandable anterior spinal fixation system with that of 2 commonly used anterior fixation systems, the Z-Plate and the Kaneda, in a porcine partial vertebral corpectomy model. Eighteen porcine thoracolumbar spine specimens were randomly divided into 3 groups of 6 each. A vertebral wedge osteotomy was performed by removing the anterior 2/3 of the L1 vertebral body and the T15/L1 disc. Vertebrae were fixed with the Z-Plate, Kaneda, or expandable fixation system. The 3-dimensional spinal range of motion (ROM) of specimens in the intact state (prior to osteotomy), injured state (after osteotomy), and after internal fixation were recorded. The pullout strength and maximum torque of common anterior screws, the expandable anterior fixation screw unexpanded, and the expandable anterior fixation screw expanded was tested. After internal fixation, the expandable device and Z-plate system exhibited higher left bending motion than the Kaneda system (5.50° and 5.37° vs. 5.04, p = 0.001 and 0.008, respectively), and the Z-plate and Kaneda groups had significantly higher left axial and right axial rotation ROM as compared to the expandable device group (left axial rotation: 5.23° and 5.02° vs. 4.53°; right axial rotation: 5.23° and 5.08° vs. 4.49°). The maximum insertion torque of the expandable device was significantly greater than of a common screw (5.10 vs. 3.75 Ns). The maximum pullout force of the expandable device expanded was significantly higher than that of the common screw and the expandable device unexpanded (3,035.48 N vs. 1,827.38 N and 2,333.49 N). The built-in anterior fixation system provides better axial rotational stability as compared to the other 2 systems, and greater maximum torque and pullout strength than a common fixation screw.


Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons.
Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life.


Assessment of natural variation in the first pore domain of the tomato HKT1;2 transporter and characterization of mutated versions of SlHKT1;2 expressed in Xenopus laevis oocytes and via complementation of the salt sensitive athkt1;1 mutant.
Single Nucleotide Polymorphisms (SNPs) within the coding sequence of HKT transporters are important for the functioning of these transporters in several plant species. To unravel the functioning of HKT transporters analysis of natural variation and multiple site-directed mutations studies are crucial. Also the in vivo functioning of HKT proteins, via complementation studies performed with athkt1;1 plants, could provide essential information about these transporters. In this work, we analyzed the natural variation present in the first pore domain of the HKT1;2 coding sequence of 93 different tomato accessions, which revealed that this region was conserved among all accessions analyzed. Analysis of mutations introduced in the first pore domain of the SlHKT1;2 gene showed, when heterologous expressed in Xenopus laevis oocytes, that the replacement of S70 by a G allowed SlHKT2;1 to transport K(+), but also caused a large reduction in both Na(+) and K(+) mediated currents. The study of the transport characteristics of SlHKT1;2 revealed that Na(+)-transport by the tomato SlHKT1;2 protein was inhibited by the presence of K(+) at the outside of the membrane. GUS expression under the AtHKT1;1 promoter gave blue staining in the vascular system of transgenic Arabidopsis. athkt1;1 mutant plants transformed with AtHKT1;1, SlHKT1;2, AtHKT1;1S68G, and SlHKT1;2S70G indicated that both AtHKT1;1 and SlHKT1;2 were able to restore the accumulation of K(+) in the shoot, although the low accumulation of Na(+) as shown by WT plants was only partially restored. The inhibition of Na(+) transport by K(+), shown by the SlHKT1;2 transporter in oocytes (and not by AtHKT1;1), was not reflected in Na(+) accumulation in the plants transformed with SlHKT1;2. Both AtHKT1;1-S68G and SlHKT1;2-S70G were not able to restore the phenotype of athkt1;1 mutant plants.


Poliomyelitis control in Japan.
The Sabin oral poliovirus vaccine ( OPV ) has been used in Japan since 1961. Since then the number of paralytic cases has decreased markedly. The incidence of paralytic and positive rates for antibodies to poliovirus were analyzed. The number of paralytic cases associated with OPV was low for cases due to type 1 virus and high for those due to type 2 virus. As for cases due to type 3 virus, the number was high until 1969 and has been low since 1970. This difference was brought about by changing the batch of type 3 virus used in the preparation of OPV . The analysis of titers of neutralizing antibody showed that response to type 1 virus in OPV used in 1977 and to type 3 virus in OPV used in 1972 and 1973 was not adequate. Both situations were improved by changing the batches of virus used for OPV . These experiences suggest that the use of good batches is necessary for safety and efficacy of OPV .


[From atopic dermatitis to asthma].
Atopic dermatitis (AD) is the most common chronic skin disorder in infancy and childhood and is the main hallmark of atopic constitution. The disease is multifactorial, and although genetic predisposition is certainly a prerequisite, a number of environmental factors modulate the phenotypic expression of AD. The majority of affected children shows IgE sensitisation towards a large variety of foods and aeroallergens. Since at least 1600, it has been recognized that patients with AD have a high predisposition to develop asthma. Recent epidemiological studies show that AD is commonly seen in individuals from families with a history of asthma. In addition, in population where asthma is uncommon, AD is also uncommon. The sex distribution of AD and asthma is the same, with boys affected significantly more often by these two atopic diseases and in similar proportions. The ETAC project (Early Treatment of the Atopic Child) is a large multicenter, multi-national, double blind, placebo controlled, randomised trial. The main objective of the study is to stop the progression from AD to asthma in young children with AD using early therapeutic intervention with Cetirizine and the second objective is to investigate the main risk factors for the onset of asthma. The results of this study indicate that exposure to potent allergens such as cat or mite significantly increased the risk of sensitisation to these allergens. Prolonged breast feeding was associated with a lowest sensitisation rate to cow milk proteins and to egg. Therefore environmental factors seem to play a crucial role in IgE sensitisation in children with AD.


[Dynamics of ammonia and pH in meat stored under various conditions].
The changes in ammonia content and pH values in beef and pork stored at different temperatures were studied in relation with sensory changes. Samples were taken from the stored meat at a temperature of +3 degrees C in the 0th, 12th, 36th, 60th, 84th, 108th and 132nd hour and at a temperature of +10 degrees C in the 0th, 6th, 24th, 36th, 54th, 72nd and 84th hour. The quantity of ammonia in the samples was determined by means of an ion-selective electrode. The pH value was determined potentiometrically. The kinds of meat (pork, beef) differed in the development of ammonia content. Ammonia content was found to be directly dependent on storage temperature. A similar relation was observed in the development of pH values. The sensory changes of stored meat were parallel to the changes in ammonia levels and pH values. The results can be used for an evaluation of the degree of biochemical changes in the meat and of the fitness of the raw material to the production of tins for long storage. Advantageous points are seen in the rapid and objective determination of ammonia content by the ion-selective electrode and the determination of the pH value by means of the combined glass electrode with the aid of the same apparatus.


Plant Response to Metal-Containing Engineered Nanomaterials: An Omics-Based Perspective.
The increasing use of engineered nanomaterials (ENMs) raises questions regarding their environmental impact. Improving the level of understanding of the genetic and molecular basis of the response to ENM exposure in biota is necessary to accurately assess the true risk to sensitive receptors. The aim of this Review is to compare the plant response to several metal-based ENMs widely used, such as quantum dots, metal oxides, and silver nanoparticles (NPs), integrating available "omics" data (transcriptomics, miRNAs, and proteomics). Although there is evidence that ENMs can release their metal components into the environment, the mechanistic basis of both ENM toxicity and tolerance is often distinct from that of metal ions and bulk materials. We show that the mechanisms of plant defense against ENM stress include the modification of root architecture, involvement of specific phytohormone signaling pathways, and activation of antioxidant mechanisms. A critical meta-analysis allowed us to identify relevant genes, miRNAs, and proteins involved in the response to ENMs and will further allow a mechanistic understanding of plant-ENM interactions.


Comparison of antiplatelet effect of loading dose of clopidogrel versus abciximab during coronary intervention.
Randomized clinical trials have evidently shown that the addition of thienopyridines or abciximab to standard aspirin results in a significant reduction of ischaemic complications after coronary stent implantation. A head-to-head comparison of these antithrombotic drug regimens during coronary intervention is, however, lacking, and this was the main aim of the present study. Thirty-nine patients with angina pectoris who were scheduled for coronary stent implantation were assigned to either group 1 (160 mg aspirin + 500 mg ticlopidine post-stent), group 2 (160 mg aspirin + abciximab + 500 mg ticlopidine post-stent) or group 3 (160 mg aspirin + loading dose (375/450 mg) clopidogrel pre-stent and 75 mg clopidogrel post-stent). A loading dose of 450 mg clopidogrel was found to be more effective than the standard loading dose of 375 mg. Platelet aggregation induced by 4 micromol/l adenosine diphosphate (ADP) was assessed in samples collected before intervention and 10 min, 4 h and 20 h after intervention. Before intervention, a moderate antiplatelet effect because of aspirin intake was observed (ADP aggregation level, +/- 50%) in all study groups. After intervention, platelet aggregation tended to be enhanced in group 1 while it was strongly inhibited in the groups pre-treated with clopidogrel or abciximab: ADP induced an aggregation level early after intervention of 60 +/- 12% in group 1 (ticlopidine post-stenting) versus 30 +/- 10% in group 3 (loading dose clopidogrel) versus 3 +/- 6% in group 2 (abciximab). Abciximab achieved a more complete inhibition of aggregation than clopidogrel (P = 0.007). The overall complication rate was low with only one major bleeding and one death due to side-branch occlusion with re-infarction occurring, both in the abciximab group. Platelet aggregation during coronary intervention is strongly inhibited by both abciximab and by high loading dose of clopidogrel. Although abciximab showed a stronger antiplatelet effect than clopidogrel, it remains to be established whether this ex vivo superiority of abciximab also translates into an overall clinical benefit in patients with elective stent implantation.


