József Molnár

Previous studies have shown conflicting results as to whether periodontitis (PD) is associated with increased risk of coronary heart disease (CHD). The aim of the current study was to evaluate whether such an association exists. A systematic review of the literature revealed 5 prospective cohort studies (follow-up >6 years), 5 case-control studies, and 5 cross-sectional studies that were eligible for meta-analysis. Individual studies were adjusted for confounding factors such as age, sex, diabetes mellitus, and smoking. The 3 study categories were analyzed separately. Heterogeneity of the studies was assessed by Cochran Q test. The studies were homogeneous; therefore, the Mantel-Haenszel fixed-effect model was used to compute common relative risk and odds ratio (OR). Meta-analysis of the 5 prospective cohort studies (86 092 patients) indicated that individuals with PD had a 1.14 times higher risk of developing CHD than the controls (relative risk 1.14, 95% CI 1.074-1.213, P < .001). The case-control studies (1423 patients) showed an even greater risk of developing CHD (OR 2.22, 95% CI 1.59-3.117, P < .001). The prevalence of CHD in the cross-sectional studies (17 724 patients) was significantly greater among individuals with PD than in those without PD (OR 1.59, 95% CI 1.329-1.907, P < .001). When the relationship between number of teeth and incidence of CHD was analyzed, cohort studies showed 1.24 times increased risk (95% CI 1.14-1.36, P < .0001) of development of CHD in patients with <10 teeth. This meta-analysis indicates that both the prevalence and incidence of CHD are significantly increased in PD. Therefore, PD may be a risk factor for CHD. Prospective studies are required to prove this assumption and evaluate risk reduction with the treatment of PD.

Measurements of charged pion and kaon production in central Pb+Pb collisions at 40, 80, and 158 A GeV are presented. These are compared with data at lower and higher energies as well as with results from p+p interactions. The mean pion multiplicity per wounded nucleon increases approximately linearly with s1/4NN with a change of slope starting in the region 15–40 A GeV. The change from pion suppression with respect to p+p interactions, as observed at low collision energies, to pion enhancement at high energies occurs at about 40A GeV. A nonmonotonic energy dependence of the ratio of K+ to π+ yields is observed, with a maximum close to 40A GeV and an indication of a nearly constant value at higher energies. The measured dependences may be related to an increase of the entropy production and a decrease of the strangeness to entropy ratio in central Pb+Pb collisions in the low SPS energy range, which is consistent with the hypothesis that a transient state of deconfined matter is created above these energies. Other interpretations of the data are also discussed.Received 6 May 2002DOI:https://doi.org/10.1103/PhysRevC.66.054902©2002 American Physical Society

In previous reports it was shown that the main part of nuclear DNA-like RNA (D-RNA) can be found in homogeneous 30 s particles which are complexes of specific protein particles with D-RNA strands bound to them. It has now been established that 30 s particles are monomers of a more complex polysome-like structure. Such a structure is formed by a long D-RNA strand and a number of globular protein particles bound to it and tightly packed along the D-RNA strand. These complexes occupy a wide zone in sucrose gradients between 30 and 200 s. In the electron microscope, one finds the 30 8 peak contains only single particles; the 45 s peak, dimers; the 55 to 60 s peak, trimers, and so on. In heavier zones long chains of particles (n = 8 to 12) were observed. Treatment with small amounts of RNase quantitatively converts large polyparticles into the 30 s particles. The buoyant density and the protein composition of mono- and poly-particles are the same. They are very different from those of ribosomes. The sedimentation coefficient of RNA isolated from particles is related to the number of monomers in the complex. It is calculated that one protein particle is bound to an RNA strand having a molecular weight of about 2 × 105. The structure and function of the nuclear complexes containing D-RNA are discussed. The name “informofer” is suggested for monomeric protein particles.