Cystatin C level is associated with the recovery of renal function in cancer patients after onset of acute kidney injury.
The risk of injury to the kidney can be significantly exacerbated by the presence of tumors and the effects of related treatments. Kidney injury associated with cancer is common in multiple myeloma, tumor lysis syndrome, hematopoietic stem cell therapy, and chemotherapy. Cancer patients are at increased risk of infection, sepsis, tumor lysis syndrome, drug-related toxicity, and other comorbidities, leading to a significantly increased risk of acute kidney injury (AKI). This study retrospectively analyzed the clinical data of AKI in cancer patients and explored the predictive value of Cystatin C (CysC) in the prognosis of cancer patients with AKI. Cancer patients attending the Fifth People's Hospital of Shenyang from April 2014 to March 2019 were enrolled according to inclusion and exclusion criteria. Cancer patients with AKI were divided into two groups according to the changes in renal function during the follow-up period: a renal function recovery group and a nonrecovery group. The differences in baseline data of the two groups were compared. Logistic univariate and multivariate regression analyses were conducted to determine the risk of renal function failure. A total of 3,127 cases were included. Among them, 659 cases (21.1%) had AKI, and 2,468 cases had no AKI. Among the 659 AKI patients, 473 (71.8%) patients' renal function recovered, while 186 (28.2%) did not. Logistic univariate and multivariate regression analyses indicated that age [odds ratio (OR) =1.133, 95% confidence interval (CI): 1.064-1.219], diabetes (OR =1.226, 95% CI: 1.093-1.385), chronic kidney disease (CKD) (OR =1.347, 95% CI: 1.108-1.624), hematological malignancies (OR =1.174, 95% CI: 1.063-1.311), chemotherapy (OR =1.119, 95% CI: 1.055-1.304), systolic blood pressure (OR =1.108, 95% CI: 1.062-1.267), serum creatinine (Scr) (OR =1.262, 95% CI: 1.105-1.446), and CysC (OR =1.416, 95% CI: 1.251-1.739) were related to the failure of renal function to recover after AKI. Baseline CysC level is associated with the occurrence of AKI in cancer patients and a failure to recover renal function during follow-up.


Nano lipid-drug conjugate: An integrated review.
Lipid-drug conjugates (LDC), which may also be addressed as lipoidal prodrug, have the therapeutic actives chemically bound to a lipid moiety like fatty acids or phospholipids. Fabricated in nano-size, lipid-drug conjugate forms another breed of lipid nanoparticles. LDCs are prepared in order to increase the drug loading and hence prevent leakage of a highly polar drug from a lipophilic matrix. In turn, it assists to achieve active targeting of therapeutics with reduced side effect by altering the pharmacokinetic profile of the drug. These self-assembled systems take the benefit of metabolic pathways of lipid biochemistry, allowing suitable organ targeting depending upon its size. These lipids because of its similarities with physiological lipids, enhances the solubility of the therapeutic agents and thereby improve the bioavailability. This present review is meant to encompass different aspects related to lipid drug conjugates which include types of lipids and drugs that can be used to develop this type of formulation. Here, we throw light on methods of preparation of lipid drug conjugate, processing them into nanoparticle, its characterization and different applications of lipid drug conjugate. We aim to present a holistic view on lipid drug conjugate as a suitable drug delivery approach.


The effect of inter-electrode distance on the electric field distribution during transcutaneous lumbar spinal cord direct current stimulation.
Previous studies have indicated potential neuromodulation of the spinal circuitry by transcutaneous spinal direct current stimulation (tsDCS), such as changes in motor unit recruitment, shortening of the peripheral silent period and interference with supraspinal input to lower motor neurons. All of these effects were dependent on the polarity of the electrodes. The present study investigates how the distance between the electrodes during tsDCS influences the electric field's (E-field) spatial distribution in the lumbar and sacral spinal cord (SC). The electrodes were placed longitudinally along the SC, with the target electrode over the lumbar spine, and the return electrode above the former, considering four different distances (4, 8, 12 and 16 cm from the target). A fifth configuration was also tested with the return electrode over the right deltoid muscle. Peak values of the E-field's magnitude are found in the lumbo-sacral region of the SC for all tested configurations. Increasing the distance between the electrodes results in a wider spread of the E-field magnitude distribution along the SC, with larger maximum peak values and a smoother variation. The fifth configuration does not present the highest maximum values when compared to the other configurations. The results indicate that the choice of the return electrode position relative to the target can influence the distribution and the range of values of the E-field magnitude in the SC. Possible clinical significance of the observed effects will be discussed.


Evaluation of different antimicrobial agents used as selective supplements for isolation and recovery of Yersinia enterocolitica.
Seventeen antimicrobial agents were evaluated separately or in combination for their efficiency as selective supplements in a broth medium against six different serotypes of Yersinia enterocolitica and 20 selected strains of different Gram-negative bacteria. Irgasan (DP300, 5-chloro-2-(2,4- dichlorophenoxy) phenol) at a concentration of 4 micrograms ml-1 inhibited the growth of most Gram-negative bacteria with the exceptions of Aeromonas hydrophila, Morganella morganii, Pseudomonas aeruginosa and Serratia liquefaciens. Other antimicrobial agents incorporated in the growth medium, separately or in combination with Irgasan, either inhibited some strains of Y. enterocolitica or did not inhibit the growth of Irgasan-resistant Gram-negative bacteria.


Treatment of postpartum psychosis in a mother-baby unit: do both mother and baby benefit?
To describe characteristics and treatments of mother-baby dyads affected by postpartum psychosis admitted to a specialist mother-baby inpatient psychiatric unit in Australia. A retrospective review of medical records for all mothers with postpartum psychosis and their babies admitted to a mother-baby unit over a 5-year period was conducted. A total of 25 dyads met the study criteria. Affected women were found to be severely ill with a high rate of involuntary status (64%). They waited an average 4.7 days for a bed in the mother-baby unit. All received an atypical antipsychotic, with 16% receiving lithium augmentation. Infants were found to have generally normative growth and development, with relationship concerns noted in 5. A total of 36% of the cohort maintained some breastfeeding, and all had their infants in their care at discharge. The mother-baby unit enabled severely ill women to remain with their infants during treatment. While a minority of infants showed developmental concerns, appropriate development was noted in most. Future efforts should focus on determining the most effective treatments and further defining the risks and benefits for infants in mother-baby units.


Pars plana vitrectomy for ocular complications of Behçet's disease.
To evaluate the outcomes of vitreoretinal surgery for the ocular complications of Behcet's disease. This retrospective study included 20 eyes of 15 patients with Behçet's disease (9 men, 6 women; mean age at surgery, 31.0 +/- 1.8 years; range, 21-44 years) who had undergone vitreoretinal surgery for Behcet's disease at Ondokuz Mayis University, Faculty of Medicine, Department of Ophthalmology, Samsun, Turkey, between January 2000 and September 2003. Postoperative visual acuity outcome, course of uveitis, and complications were evaluated in all patients. Indications for surgery were vitreous opacities in 10 eyes (50%), cystoid macular edema in 5 eyes (25%), epiretinal membrane in 3 eyes (15%), and vitreous hemorrhage in 2 eyes (10%). At the last postoperative follow-up, visual acuity had increased 2 Snellen lines or more in 10 (50%) of 20 eyes. Cystoid macular edema completely improved in 3 (60%) of 5 eyes after vitrectomy. Uveitis attacks significantly decreased during follow-up (P = .015). Immunosuppressive treatment was stopped in 11 (73%) of 15 patients. Retinal detachment and phthisis were not observed in any eye. Vitreoretinal surgery may be useful in the treatment of posterior segment complications of Behcet's disease.


An emergency EVAR service reduces mortality in ruptured abdominal aortic aneurysms.
The aim of this study was to compare all in-hospital mortality for ruptured abdominal aortic aneurysms (rAAAs) before and after the establishment of an emergency EVAR (eEVAR) service. An eEVAR service was established in January 2006, since when all patients presenting with rAAAs have been considered for endovascular repair. Data for all rAAAs presenting between January 2006 and December 2007 was prospectively collected (Group 1). This patient group was compared to those presenting with rAAA between January 2003 and December 2005 when eEVAR was not offered at our institution (Group 2). These records had also been collected prospectively and submitted to the National Vascular Database (NVD). A total of 50 rAAAs (17 eEVAR, 29 open repairs, 4 palliated) presented after the introduction of eEVAR (Group 1) and 71 in the historical Group 2 of which 54 underwent open repair and 17 were palliated. The total in-hospital mortality was significantly lower in Group 1 20% (eEVAR (n=1), 6%: Open (n=5), 17%: palliated (n=4), 100%) when compared to Group 2 54% (Open (n=21), 39%: palliated (n=17), 100%) (p=0.000001). Furthermore similar significant differences were seen in 30-day operative mortalities between the two groups 13% in Group 1 versus 39% in Group 2 (p=0.0003). In addition the proportion of patients who were palliated has significantly decreased (8% Group 1 versus 24% Group 2, p=0.01). The establishment of an eEVAR service has significantly reduced in-hospital mortality for patients presenting with ruptured abdominal aortic aneurysms.


Recovery of opercular anomalies in gilthead sea bream, Sparus aurata L.: morphological and morphometric analysis.
Opercular anomalies are very frequent in reared gilthead sea bream and these can negatively influence the product value. Field observations have suggested that opercular malformations can recover over time. In order to verify this hypothesis, 140-day-old gilthead sea bream with monolateral opercular anomalies were divided into three groups, according to the type and increasing seriousness of the opercular malformations, and another group was composed of fish with bilateral opercular anomalies. All groups were monitored for 16 months. In the group with monolateral anomalies, the opercular recovery process was documented by morphological (stereomicroscope) and morphometric analysis. For the latter analysis, two relevant areas, A and T, were identified in the cephalic region. The ratio (T - A)/T, tending to 1, represents the recovery index (RI) of anatomical integrity and quantifies the recovery level of opercular complex anomalies. Results suggested that the recovery process was considerable over the 16 months of investigation but should not be considered complete. At the end of the study, 61% of the gilthead sea bream population with monolateral opercular defects recovered external integrity, whereas the population with bilateral defects showed a poorer recovery capability.


Association between smoking habits and tryptophan hydroxylase gene C218A polymorphism among the Japanese population.
Genetic polymorphisms have proposed a new insight in smoking behavior. Genes in serotonin system are one of the candidates because of serotonin's role in mood regulation. A polymorphism C218A in intron 7 of the tryptophan hydroxylase (TPH) gene has been hypothesized in relation to smoking predisposition. We examined the association on two Japanese populations: one was from the first-visit outpatients of Aichi Cancer Center Hospital during 3-month period between April and June, 2001 (N=591), and the second was from the examinees who attended a health checkup program supported by the Nagoya municipal government in 2000 (N=446). Written documents on informed consent were obtained and lifestyle questionnaires were recorded. TPH C218A genotypes were determined by the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) method. The frequencies of the C- and A-allele were 52% and 48%, respectively, which was in Hardy-Weinberg equilibrium. As for current smoking status, no associations were statistically observed. It was, however, indicated that smokers with A/A genotype started smoking earlier in their life. Among male health examinees, mean ages at starting smoking were 18.7 (A/A), 19.9 (C/A), and 22.4 years (C/C), (P<0.01). Also, on the Aichi Cancer Center Hospital subjects aged 60 and older, mean ages were 19.0 (A/A), 20.2 (C/A), and 20.3 years (C/C) for males and 22.3 (A/A), 31.0 (C/A), and 33.0 years (C/C) for females (P<0.05). The present study demonstrated that the TPH C218A polymorphism in intron 7 had no association with current smoking status in Japanese population. The hypothesis of early smoking initiation of A/A genotype was partially in agreement.


Efficacy of sulfamethoxypyridazine in a murine model of Pneumocystis carinii pneumonia.
Sulfamethoxazole is the component of co-trimoxazole responsible for its efficacy against Pneumocystis carinii pneumonia, but this drug is associated with frequent adverse effects. Sulfamethoxypyridazine is significantly more effective than sulfamethoxazole against a murine model of P. carinii and might be a candidate for testing in infected patients.


Mechanisms and clinical implications of hepatocyte lipoapoptosis.
Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, elevated serum levels of free fatty acids (FFAs) and fatty infiltration of the liver. Accumulation of triglycerides in the hepatocyte results from the uptake and esterification of circulating FFAs by the liver. Contrary to current theory, hepatic steatosis appears to be a detoxification process, as FFAs are directly cytotoxic for the hepatocyte and inhibition of triglyceride formation enhances FFAs toxicity. Hepatocyte apoptosis is a key feature of NAFLD and correlates with disease severity. Since FFA-induced toxicity, or lipoapoptosis, represents a mechanism for the pathogenesis of NAFLD, this article will highlight the cellular pathways contributing to hepatocyte lipoapoptosis. To date, there is no proven effective therapy for patients with NAFLD and insights into the molecular mediators of lipoapoptosis should help promote effective therapeutic strategies for this disease.


Significance of non-dermatophyte moulds and yeasts in onychomycosis.
In a multicentre, randomised, double-blind, 48-week clinical trial, 118 patients with toe-nail onychomycosis were given terbinafine (250 mg daily) or placebo for 12 weeks, followed by 12 weeks of observation. Non-responders were offered 12 further weeks of terbinafine (250 mg daily) from week 28. Each patient had 8-12 consecutive nail specimens collected from the same nail, allowing for an assessment of the fungal nail flora from 1,321 nail specimens. By week 48, the overall mycological cure rate for terbinafine patients was 94%. 64% of patients had an underlying dermatophyte infection with at least 1 non-dermatophyte mould or yeast isolated from at least 1 specimen. These contaminants often overgrow or mask the presence of a dermatophyte. In only 2.5% of all patients was the same non-dermatophyte isolated from 2 or more consecutive specimens, probably representing secondary colonisation which exploits nutrients released by the underlying dermatophyte. The presence of incidental non-dermatophyte contaminants or secondary colonisers did not affect treatment outcome, and in this study treatment of the primary dermatophyte pathogen with terbinafine cleared the nails from infection in all cases. 80% of patients remained mycologically negative after 2 years.


Double contrast MR imaging with iron colloid and Gd-DTPA in cholangiocellular carcinoma.
Double contrast MR imaging with combined use of chondroitin sulfate iron colloid (CSIC) and Gd-DTPA was attempted in 3 cases of cholangiocellular carcinoma (CCC). In all cases, nonenhanced spin echo T1- and T2-weighted images, and T1-weighted images after i.v. injection of Gd-DTPA were obtained. Within one week, the MR sequences were repeated one hour after i.v. injection of CSIC. Double contrast (CSIC/Gd-DTPA) T1-weighted imaging was evaluated and compared with the other sequences in terms of tumor detectability, tumor spreading and tumor characterization. Double contrast MR imaging was comparable in tumor detectability and superior as to the evaluation of spreading and characterization to the other MR imaging modalities.


Isotachophoresis and immunoelectrophoresis of water-soluble and -insoluble crystallins of the ageing bovine lens.
Water-soluble (WS) and water-insoluble (WI) crystallins were prepared from calf and bovine lenses. The WS-crystallins were analyzed by capillary isotachophoresis and by immunoelectrophoresis with polyvalent and alpha-, beta-, gamma-crystallin specific antisera. The WI-crystallins were first solubilized in formamide and then analyzed by the same methods. The WS-crystallins, which increase in weight, but decrease in % with increasing age, show an increase of alpha-crystallins from 36 to 43%, an increase of beta-crystallins from 42 to 48% and a decrease of gamma-crystallins from 22 to 9%. In the WI-crystallins, which increase in weight and in % with increasing age, the alpha-crystallins form the main portion with an increase from 54 to 61%. The beta-crystallins in WI remain fairly constant at about 37% and the gamma-crystallins decrease from 8 to 2%. Quantitatively, the alpha-crystallin is the major constituent of the lens. The alpha-crystallin and the beta-crystallin components are increasingly incorporated in WI with increasing age. The gamma-crystallin components are selectively incorporated into WI-protein. Immunologically, alpha-, beta- and gamma-crystallins were detected by the polyvalent and specific antisera in WS- and in WI- crystallins.


Gender debate as a challenge in nursing training.
to understand the challenges of introducing gender debate in nursing training from undergraduate students' perspective. a qualitative, exploratory-explanatory study. Data were collected through a semi-structured interview applied to 12 undergraduate nursing students at a public university in São Paulo. For data treatment and analysis, the Discourse of the Collective Subject was used in light of Boaventura de Sousa Santos' knowledge production paradigm theoretical framework. nursing education remains centered on the traditional scientific model, neglecting gender and strengthening stereotypes aimed at the feminization of the profession. nursing training has a challenge of implementing actions that deepen the gender theme. Therefore, some strategies are suggested, such as improving professor training and appropriating emancipatory pedagogical practices; reviewing pedagogical political projects; curriculum theorization and restructuring; problematizing gender issues for nursing leadership.


A wearable device for emotional recognition using facial expression and physiological response.
This paper introduces a glasses-typed wearable system to detect user's emotions using facial expression and physiological responses. The system is designed to acquire facial expression through a built-in camera and physiological responses such as photoplethysmogram (PPG) and electrodermal activity (EDA) in unobtrusive way. We used video clips for induced emotions to test the system suitability in the experiment. The results showed a few meaningful properties that associate emotions with facial expressions and physiological responses captured by the developed wearable device. We expect that this wearable system with a built-in camera and physiological sensors may be a good solution to monitor user's emotional state in daily life.


Adsorbate doping of MoS2 and WSe2: the influence of Na and Co.
We have investigated the influence of metal adsorbates (sodium and cobalt) on the occupied and unoccupied electronic structure of MoS2(0 0 0 1) and WSe2(0 0 0 1), through a combination of both photoemission and inverse photoemission. The electronic structure is rigidly shifted in both the WSe2 and MoS2 systems, with either Na or Co adsorption, generally as predicted by accompanying density functional theory based calculations. Na adsorption is found to behave as an electron donor (n-type) in MoS2, while Co adsorption acts as an electron acceptor (p-type) in WSe2. The n-type transition metal dichalcogenide (MoS2) is easily doped more n-type with Na deposition while the p-type transition metal dichalcogenide (WSe2) is easily doped more p-type with Co deposition. The binding energy shifts have some correlation with the work function differences between the metallic adlayer and the transition metal dichalcogenide substrate.