Obstructive sleep apnea (OSA) has been linked to and is associated with increased cardiovascular and cerebrovascular morbidity. Ongoing inflammatory responses play an important role in this association. Multiple small size studies addressing the profile of the inflammatory markers in OSA are available therefore we performed a meta-analysis.Systematic review of medical literature was conducted using PubMed, Cochrane, and EMBASE databases from 1968 to 2011 by utilizing the key words obstructive sleep apnea, C-Reactive protein, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) and Selectins. Inclusion criteria were: full text English articles; studies with adult population; reported values for at least one of the markers of interest; with at least two separate groups (subjects with OSA and control group); OSA was defined as AHI of ≥ 5/h.Five hundred and twelve studies were reviewed for inclusion with 51 studies pooled for analysis (30 studies for CRP, 19 studies for TNF-α, 8 studies for ICAM, 18 studies for IL-6, six studies for VCAM and 5 studies for Selectins). The levels of inflammatory markers were higher in patients with OSA compared to control group. Standardized pooled Mean differences were calculated to be 1.77 for CRP, 1.03 for TNF-α, 2.16 for IL-6, 4.22 for IL-8, 2.93 for ICAM, 1.45 for Selectins and 2.08 for VCAM.In this meta-analysis, the levels of systemic inflammatory markers were found to be higher in OSA patients compared to control subjects.

Results on charged pion and kaon production in central Pb+Pb collisions at 20A and 30A GeV are presented and compared to data at lower and higher energies. A rapid change of the energy dependence is observed around 30A GeV for the yields of pions and kaons as well as for the shape of the transverse mass spectra. The change is compatible with the prediction that the threshold for production of a state of deconfined matter at the early stage of the collisions is located at low SPS energies.

Purification steps, additional to those reported in the literature (8, 18), using diethylaminoethylcellulose and Amberlite CG-50 chromatographic columns, have been worked out for “apyrase.” The nucleotide-hydrolyzing activity can be resolved into two distinct fractions (apyrase A and B) on DEAE-cellulose and both can be further purified separately on Amberlite CG-50. The ATP to ADP hydrolytic ratios obtained with these enzymes greatly depend on the nature of the potatoes used as a source and are also somewhat influenced by pH. Apyrase A from white potatoes removes the terminal phosphate of ATP much faster than that in the penultimate position, whereas the B enzyme from the same source liberates two equivalents of orthophosphate from ATP at identical rales. The two enzymes from russets, though readily separated on DEAE-cellulose and differing in their pH optima, cannot be distinguished by their mode of attacking the two terminal phosphates of ATP. Michaelis constants, turnover numbers, and Arrhenius activation energies for apyrases A and B isolated from various kinds of potatoes are given for ATP and ADP as substrates. Calcium or magnesium ions activate the two enzymes with regard to hydrolyzing both nucleotides.

Single-cell segmentation is typically a crucial task of image-based cellular analysis. We present nucleAIzer, a deep-learning approach aiming toward a truly general method for localizing 2D cell nuclei across a diverse range of assays and light microscopy modalities. We outperform the 739 methods submitted to the 2018 Data Science Bowl on images representing a variety of realistic conditions, some of which were not represented in the training data. The key to our approach is that during training nucleAIzer automatically adapts its nucleus-style model to unseen and unlabeled data using image style transfer to automatically generate augmented training samples. This allows the model to recognize nuclei in new and different experiments efficiently without requiring expert annotations, making deep learning for nucleus segmentation fairly simple and labor free for most biological light microscopy experiments. It can also be used online, integrated into CellProfiler and freely downloaded at www.nucleaizer.org. A record of this paper's transparent peer review process is included in the Supplemental Information.