Nonstoichiometric, Protic Azolium Azolate Ionic Liquids Provide Unique Environments for N-Donor Coordination Chemistry.
Here we demonstrate that neat reactions of amphoteric azoles with more basic azoles give a family of finely tunable, nonstoichiometric liquids which are useful for N-donor coordination chemistry. Reacting 4,5-dicyanoimidazole (4,5-DCNIm) with 1-methylimidazole (1-mim) gives new compounds with composition-dependent speciation. Two crystalline compounds, a 1:1 protic salt, [H(1-mim)][4,5-DCNIm], and a 1:2 salt co-crystal, [H(1-mim)][4,5-DCNIm]⋅4,5-DCNIm, were isolated and structurally characterized, while differential scanning calorimetry revealed both suppression of crystallization and the presence of neutral and anionic species in the melt. Reactions of Cu(NO3 )2 ⋅2.5 H2 O, CuO, and ZnO with the neat 2:1 1-mim/4,5-DCNIm melt resulted in the isolation of entirely N-donor ligated complexes of the formula M(4,5-DCNIm)2 (1-mim)4 (M=Cu, Zn).


Efficient COVID-19 CT Scan Image Segmentation by Automatic Clustering Algorithm.
This article addresses automated segmentation and classification of COVID-19 and normal chest CT scan images. Segmentation is the preprocessing step for classification, and 12 DWT-PCA-based texture features extracted from the segmented image are utilized as input for the random forest machine-learning algorithm to classify COVID-19/non-COVID-19 disease. Diagnosing COVID-19 disease through an RT-PCR test is a time-consuming process. Sometimes, the RT-PCR test result is not accurate; that is, it has a false negative, which can cause a threat to the person's life due to delay in starting the specified treatment. At this moment, there is an urgent need to develop a reliable automatic COVID-19 detection tool that can detect COVID-19 disease from chest CT scan images within a shorter period and can help doctors to start COVID-19 treatment at the earliest. In this article, a variant of the whale optimization algorithm named improved whale optimization algorithm (IWOA) is introduced. The efficiency of the IWOA is tested for unimodal (F1-F7), multimodal (F8-F13), and fixed-dimension multimodal (F14-F23) benchmark functions and is compared with the whale optimization algorithm (WOA), salp swarm optimization (SSA), and sine cosine algorithm (SCA). The experiment is carried out in 30 trials and population size, and iterations are set as 30 and 100 under each trial. IWOA achieves faster convergence than WOA, SSA, and SCA and enhances the exploitation and exploration phases of WOA, avoiding local entrapment. IWOA, WOA, SSA, and SCA utilized Otsu's maximum between-class variance criteria as fitness function to compute optimal threshold values for multilevel medical CT scan image segmentation. Evaluation measures such as accuracy, specificity, precision, recall, Gmean, F_measure, SSIM, and 12 DWT-PCA-based texture features are computed. The experiment showed that the IWOA is efficient and achieved better segmentation evaluation measures and better segmentation mask in comparison with other methods. DWT-PCA-based texture features extracted from each of the 160 IWOA-, WOA-, SSA-, and SCA-based segmented images are fed into random forest for training, and random forest is tested with DWT-PCA-based texture features extracted from each of the 40 IWOA-, WOA-, SSA-, and SCA-based segmented images. Random forest has reported a promising classification accuracy of 97.49% for the DWT-PCA-based texture features, which are extracted from IWOA-based segmented images.


Effect of treadmill exercise on social interaction and tyrosine hydroxylase expression in the attention-deficit/ hyperactivity disorder rats.
Attention-deficit/hyperactivity disorder (ADHD) involves clinically heterogeneous dysfunctions of sustained attention, with behavioral hyper-activity and impulsivity. The exact underlying mechanisms of ADHD are not known, however, impairment of dopaminergic system in the nigrostriatal pathway was suggested as the one of the possible mechanisms of ADHD. Tyrosine hydroxylase (TH) is the rate-limiting enzyme that is involved in the synthesis of dopamine. Spontaneous hypertensive rats have been used as the animal model for ADHD. Physical exercise is known to restore the brain functions disrupted by several neurode-generative and psychiatric disorders. In the present study, we investigated whether treadmill exercise exerts therapeutic effect on ADHD. Social interaction test for the evaluation of impulsivity was performed using spontaneous hypertensive rats. TH expressions in the substantia nigra and striatum were evaluated by immunohistochemistry. In the present results, the rats of ADHD model showed hyper-social behaviors. TH expressions in the substantia nigra and striatum were decreased in the rats of ADHD model. Treadmill exercise alleviated hyper-social behaviors in the ADHD rats. TH expressions of ADHD rats were also enhanced by treadmill exercise. Here in this study, we showed that treadmill exercise effectively alleviates the ADHD-induced symptoms through enhancing of TH expression in the brain.


High power terahertz radiation source based on electron beam wakefields.
A table top device for producing high peak power (tens of megawatts to a gigawatt) T-ray beams is described. An electron beam with a rectangular longitudinal profile is produced out of a photoinjector via stacking of the laser pulses. The beam is also run off-crest of the photoinjector rf to develop an energy chirp. After passing through a dielectric loaded waveguide, the beam's energy becomes modulated by its self-wake. In a chicane beamline following the dielectric energy-bunching section this energy modulation is converted to a density modulation-a bunch train. The density modulated beam can be sent through a power extraction section, like a dielectric loaded accelerating structure, or simply can intercept a foil target, producing THz radiation of various bandwidths and power levels.


Vagus nerve stimulation modulates arachidonic acid production in the mesenteric lymph following intestinal ischemia-reperfusion injury.
Inflammatory lipid mediators in mesenteric lymph (ML), including arachidonic acid (AA), are considered to play an important role in the pathogenesis of multiple-organ dysfunction after hemorrhagic shock. A previous study suggested that vagus nerve stimulation (VNS) could relieve shock-induced gut injury and abrogate ML toxicity, resulting in the prevention of multiple-organ dysfunction. However, the detailed mechanism of VNS in lymph toxicity remains unclear. The study aimed to investigate the relationship between VNS and inflammatory lipid mediators in ML. Male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery obstruction (SMAO) for 60 minutes to induce intestinal ischemia followed by reperfusion and observation. The ML duct was cannulated, and ML samples were obtained both before and after SMAO. The distal ileum was removed at the end of the observation period. In one group of animals, VNS was performed from 10 minutes before 10 minutes after SMAO (5 V, 0.5 Hz). Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of AA was performed for each ML sample. The biological activity of ML was examined using a monocyte nuclear factor κ-light-chain-enhancer of activated B cells activation assay. Western blotting of phospholipase A2 group IIA (PLA2-IIA) was also performed for ML and ileum samples. Vagus nerve stimulation relieved the SMAO-induced histological gut injury. The concentration of AA and level of nuclear factor κ-light-chain-enhancer of activated B cells activation in ML increased significantly after SMAO, whereas VNS prevented these responses. Western blotting showed PLA2-IIA expression in the ML and ileum after SMAO; however, the appearance of PLA2-IIA band was remarkably decreased in the samples from VNS-treated animals. The results suggested that VNS could relieve gut injury induced by SMAO and decrease the production of AA in ML by altering PLA2-IIA expression in the gut and ML.


Least restrictive or least understood? Waist restraints, provider practices, and risk of harm.
Since implementation of The Omnibus Budget Reconciliation Act of 1987, restraint use in American nursing homes has reduced dramatically. The reduction in vest restraints has resulted in an increase in "least restrictive" devices such as waist restraints. Although this analysis of U.S. Food and Drug Administration Adverse Event Reporting Data Files found that waist devices pose the same potential risk for asphyxial death as vest restraints, few health professionals and consumers are aware of this outcome. Post-marketing device reporting needs better data quality and surveillance, which can certainly benefit the Centers for Medicare and Medicaid Services in their efforts to regulate and enforce standards of care that reduce deaths and injuries to vulnerable nursing home residents.


First year pre-registration nursing student perceptions of community nursing roles: a thematic analysis.
Nursing is the largest qualified professional workforce in the UK, with TV programmes, films, books and other media sources frequently informing the general public's views of nursing roles. This study examines first year pre-registration nursing students' perceptions of community nursing roles, using a qualitative design and questionnaire. Participants included pre-registration nursing students from a university in north west England: a mean of 240 and 68.5% across all questions. Of those invited, 267 were adult nursing students; 53 were mental health nursing students; and 30 were child nursing students. Data were collected using an online questionnaire across two groups and analysed thematically. Four questions were considered relating to students' knowledge of community nursing. Results uncovered knowledge gaps, and community roles were perceived to be less dynamic than secondary care roles, correlating to clinical tasks and popularised media sources. Results provided insight into student nurse perceptions, offering an understanding from which to construct a more inclusive, community-focused nursing curriculum.


Segmentations of the cartilaginous skeletons of chondrichthyan fishes by the use of state-of-the-art computed tomography.
To apply dual-source multidetector computed tomography (DSCT) scanning technology in conjunction with computationally assisted segmentation in order to explore and document skeletal variation that has occurred over the course of evolution. We examined 4 divergent species of elasmobranchs with high-resolution 3rd generation DSCT. The formalin prepared species examined were: Aptychotrema vincentiana, Mitsukurina owstoni, Negaprion brevirostris and Dactylobatus armatus. All three structures of the hyoid arch (hyomandibular, ceratohyal, and basihyal) were clearly visible whereas in the two batoids, the hyomandibular was the prominent feature, the ceratohyal was not visible and the basihyal was more reduced and closer to the gill arches. The general shape of the puboischiadic bar, or pelvic girdle, illustrated a closer relationship between the two sharks and the two batoids than between the two groups. In exquisite detail, DSCT imaging revealed important morphological variations in various common structures in the four elasmobranch specimens studied, providing insights into their evolutionary diversification.


Cortical sensorimotor reorganization after spinal cord injury: an electroencephalographic study.
The aim of this study was to determine if cortical motor representation and generators change after partial or complete paralysis after spinal cord injury (SCI). Previously reported evidence for a change in cortical motor function after SCI was derived from transcranial magnetic stimulation. These studies inferred a reorganization of the cortical motor system. We applied the new technique of high-resolution EEG to measure changes in cortical motor representation directly. We recorded and mapped the motor potential (MP) of the movement-related cortical potentials in 12 SCI patients and 11 control subjects. Results were analyzed using a distance metric to compare MP locations between patients and control subjects. EEG was coregistered with subject-specific MR images and a boundary element model created for dipole source analysis (DSA). When compared with normal control subjects, seven quadriparetics had posteriorly located MPs with finger movements. One paraparetic had a posterior MP with toe movements, but three who could not move the toes had normally located MPs on attempts to move. DSA confirmed the electrical field map distributions of the MPs. We are reporting a reorganization of cortical motor activity to a posterior location after SCI. These results suggest an important role of the somatosensory cortex (S1) in the recovery process after SCI.


A DMD case caused by X chromosome rearrangement.
Duchenne/Becker muscular dystrophy (DMD/BMD) is one of the most common progressive muscular dystrophy diseases with X-linked recessive inheritance. It is mainly caused by the deletion, duplication and point mutation of DMD gene. In rare cases, it is also caused by the destruction of DMD gene by chromosomal structural rearrangement. Here, we report a case of Duchenne/Becker Muscular dystrophy (DMD/BMD) with typical symptoms but unknown genetic defects after MLPA and next generation sequencing tests in other hospitals. Interestingly, we find a pericentric inversion of X chromosome (Chr.X: g. [31939463-31939465del; 31939466-131765063 inv; 131765064-131765067del]) in this patient. We then use the karyotyping, FISH, long-read sequencing and Sanger sequencing technologies to characterize the chromosome rearrangement. We find that this chromosomal aberration disrupt both the DMD gene and the HS6ST2 gene. The patient present with typical DMD symptoms such as muscle weakness, but no obvious symptoms of Paganini-Miozzo syndrome. Our results suggest that the destruction of DMD gene by structural rearrangement is also one of the important causes of DMD. Therefore, we suggest to provide further genetic testing for those DMD patients with unknown genetic defects through routine genetic testing. Cost-effective karyotyping and FISH should be considered firstly to identify chromosome rearrangements. Long-read sequencing followed by Sanger sequencing could be useful to locate the precise breakpoints. The genetic diagnosis of this case made it possible for reproductive intervention in the patient's family.


Stasis dermatitis: practical pearls for the dermatologic nurse.
Stasis dermatitis is a common, chronic skin condition. Treatment requires attention to local skin-care measures, systemic factors contributing to pedal edema, and surgical/mechanical approaches to promote venous outflow and decrease pooling. Compliance problems can result when patients have a poor understanding of their treatment program, have anxiety regarding costs, or experience the discomfort associated with therapy. Understanding the pathophysiology of stasis dermatitis, and treatment options with emphasis on practical treatment can improve patient compliance.


Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep.
We found previously that damage to a cluster of sleep-active neurons (Fos-positive during sleep) in the ventrolateral preoptic nucleus (VLPO) decreases non-rapid eye movement (NREM) sleep in rats, whereas injury to the sleep-active cells extending dorsally and medially from the VLPO cluster (the extended VLPO) diminishes REM sleep. These results led us to examine whether neurons in the extended VLPO are activated during REM sleep and the connectivity of these neurons with pontine sites implicated in producing REM sleep: the laterodorsal tegmental nucleus (LDT), dorsal raphe nucleus (DRN), and locus ceruleus (LC). After periods of dark exposure that triggered enrichment of REM sleep, the number of Fos-positive cells in the extended VLPO was highly correlated with REM but not NREM sleep. In contrast, the number of Fos-positive cells in the VLPO cluster was correlated with NREM but not REM sleep. Sixty percent of sleep-active cells in the extended VLPO and 90% of sleep-active cells in the VLPO cluster in dark-treated animals contained galanin mRNA. Retrograde tracing from the LDT, DRN, and LC demonstrated more labeled cells in the extended VLPO than the VLPO cluster, and 50% of these in the extended VLPO were sleep-active. Anterograde tracing showed that projections from the extended VLPO and VLPO cluster targeted the cell bodies and dendrites of DRN serotoninergic neurons and LC noradrenergic neurons but were not apposed to cholinergic neurons in the LDT. The connections and physiological activity of the extended VLPO suggest a specialized role in the regulation of REM sleep.


Antioxidant and anti-inflammatory related activities of selected synthetic chalcones: structure-activity relationship studies using computational tools.
Synthetic derivatives of 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone were evaluated in-vitro for their activities related to antioxidant and anti-inflammatory. The antioxidant potential was determined by calculating reducing potential, OH and DPPH (2,2-diphenyl-1-picryl hydrazine) radical scavenging activities. The in-vitro anti-inflammatory related activities of synthetic chalcones (SCs) were demonstrated by performing inhibition assays of trypsin, beta-glucuronidase and diene conjugates. The results of the various parameters studied shows that the selected derivatives were found to be effective reducing agents and were reactive towards stabilizing the OH and DPPH radicals. The compounds have showed moderate to poor or no inhibition profile towards trypsin and beta-glucuronidase, but were found to be effective inhibitor of dien conjugates (hydroperoxides). An attempt has been made to define structure activity relationship using BioMed CAChe 6.1.10: a computer-aided molecular modeling tool which applies equations from classical and quantum mechanics. The experimental and in silico results of the present investigation shows that the basic nucleus 1-(2-hydroxy-3-(2-hydroxy-cyclohexyl)-4,6-dimethoxy-phenyl)-methanone can be considered as a potential candidate for the design and development of lead antioxidant and anti-inflammatory agents.


Nutrients that limit growth in the ocean.
Phytoplankton form the basis of the marine food web and are responsible for approximately half of global carbon dioxide (CO2) fixation (∼ 50 Pg of carbon per year). Thus, these microscopic, photosynthetic organisms are vital in controlling the atmospheric CO2 concentration and Earth's climate. Phytoplankton are dependent on sunlight and their CO2-fixation activity is therefore restricted to the upper, sunlit surface ocean (that is, the euphotic zone). CO2 usually does not limit phytoplankton growth due to its high concentration in seawater. However, the vast majority of oceanic surface waters are depleted in inorganic nitrogen, phosphorus, iron and/or silica; nutrients that limit primary production in the ocean (Figure 1). Phytoplankton growth is mainly supported by either the recycling of nutrients or by reintroduction of nutrients from deeper waters by mixing. A small percentage of primary production, though, is fueled by 'external' or 'new' nutrients and it is these nutrients that determine the amount of carbon that can be sequestered long term in the deep ocean. For most nutrients such as phosphorus, iron, and silica, the external supply is limited to atmospheric deposition and/or coastal and riverine inputs, whereas their main sink is the sedimentation of particulate matter. Nitrogen, however, has an additional, biological source, the fixation of N2 gas, as well as biological sinks via the processes of denitrification and anammox. Despite the comparatively small contributions to the overall turnover of nutrients in the ocean, it is these biological processes that determine the ocean's capacity to sequester CO2 from the atmosphere on time scales of ocean circulation (∼ 1000 years). This primer will highlight shifts in the traditional paradigms of nutrient limitation in the ocean, with a focus on the uniqueness of the nitrogen cycling and its biological sources and sinks.


Effect of aprotinin on growth of 3-methylcholanthrene-induced squamous cell-carcinoma in mice.
The effect of aprotinin (Trasylol), a broad-spectrum inhibitor of proteinase, was studied on the growth of murine squamous cell carcinoma induced by 3-methylcholanthrene. In this tumor system, the administration of aprotinin was therapeutically effective. Histologically, aprotinin-treated tumor showed a significant hyperkeratosis.


Knowledge and attitude of healthcare professionals to frailty screening in primary care: a systematic review protocol.
Frailty is an increasingly common condition in which physiological decline as a result of accumulated deficits renders older people more vulnerable to adverse outcomes. An increasing range of frailty screening programmes have been introduced in primary care to identify frail older people in order to deliver appropriate interventions. However, limited information on the knowledge and attitude of healthcare professionals (HCPs) with respect to frailty screening is known. The aim of this systematic review is to provide evidence on the knowledge and attitude of HCP in terms of frailty screening, and potentially identify barriers and facilitators to frailty screening to improve implementation of frailty screening in primary care. A systematic review of qualitative research will be conducted. Databases searched will be MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO and Web of Science from January 2001 to August 2019. Methods will be reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Population, interest, context and study design methodology was used to develop inclusion and exclusion criteria with HCPs as population, frailty screening as interest and knowledge or attitude of HCPs to frailty screening as context. Studies with a qualitative methodology or a mixed-method design where the qualitative component is analysed separately will also be included. Quality appraisal will be carried out using the Joanna Briggs Institute appraisal tool for qualitative studies. Data will be extracted from each selected study with thematic framework analysis used to synthesise findings. This systematic review does not require ethical approval as primary data will not be collected. The findings will be disseminated at conferences and in a relevant academic journal. This review will assist HCPs and relevant stakeholders to tackle the challenges of frailty screening in primary care. CRD42019159007.