Genomic mutations caused by cytotoxic agents used in cancer chemotherapy may cause secondary malignancies as well as contribute to the evolution of treatment-resistant tumour cells. The stable diploid genome of the chicken DT40 lymphoblast cell line, an established DNA repair model system, is well suited to accurately assay genomic mutations. We use whole genome sequencing of multiple DT40 clones to determine the mutagenic effect of eight common cytotoxics used for the treatment of millions of patients worldwide. We determine the spontaneous mutagenesis rate at 2.3 × 10–10 per base per cell division and find that cisplatin, cyclophosphamide and etoposide induce extra base substitutions with distinct spectra. After four cycles of exposure, cisplatin induces 0.8 mutations per Mb, equivalent to the median mutational burden in common leukaemias. Cisplatin-induced mutations, including short insertions and deletions, are mainly located at sites of putative intrastrand crosslinks. We find two of the newly defined cisplatin-specific mutation types as causes of the reversion of BRCA2 mutations in emerging cisplatin-resistant tumours or cell clones. Gemcitabine, 5-fluorouracil, hydroxyurea, doxorubicin and paclitaxel have no measurable mutagenic effect. The cisplatin-induced mutation spectrum shows good correlation with cancer mutation signatures attributed to smoking and other sources of guanine-directed base damage. This study provides support for the use of cell line mutagenesis assays to validate or predict the mutagenic effect of environmental and iatrogenic exposures. Our results suggest genetic reversion due to cisplatin-induced mutations as a distinct mechanism for developing resistance.

This study sought to evaluate the range and variability of the QT and corrected QT (QTc) intervals over 24 h and to assess their pattern and relation to heart rate variability.Recent Holter monitoring data have revealed a high degree of daily variability in the QTc interval. The pattern of this variability and its relation to heart rate variability remain poorly characterized.We developed and validated a new method for continuous measurement of QT intervals from three-channel, 24-h Holter recordings. Average RR, QT, QTc and heart rate variability were measured from 5-min segments of data from 21 healthy subjects.Measurement of 6,048 segments showed mean (+/- SD) RR, QT and QTc intervals of 830 +/- 100, 407 +/- 23 and 445 +/- 16 ms, respectively (mean QTc interval for men 434 +/- 12 ms, 457 +/- 10 ms for women, p < 0.0001). The average maximal QTc interval was 495 +/- 21 ms and the average QTc range 95 +/- 20 ms. The maximal QTc interval was > or = 500 ms in 6 subjects and > or = 490 ms in 13. The 95% upper confidence limit for the mean 24-h QTc interval was 452 ms (men 439 ms, women 461 ms). The RR, QT and QTc intervals and the high frequency component of heart rate variability were greater during sleep. Both the QTc interval and the variability between hourly minimal and maximal QTc intervals reached their circadian peak shortly after awakening, before declining to daytime levels.The maximal QTc interval over 24 h in normal subjects is longer than heretofore thought. Both QT and QTc intervals are longer during sleep. The QTc interval and QTc variability reach a peak shortly after awakening, which may reflect increased autonomic instability during early waking hours, and the time of the peak value corresponds in time to the period of reported increased vulnerability to ventricular tachycardia and sudden cardiac death. These findings have implications regarding the definition of QT prolongation and its use in predicting arrhythmias and sudden death.

Directed and elliptic flow measurements for charged pions and protons are reported as a function of transverse momentum, rapidity, and centrality for 40 and 158A GeV Pb + Pb collisions as recorded by the NA49 detector. Both the standard method of correlating particles with an event plane, and the cumulant method of studying multiparticle correlations are used. In the standard method the directed flow is corrected for conservation of momentum. In the cumulant method elliptic flow is reconstructed from genuine 4, 6, and 8-particle correlations, showing the first unequivocal evidence for collective motion in A+A collisions at SPS energies.

The NA49 detector is a wide acceptance spectrometer for the study of hadron production in p+p, p+A, and A+A collisions at the CERN SPS. The main components are 4 large-volume TPCs for tracking and particle identification via dE/dx. TOF scintillator arrays complement particle identification. Calorimeters for transverse energy determination and triggering, a detector for centrality selection in p+A collisions, and beam definition detectors complete the set-up. A description of all detector components is given with emphasis on new technical realizations. Performance and operational experience are discussed in particular with respect to the high track density environment of central Pb+Pb collisions.