A comparison of speech intelligibility between esophageal and normal speakers via three modes of presentation.
This study compared intelligibility scores obtained for sentences read by good-to-superior esophageal speakers with scores obtained for sentences read by normal speakers via three modes of presentation: visual, auditory and auditory-visual combined. Statistical analysis showed significant differences between intelligibility scores for esophageal speakers and for normal speakers in the auditory and in the combined conditions. No significant difference was found between the scores for the two groups in the visual condition. Further analysis showed that the esophageal speakers' intelligibility scores improved significantly from the auditory to the combined auditory-visual condition where they most closely approximated, but never equaled, the highest intelligibility scores for normal speakers. Implications of the findings for rehabilitation of esophageal speakers are discussed.


Considering and enjoying tomorrow: global aging through a human becoming lens.
The aging of the world's population is a global issue of considerable importance to everyone, particularly nursing. Traditional developmental theories and the medical model have either neglected later life or highlighted the losses and deficits associated with advanced age, while more recent research on aging and the human becoming theory has provided a more balanced view. In this column, information from health and social sciences, the human becoming school of thought, and international political debates about aging are interwoven. Some attention is also given to the issues of the retirement and aging of the nurses.


Photocatalytic Co-Reduction of N2 and CO2 with CeO2 Catalyst for Urea Synthesis.
The effective conversion of carbon dioxide (CO2 ) and nitrogen (N2 ) into urea by photocatalytic reaction under mild conditions is considered to be a more environmentally friendly and promising alternative strategies. However, the weak adsorption and activation ability of inert gas on photocatalysts has become the main challenge that hinder the advancement of this technique. Herein, we have successfully established mesoporous CeO2-x nanorods with adjustable oxygen vacancy concentration by heat treatment in Ar/H2 (90 % : 10 %) atmosphere, enhancing the targeted adsorption and activation of N2 and CO2 by introducing oxygen vacancies. Particularly, CeO2 -500 (CeO2 nanorods heated treatment at 500 °C) revealed high photocatalytic activity toward the C-N coupling reaction for urea synthesis with a remarkable urea yield rate of 15.5 μg/h. Besides, both aberration corrected transmission electron microscopy (AC-TEM) and Fourier transform infrared (FT-IR) spectroscopy were used to research the atomic surface structure of CeO2 -500 at high resolution and to monitor the key intermediate precursors generated. The reaction mechanism of photocatalytic C-N coupling was studied in detail by combining Density Functional Theory (DFT) with specific experiments. We hope this work provides important inspiration and guiding significance towards highly efficient photocatalytic synthesis of urea.


Recent advances in soybean protein processing technologies: A review of preparation, alterations in the conformational and functional properties.
Currently, growing concerns about sustainable development and health awareness have driven the development of plant-based meat substitutes. Soybean proteins (SPs) are eco-friendly and high-quality food sources with well-balanced amino acids to meet consumer demand. The functionality and physicochemical attributes of SPs can be improved by appropriate processing and modification. With the burgeoning advances of modern processing technologies in the food industry, a multitude of functional foods and ingredients can be manufactured based on SPs. This review mainly highlights the conformational changes of SPs under traditional and emerging processing technologies and the resultant functionality modifications. By elucidating the relationship between processing-induced structural and functional alterations, detailed and systematic insights are provided regarding the exploitation of these techniques to develop different nutritional and functional soybean products. Some popular methods to modify SPs properties are discussed in this paper, including thermal treatment, fermentation, enzyme catalysis, high hydrostatic pressure, high-intensity ultrasound, atmospheric cold plasma, high-moisture extrusion, glycosylation, pulsed ultraviolet light and interaction with polyphenols. Given these processing technologies, it is promising to expand the application market for SPs and boost the advancement of the soybean industry.


Managing Sjogren's Syndrome.
There are approximately 4 million Americans diagnosed with Sjogren's Syndrome. This article discusses the epidemiology, pathophysiology, diagnostics, and implications for home care clinicians who may encounter patients with this syndrome. Chronic pain is discussed as well as interventions to manage symptoms such fatigue, dry eyes mouth and skin.


How Digital Therapeutics Are Urging the Need for a Paradigm Shift: From Evidence-Based Health Care to Evidence-Based Well-being.
A scientific paradigm consists of a set of shared rules, beliefs, values, methods, and instruments for addressing scientific problems. Currently, health care embraces the paradigm of evidence-based health care (EBH). This paradigm prompts health care institutions to base decisions on the best available evidence, which is commonly generated in large-scale randomized controlled trials. We illustrate the application of EBH via the evaluation of drugs. We show how EBH is challenged when it is applied to the evaluation of digital therapeutics, which refers to technology and data to prevent, manage, or treat a medical disorder or disease. We conclude that amid the growing application of digital therapeutics, the paradigm of EBH is challenged in four domains: population, intervention, comparison, outcome. In the second part of this viewpoint, we argue for a paradigm shift in health care so we can optimally evaluate and implement digital therapeutics, and we sketch out the contours of this novel paradigm. We address the need for considering design in health care and evaluation processes, studying user values so that health care can move from a focus on health to well-being, focusing on individual experiences rather than the average, addressing the need for evaluation in authentic use contexts, and stressing the need for continuous evaluation of the dynamic relations between users, context, and digital therapeutics. We conclude that the transition from EBH toward evidence-based well-being would improve the successful implementation of digital technologies in health care.


Electrical Cardiometry to Monitor Cardiac Output in Preterm Infants with Patent Ductus Arteriosus: A Comparison with Echocardiography.
Electrical cardiometry (EC) is an impedance-based monitoring that provides noninvasive cardiac output (CO) assessment. Through comparison to transthoracic echocardiography (Echo), the accuracy of EC has been verified. However, left-to-right patent ductus arteriosus (PDA) shunting is a concern because PDA shunts aortic flow to the pulmonary artery and may interfere with EC in measuring CO. To determine the agreement between EC and Echo in preterm infants with a hemodynamically significant PDA (hsPDA). We reviewed our hemodynamic database in which simultaneous CO measurements by Echo and EC (Aesculon®) were recorded. Preterm infants with left-to-right shunting hsPDA were enrolled. A total of 105 paired measurements in 36 preterm infants were compared. Infants' median (range) age and weight at measurement were 27+2 weeks (24+0-33+1) and 1,015 g (518-1,880), with mean (95% CI) ductal diameter 2.11 mm (1.99-2.22) or 2.15 mm/kg (2.00-2.30). Mean COEC and COEcho were 252 ± 32 and 258 ± 45 mL/kg/min, respectively, which demonstrated a moderate correlation and without a significant between-measurement difference. Bland-Altman analysis showed a bias, limits of agreement, and error percentage of -5.3 mL/kg/min, -78.3 to 67.7 mL/kg/min, and 28.6%, respectively. There was a trend of increased bias and error percentage of infants with high CO ≥280 mL/kg/min and supported with high-frequency ventilator. EC and Echo have a wide but clinically acceptable agreement in measuring CO in preterm infants with hsPDA. However, for infants with high CO or ventilated by high-frequency ventilation, interpretation of COEC should be approached with caution.


Multipotent mesenchymal stem cells with immunosuppressive activity can be easily isolated from dental pulp.
Bone marrow mesenchymal stem cells (MSCs) are currently being investigated in preclinical and clinical settings because of their multipotent differentiative capacity or, alternatively, their immunosuppressive function. The aim of this study was to evaluate dental pulp (DP) as a potential source of MSCs instead of bone marrow (BM). Flow cytometric analysis showed that DP-MSCs and BM-MSCs were equally SH2, SH3, SH4, CD29 and CD 166 positive. The in vitro proliferative kinetics of MSCs were measured by 3H-thymidine incorporation uptake. The immunosuppressive function of MSCs was then tested by coculturing PHA-stimulated allogeneic T cells with or without MSCs for 3 days. BM-MSCs could be differentiated in vitro into osteogenic, chondrogenic and adipogenic lineages. DP-MSCs showed osteogenic and adipocytic differentiation, but did not differentiate into chondrocytes. Although DP-MSCs grow rapidly in vitro between day 3 and day 8 of culture and then decrease their proliferation by day 15, BM-MSCs have a stable and continuous proliferation over the same period of time. The addition of DP-MSCs or BM-MSCs resulted in 91 +/- 4% and 75 +/- 3% inhibition of T cell response, respectively, assessed by a 3H-thymidine assay. Dental pulp is an easily accessible and efficient source of MSCs, with different kinetics and differentiation potentialities from MSCs as isolated from the bone marrow. The rapid proliferative capacity together with the immunoregulatory characteristics of DP-MSCs may prompt future studies aimed at using these cells in the treatment or prevention of T-cell alloreactivity in hematopoietic or solid organ allogeneic transplantation.