Results of resonance searches in the Xi(-)pi(-), Xi(-)pi(+), Xi;(+)pi(-), and Xi;(+)pi(+) invariant mass spectra in proton-proton collisions at sqrt[s]=17.2 GeV are presented. Evidence is shown for the existence of a narrow Xi(-)pi(-) baryon resonance with mass of 1.862+/-0.002 GeV/c(2) and width below the detector resolution of about 0.018 GeV/c(2). The significance is estimated to be above 4.2sigma. This state is a candidate for the hypothetical exotic Xi(--)(3/2) baryon with S=-2, I=3 / 2, and a quark content of (dsdsū). At the same mass, a peak is observed in the Xi(-)pi(+) spectrum which is a candidate for the Xi(0)(3/2) member of this isospin quartet with a quark content of (dsus[-]d). The corresponding antibaryon spectra also show enhancements at the same invariant mass.

Net proton and negative hadron spectra for central Pb+Pb collisions at 158 GeV per nucleon at the CERN Super Proton Synchrotron were measured and compared to spectra from lighter systems. Net baryon distributions were derived from those of net protons. Stopping (rapidity shift with respect to the beam) and mean transverse momentum ⟨pT⟩ of net baryons increase with system size. The rapidity density of negative hadrons scales with the number of participant nucleons for nuclear collisions, whereas their ⟨pT⟩ is independent of system size. The ⟨pT⟩ dependence upon particle mass and system size is consistent with larger transverse flow velocity at midrapidity for Pb+Pb compared to S+S central collisions.Received 22 October 1998DOI:https://doi.org/10.1103/PhysRevLett.82.2471©1999 American Physical Society

Lysyl oxidase (LOX) and four lysyl oxidase-like proteins, LOXL, LOXL2, LOXL3 and LOXL4, each contain a copper binding site, conserved lysyl and tyrosyl residues that may contribute to quinone co-factor formation, and a cytokine receptor-like domain. Each protein differs mainly in their N-terminal sequence, which may confer individual functions. Processing of the LOX proteins by BMP-1 and possibly other mechanisms may result in multiple functional forms. Splicing, reported for LOXL3, may also generate additional variants with unique functions. Each LOX, with its individual, developmentally regulated tissue and cell-specific expression and localization, results in a complex structural and functional variation for the LOX amine oxidases. The presence of only two LOX-like proteins in Drosophila, each with distinct spatial and temporal expression, allows for the assignment of individual function to one of these amine oxidases. Comparative expression analysis of each LOX protein is presented to help determine their functional significance.

Previous studies have suggested that sub-clinical thyroid states may have detrimental effects on the coronary heart disease (CHD). Whether subclinical thyroid dysfunction is a risk factor for the above is controversial.A systemic search of the literature using Pubmed, Medline and Ovid online tool was performed to identify relevant studies. Amongst the clinical studies, crossectional study and studies with follow-up period ranging between 4 and 20 yr were identified (Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005 Nov 28;165 (21):2467-72.; Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005 Nov 28; 165 (21):2460-6.; Rotterdam study, Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for coronary heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 2004 Jul; 89 (7):3365-70.; Capolla et al.; Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001 Sep 15; 358 (9285):861-5).Sub-clinical hypothyroidism: The pooled estimate of the relative risk of CHD revealed significant difference both at baseline [RR with 95% CI: 1.533 (1.312-1.791), P<0.05] and at follow-up [RR with 95% CI: 1.188 (1.024-1.379), P<0.05]. The relative risk of all-cause mortality at follow-up revealed no significant difference. However, the relative risk of death from cardiovascular causes at follow-up was significantly higher [RR with 95% CI: 1.278 (1.023-1.597), P<0.05]. Sub-clinical hyperthyroidism: The pooled estimate of the relative risk of CHD revealed no significant difference both at baseline [RR with 95% CI: 1.156 (0.709-1.883)] and at follow-up [RR with 95% CI: 1.207 (0.780-1.870)].The relative risk of death from cardiovascular causes at follow-up was also not significantly higher.The present meta-analysis indicates that sub-clinical hypothyroidism is associated with both, a significant risk of CHD at baseline and at follow-up. In addition, mortality from cardiovascular causes is significantly higher at follow-up. Sub-clinical hyperthyroidism is not associated with CHD or mortality from cardiovascular causes.

The present study demonstrates the ability of plasma fibronectin or cold-insoluble globulin (Clg) to promote the uptake of 125I-labeled, gelatin-coated latex beads (g-Ltx*) by monolayers of peritoneal macrophages (PM). The uptake of g-Ltx* by PM was enhanced by Clg in a concentration-dependent fashion and required the presence of heparin (10 U/ml) as an obligatory cofactor for maximal particle uptake. Treatment of PM monolayers with trypsin (1 mg/ml) for 15 min at 37 degrees C after particle uptake removed less than 15% of the radioactivity incorporated by the monolayers. However, a similar trypsin treatment of the monolayers before the addition of latex particles depressed Clg-dependent uptake by greater than 75%. Pretreatment of PM monolayers with inhibitors of glycolysis effectively reduced the Clg-dependent uptake of latex. Similarly, pretreatment of monolayers with either inhibitors of protein synthesis or agents that disrupt cytoskeletal elements also significantly depressed Clg-dependent particle uptake. Phagocytosis of g-Ltx* by PM in the presence of Clg and heparin was confirmed by electron microscopy. Finally, g-Ltx* could also be effectively opsonized with Clg at 37 degrees C before their addition to the monolayers. These studies suggest that the recognition of g-Ltx* in the presence of Clg required cell surface protein(s) and that subsequent phagocytosis of these particles by PM was energy dependent and required intact intracellular cytoskeleton elements. Thus, PM monolayers provide a suitable system for further studies on the function of Clg in the recognition and phagocytosis of gelatin-coated particles by phagocytic cells.

The directed and elliptic flow of protons and charged pions has been observed from the semicentral collisions of a 158 GeV͞nucleon Pb beam with a Pb target.The rapidity and transverse momentum dependence of the flow has been measured.The directed flow of the pions is opposite to that of the protons but both exhibit negative flow at low p t .The elliptic flow of both is fairly independent of rapidity but rises with p t .

The effectiveness of intravenous amiodarone for the treatment of incessant (shock resistant) ventricular tachycardia (VT) has not been established. This study evaluated the efficacy of a water-soluble amiodarone preparation or lidocaine for the treatment of shock-resistant VT. The trial was a double-blinded parallel design. Patients were randomized to receive up to 2 boluses of either 150 mg intravenous amiodarone or 2 boluses of 100 mg lidocaine followed by a 24-hour infusion. If the first assigned medication failed to terminate VT, the patient was crossed over to the alternative therapy. Twenty-nine patients were randomized to the study (18 received amiodarone and 11 received lidocaine). There were no significant differences between groups with regard to baseline characteristics. Immediate VT termination was achieved in 14 patients (78%) with amiodarone versus 3 patients (27%) on lidocaine (p <0.05). After 1 hour, 12 patients (67%) on amiodarone and 1 patient (9%) on lidocaine were alive and free of VT (p <0.01). Amiodarone had a 33% drug failure rate, whereas there was a 91% drug failure rate for lidocaine. The 24-hour survival was 39% on amiodarone and 9% on lidocaine (p <0.01). Drug-related hypotension with aqueous amiodarone was less frequent than with lidocaine. This study found that amiodarone is more effective than lidocaine in the treatment of shock-resistant VT.

The majority of brain metastases originate from lung cancer, breast cancer and malignant melanoma. In order to reach the brain, parenchyma metastatic cells have to transmigrate through the endothelial cell layer of brain capillaries, which forms the morphological basis of the blood-brain barrier (BBB). The BBB has a dual role in brain metastasis formation: it forms a tight barrier protecting the central nervous system from entering cancer cells, but it is also actively involved in protecting metastatic cells during extravasation and proliferation in the brain. The mechanisms of interaction of cancer cells and cerebral endothelial cells are largely uncharacterized. Here, we provide a comprehensive review on our current knowledge about the role of junctional and adhesion molecules, soluble factors, proteolytic enzymes and signaling pathways mediating the attachment of tumor cells to brain endothelial cells and the transendothelial migration of metastatic cells. Since brain metastases represent a great therapeutic challenge, it is indispensable to understand the mechanisms of the interaction of tumor cells with the BBB in order to find targets of prevention of brain metastasis formation.