Graphene oxide as a chemosensitizer: diverted autophagic flux, enhanced nuclear import, elevated necrosis and improved antitumor effects.
Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we demonstrated that both GO and the chemotherapy drug cisplatin (CDDP) induced autophagy but elicited low degrees of CT26 cell death. Strikingly, GO combined with CDDP (GO/CDDP) potentiated the CT26 cell killing via necrosis. GO/CDDP not only elicited autophagy, but induced the nuclear import of CDDP and the autophagy marker LC3. The nuclear LC3 did not co-localize with p62 or Lamp-2, neither did blocking autolysosome formation significantly hinder the nuclear import of LC3/CDDP and necrosis, indicating that autophagosome and autolysosome formation was dispensable. Conversely, suppressing phagophore formation and importin-α/β significantly alleviated the nuclear import of LC3/CDDP and necrosis. These data suggested that GO/CDDP diverted the LC3 flux in the early phase of autophagy, resulting in LC3 trafficking towards the nucleus in an importin-α/β-dependent manner, which concurred with the CDDP nuclear import and necrosis. Intratumoral injection of GO/CDDP into mice bearing CT26 colon tumors potentiated immune cell infiltration and promoted cell death, autophagy and HMGB1 release, thereby synergistically augmenting the antitumor effects. Altogether, we unveiled a mechanism concerning how nanomaterials chemosensitize cancer cells and demonstrated the potentials of GO as a chemosensitizer.


Polypharmacy and Adherence to Adjuvant Endocrine Therapy for Breast Cancer.
Many patients with breast cancer are treated for other conditions and experience polypharmacy with multiple concurrent medications. Our aim was to evaluate polypharmacy in relation to adherence to adjuvant endocrine therapy (AET) in breast cancer. We conducted a retrospective cohort study of women with incident, invasive breast cancer initiating AET (tamoxifen, letrozole, anastrozole, exemestane) between 2009 and 2013 in the Truven Health MarketScan Database. Polypharmacy and pill burden were measured for commonly used concurrent medications, including lipid-lowering drugs, antihypertensives, oral diabetes medications, insulin analogs, antidepressants, anxiolytics/antipsychotics, and opioid-containing analgesics. Polypharmacy was defined as frequent use (three or more dispensings) of a given medication class and by pill burden (total dispensings). Medication possession ratios (MPR) were estimated for subsequent 12-month intervals. Multivariable generalized estimating equation models were used to calculate odds ratios (ORs) and robust 95% CIs for associations with AET adherence (MPR ≥ 0.80). Among 40,009 women, 74% were adherent in year +1 and continued to have high mean adherence (MPR = 0.79) among those continuing AET through year +3. Increasing polypharmacy ( P < .001) and pill burden ( P < .001) were associated with greater adherence, but effects differed by medication class. Frequent use of lipid-lowering drugs (OR, 1.42; 95% CI, 1.36 to 1.49) and antihypertensives (OR, 1.15; 95% CI, 1.10 to 1.20) were associated with higher odds of adherence; frequent use of opioid-containing analgesics (OR, 0.80; 95% CI, 0.77 to 0.83), anxiolytics/antipsychotics (OR, 0.95; 95% CI, 0.91 to 0.99), antidepressants (OR, 0.85; 95% CI, 0.82 to 0.89), and insulin therapy (OR, 0.82; 95% CI, 0.72 to 0.95) were associated with lower odds of adherence. Associations between polypharmacy and adherence in breast cancer may be better characterized by understanding specific classes of medications used concurrently. Comprehensive medication therapy management, including ongoing pain evaluation and psychoactive therapies, is warranted.


Bombay Blood Group Phenotype Misdiagnosed As O Phenotype: A Case Report.
Bombay blood group is a rare type that was initially identified in the city of Bombay, India. It is characterized by the presence of serum antibodies anti-A, anti-B, and anti-H, which can cause agglutination in all blood groups within the ABO system. The clinical importance of the Bombay blood group lies in its inability to receive transfusions from other blood groups. In this case report, we present a case of a young male who was initially misdiagnosed as having an O phenotype, resulting in a hemolytic transfusion reaction. This case highlights the diagnostic and therapeutic challenges associated with rare blood phenotypes.


Schisanwilsonins H and I, two new dibenzocyclooctane lignans from the fruits of Schisandra wilsoniana.
Two new dibenzocyclooctane lignans, schisanwilsonins H (1) and I (2), together with eight known compounds gomisin J (3), wulignan A1 (4), gomisin S (5), tigloylgomisin P (6), gomisin O (7), (-)-gomisin K1 (8), rubschisantherin (9) and wuweizisu C (10) were isolated from the 95% ethanol extract of the fruits of Schisandra wilsoniana. 7 exhibited anti-HBV activity with potency against HBsAg and HBeAg secretion by 37.1% and 32.6%, respectively, at 50 μg/ml. 10 exhibited anti-HIV activity with EC50 and therapeutic index (TI) values of 2.10 μg/ml and 11.98, respectively.


The Critical Gene Screening to Prevent Chromophobe Cell Renal Carcinoma Metastasis through TCGA and WGCNA.
Common chromophobe renal cell carcinoma (chRCC) has a good prognosis when cured by surgery. However, clinical practice shows that a small number of patients with chRCC will produce metastasis, and the prognosis after metastasis is poor. In this regard, we try to find potential biological targets to prevent CRCC metastasis. In this experiment, we analyzed the clinical traits and gene expression data of chRCC samples which were provided by the TCGA database by the WGCNA method. On this basis, we selected MEtan, a module with a significant positive correlation with the M phase of chRCC, for subsequent analysis. The MEtan module genes in the biological process of chRCC were mainly related to steroid metabolic process, cholesterol metabolic process and STEM cell differentiation. KEGG analysis showed that these genes were mainly enriched in cancer-related signaling pathways, such as Neuroactive Ligand-receptor interaction, cAMP signaling pathway, and Wnt signaling pathway. Subsequently, we mapped the PPI interaction network and screened the key gene beta-arrestin 2 (ARRB2). Expression analysis showed that there was a significantly increased expression of ARRB2 in chRCC patients in comparison to the normal group. Expression survival analysis indicated that ARRB2 was inversely associated with overall survival. We firmly believe that the key genes identified in this study would be able to provide new clues and research basis for the treatment of chRCC.


Arabidopsis Proline Dehydrogenase Contributes to Flagellin-Mediated PAMP-Triggered Immunity by Affecting RBOHD.
Plants activate different defense systems to counteract the attack of microbial pathogens. Among them, the recognition of conserved microbial- or pathogen-associated molecular patterns (MAMPs or PAMPs) by pattern-recognition receptors stimulates MAMP- or PAMP-triggered immunity (PTI). In recent years, the elicitors, receptors, and signaling pathways leading to PTI have been extensively studied. However, the contribution of organelles to this program deserves further characterization. Here, we studied how processes altering the mitochondrial electron transport chain (mETC) influence PTI establishment. With particular emphasis, we evaluated the effect of proline dehydrogenase (ProDH), an enzyme that can load electrons into the mETC and regulate the cellular redox state. We found that mETC uncouplers (antimycin or rotenone) and manganese superoxide dismutase deficiency impair flg22-induced responses such as accumulation of reactive oxygen species (ROS) and bacterial growth limitation. ProDH mutants also reduce these defenses, decreasing callose deposition as well. Using ProDH inhibitors and ProDH inducers (exogenous Pro treatment), we showed that this enzyme modulates the generation of ROS by the plasma membrane respiratory burst NADPH oxidase homolog D. In this way, we contribute to the understanding of mitochondrial activities influencing early and late PTI responses and the coordination of the redox-associated mitochondrial enzyme ProDH with defense events initiated at the plasma membrane.


Control of expression of histocompatibility antigens (H-2) and beta 2-microglobulin in F9 teratocarcinoma stem cells.
Murine teratocarcinoma stem cells, unlike most other cell types, do not express major histocompatibility antigens. The steady-state levels of beta 2-microglobulin and H-2 mRNA from F9-derived teratocarcinoma stem and differentiated cells were examined by blot hybridization using cloned DNA probes specific for these mRNAs. No H-2- or beta 2-microglobulin-specific RNA was detected in F9 teratocarcinoma stem cells (clone 12-1); thus, F9 teratocarcinoma stem cells (clone 12-1) contain no more than 1/10 the H-2 and beta 2-microglobulin mRNAs of the differentiated daughter cells (clone 12-1a). We suggest that this regulation of major histocompatibility antigen expression is due to transcriptional control of the major histocompatibility antigen genes, H-2 and beta 2-microglobulin. The transcriptional regulation of these genes is accompanied by a change in their DNase I sensitivity. Normally, transcriptionally inactive genes are DNase I resistant, while active genes are DNase I sensitive. In contrast, the silent major histocompatibility antigen genes of teratocarcinoma stem cells are more DNase I sensitive than the active genes of the differentiated cells.


A proposed voltage dependence of the ionic strength of a confined electrolyte based on a grand canonical ensemble model.
Electrodes with highly porous morphologies are of great technological interest, as their exceptionally high specific surface areas make them ideal for use in capacitors, battery electrodes and electrochemical sensors. There is a large body of research focusing on the structure of confined electrolytes in these systems, but the majority of these studies focus on cases where the length scale of the porous domain is equal to or less than the Debye screening length of the electrolyte. In this work, we use a thermodynamic model to consider the structure of electrolytes in mesoscale domains, where the pore dimensions are significantly larger than the Debye screening length. In this limit, the interface is screened by the electrochemical double layer and the enclosed volume primarily consists of an electroneutral 'bulk liquid' domain. Despite the absence of direct interactions between ions in the bulk domain and the charged interface, we show that minimization of the free energy of the system leads to a reduction in the ionic strength of the electrolyte within the bulk liquid domain of the pore. Based on our model studies, we anticipate that this depletion will apply for porous domains with widths of the order of 50-200 nm even under mild experimental conditions and low applied voltages. The results imply relationships between electrolyte strength, surface morphology and applied voltage that may be important in device design.


Antagonism of type I interferon by flaviviruses.
The prompt and tightly controlled induction of type I interferon is a central event of the immune defense against viral infection. Flaviviruses comprise a large family of arthropod-borne positive-stranded RNA viruses, many of which represent a serious threat to global human health due to their high rates of morbidity and mortality. All flaviviruses studied so far have been shown to counteract the host's immune response to establish a productive infection and facilitate viral spread. Here, we review the current knowledge on the main strategies that human pathogenic flaviviruses utilize to escape both type I IFN induction and effector pathways. A better understanding of the specific mechanisms by which flaviviruses activate and evade innate immune responses is critical for the development of better therapeutics and vaccines.


Potential bioreductive alkylating agents. 5. Antineoplastic activity of quinoline-5,8-diones, naphthazarins, and naphthoquinones.
A number of 2-chloromethyl and 2-bromomethyl derivatives of naphthoquinones, quinolinediones, and naphthazarins were designed and synthesized as potential bioreductive alkylating agents, and the antitumor activity of these compounds was assessed in mice bearing Sarcoma 180 ascites cells. The results indicated that, with the exception of 3-benzamido-2-chloromethyl-1,4-naphthoquinone, which was inactive, all newly synthesized naphthoquinones possessed strong antitumor activity against this neoplasm. 6,7-Bis(bromomethyl)quinoline-5,8-dione had moderate inhibitory activity against Sarcoma 180 at its optimal daily dosage level of 15 mg/kg. 3-Bromo-2-bromomethyl- and 3-bromo-2-chloromethylnaphthazarin produced a moderate extension of the life span of tumor-bearing mice; whereas, in contrast, 6,7-dimethyl analogs of these agents were inactive when employed in daily doses up to 40 mg/kg body weight.


Study design of the DAS-OLT trial: a randomized controlled trial to evaluate the impact of dexmedetomidine on early allograft dysfunction following liver transplantation.
Perioperative ischemia/reperfusion (I/R) injury during liver transplantation is strongly associated with early allograft dysfunction (EAD), graft loss, and mortality. Hepatic I/R injury also causes remote damage to other organs including the renal and pulmonary systems. Dexmedetomidine (DEX), a selective α2-adrenoceptor agonist which is used as an adjuvant to general anesthesia, has been shown in preclinical studies to provide organ protection by ameliorating the effects of I/R injury in a range of tissues (including the liver). However, prospective clinical evidence of any potential benefits in improving outcomes in liver transplantation is lacking. This study aimed to verify the hypothesis that the application of dexmedetomidine during the perioperative period of liver transplantation can reduce the incidence of EAD and primary graft non-function (PNF). At the same time, the effects of dexmedetomidine application on perioperative renal function and lung function were studied. This is a prospective, single-center, randomized, parallel-group study. Two hundred participants (18-65 years) scheduled to undergo liver transplantation under general anesthesia will be included in this study. For participants in the treatment group, a loading dose of DEX will be given after induction of anesthesia (1 μg/kg over 10 min) followed by a continuous infusion (0.5 μg/kg /h) until the end of surgery. For participants in the placebo group, an equal volume loading dose of 0.9% saline will be given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. All other supplements, e.g., opioids, sedatives, and muscle relaxant, will be identical in both arms and administered according to routine clinical practice. The present trial will examine whether DEX confers organoprotective effects in the liver, in terms of reducing the incidence of EAD and PNF in orthotopic liver transplantation recipients. ClinicalTrials.gov NCT03770130. Registered on 10 December 2018. https://clinicaltrials.gov/ct2/show/NCT03770130.


ALLOCATION TO ATTRACTIVE STRUCTURES IN ANIMAL-POLLINATED FLOWERS.
An optimal allocation model was developed for the evolutionarily stable size of attractive structures of flowers (ESA) in animal-pollinated plants. It was assumed that a plant can change the sizes of attractive and sexual structures of a flower and the size and the number of flowers. In the absence of constraints on flower size, the ESA should not depend on the frequency of self-fertilization or the sexuality of plants. However, with constraints on flower size, the ESA decreases with increasing self-fertilization, except in special cases, and it is possible that males have a larger or a smaller ESA than females. Thus, differences in self-fertilization and sexuality alone cannot explain the differences in allocation among nondomesticated plants. In addition, attractive structures can contribute more to male or female function depending on the cost of gamete production, pollination efficiency for pollen and ovules, and pollinator availability.


Novel method to detect microRNAs using chip-based QuantStudio 3D digital PCR.
Research efforts for the management of cancer, in particular for lung cancer, are directed to identify new strategies for its early detection. MicroRNAs (miRNAs) are a new promising class of circulating biomarkers for cancer detection, but lack of consensus on data normalization methods has affected the diagnostic potential of circulating miRNAs. There is a growing interest in techniques that allow an absolute quantification of miRNAs which could be useful for early diagnosis. Recently, digital PCR, mainly based on droplets generation, emerged as an affordable technology for precise and absolute quantification of nucleic acids. In this work, we described a new interesting approach for profiling circulating miRNAs in plasma samples using a chip-based platform, the QuantStudio 3D digital PCR. The proposed method was validated using synthethic oligonucleotide at serial dilutions in plasma samples of lung cancer patients and in lung tissues and cell lines. Given its reproducibility and reliability, our approach could be potentially applied for the identification and quantification of miRNAs in other biological samples such as circulating exosomes or protein complexes. As chip-digital PCR becomes more established, it would be a robust tool for quantitative assessment of miRNA copy number for diagnosis of lung cancer and other diseases.


INTIMATE PARTNER VIOLENCE AND CONTRACEPTIVE USE IN INDIA: THE MODERATING INFLUENCE OF CONFLICTING FERTILITY PREFERENCES AND CONTRACEPTIVE INTENTIONS.
Several studies report that women exposed to intimate partner violence (IPV) are less likely to use contraception, but the evidence that violence consistently constrains contraceptive use is inconclusive. One plausible explanation for this ambiguity is that the effects of violence on contraceptive use depend on whether couples are likely to have conflicting attitudes to it. In particular, although some men may engage in violence to prevent their partners from using contraception, they are only likely to do so if they have reason to oppose its use. Using a longitudinal follow-up to the Indian National Family Health Survey (NFHS-2), conducted among a sample of rural, married women of childbearing age, this study investigated whether the relationship between IPV and contraceptive use is contingent on whether women's contraceptive intentions contradict men's fertility preferences. Results indicate that women experiencing IPV are less likely to undergo sterilization, but only if they intended to use contraception and their partners wanted more children (Average Marginal Effect (AME)=-0.06; CI=-0.10, -0.01). Violence had no effect on sterilization among women who did not plan to use contraception (AME=-0.02; CI=-0.06, 0.03) or whose spouses did not want more children (AME=-0.01; CI=-0.9, 0.06). These results imply that violence enables some men to resolve disagreements over the use of contraception by imposing their fertility preferences on their partners. They also indicate that unmet need for contraception could be an intended consequence of violence.


Structure-Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs.
Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.


Association between intraocular pressure variation and glaucoma progression: data from a United States chart review.
To evaluate whether greater intraocular pressure (IOP) variation between visits was associated with higher likelihood of glaucoma progression. Cohort study. A five-year minimum of data (June 1, 1990 through January 22, 2002) was collected on 151 patients (302 eyes) from 12 United States specialty centers. A post hoc analysis of visual field (VF) progression, glaucoma medication, intraocular pressure (IOP), and other ocular data was conducted for two nonmutually exclusive cohorts based on retrospective data abstracted well after actual patient visits. Mean IOP and standard deviations (SD) were calculated before treatment (medication or surgery) or progression, whichever occurred first, and before progression regardless of treatment. IOP variables were assessed in a univariate fashion; Cox proportional hazards models evaluated glaucoma progression as an outcome measure and IOP SD as a main predictor, controlling for covariates. In cohort 1 (55 patients; 84 eyes), mean age was 63 years (range, 37 to 85 years), 58% were female, and 19% of eyes underwent VF progression. In cohort 2 (129 patients; 251 eyes), mean age was 66 years (range, 19 to 88 years), 55% were female, and 27% of eyes underwent VF progression. Mean IOP was 16.5 mm Hg (IOP SD, 2.0 mm Hg), and 16.4 mm Hg (IOP SD, 2.7 mm Hg) in cohorts 1 and 2, respectively. Controlling for age, mean IOP, VF stage, and other covariates, each unit increase in IOP SD resulted in a 4.2 times and 5.5 times higher risk of glaucoma progression for cohort 1 (95% confidence interval [CI], 1.3 to 12.9) and cohort 2 (95% CI, 3.4 to 9.1), respectively. IOP variability is an important predictor of glaucoma progression; SD is a convenient measure of variability to assess glaucoma progression risk.