In nuclei with equal neutron (N) and proton (Z) numbers, the observed enhanced neutron–proton correlations are predicted to favour isoscalar neutron–proton pairing, an unusual interaction that is distinct from normal nuclear superfluidity. Now, in a major experiment at the GANIL heavy-ion accelerator in France, observations of excited states of the N = Z = 46 palladium nucleus 92Pd provide evidence for spin-aligned isoscalar neutron–proton pairing that is rather different to that predicted, and which has not been seen previously in nuclei. Nuclei with equal neutron (N) and proton (Z) numbers show enhanced correlations that have been predicted to favour an unusual type of pairing, distinct from normal nuclear superfluidity. Here, technically challenging observations are reported of excited states in the N = Z = 46 nucleus 92Pd, from which evidence is inferred for a type of spin-aligned structure in the ground and low-lying excited states, not established in nuclei before and differing from previous predictions. Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work1 that introduced a strong spin–orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron–proton pairing2,3,4,5,6, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus 92Pd. Gamma rays emitted following the 58Ni(36Ar,2n)92Pd fusion–evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron–proton coupling scheme, different from the previous prediction2,3,4,5,6. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling7,8) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron–proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.

The role of quorum sensing (QS) is well known in microbial pathogenicity and antibiotic resistance. QS is responsible for motility, swarming, and biofilm production based on the signal molecules, e.g., acylated homoserine lactones (AHLs) produced by micro-organisms above certain population density. The inhibition of QS may reduce pathogenicity, antibiotic resistance and biofilm formation in systemic and local infections. The homoserine lactones and other transmitters contribute to antibiotic resistance and pathogenicity of several bacteria; consequently the inhibition of QS signals reduces the problem of resistance and virulence. Due to the increasing number of persistent non-treatable infections, there is an urgent need to develop new strategies to combat infections that destabilize bacterial communities in the host. The effect of essential oils on bacterial growth and QS were evaluated using the sensor strain Chromobacterium violaceum CV026 and N-acyl homoserine lactone (AHL) producing Escherichia coli ATTC 31298 and the grapevine colonizing Ezf 10-17 strains. Of the tested oils, rose, geranium, lavender and rosemary oils were the most potent QS inhibitors. Eucalyptus and citrus oils moderately reduced pigment production by CV026, whereas the chamomile, orange and juniper oils were ineffective.

φ meson production is studied by the NA49 Collaboration in central Pb + Pb collisions at 20A, 30A, 40A, 80A, and 158A GeV beam energy.The data are compared with measurements at lower and higher energies and with microscopic and thermal models.The energy dependence of yields and spectral distributions is compatible with the assumption that partonic degrees of freedom set in at low SPS energies.

Malignant melanoma represents the third common cause of brain metastasis, having the highest propensity to metastasize to the brain of all primary neoplasms in adults. Since the central nervous system lacks a lymphatic system, the only possibility for melanoma cells to reach the brain is via the blood stream and the blood-brain barrier. Despite the great clinical importance, mechanisms of transmigration of melanoma cells through the blood-brain barrier are incompletely understood. In order to investigate this question we have used an in vitro experimental setup based on the culture of cerebral endothelial cells (CECs) and the A2058 and B16/F10 melanoma cell lines, respectively. Melanoma cells were able to adhere to confluent brain endothelial cells, a process followed by elimination of protrusions and transmigration from the luminal to the basolateral side of the endothelial monolayers. The transmigration process of certain cells was accelerated when they were able to use the routes preformed by previously transmigrated melanoma cells. After migrating through the endothelial monolayer several melanoma cells continued their movement beneath the endothelial cell layer. Melanoma cells coming in contact with brain endothelial cells disrupted the tight and adherens junctions of CECs and used (at least partially) the paracellular transmigration pathway. During this process melanoma cells produced and released large amounts of proteolytic enzymes, mainly gelatinolytic serine proteases, including seprase. The serine protease inhibitor Pefabloc® was able to decrease to 44-55% the number of melanoma cells migrating through CECs. Our results suggest that release of serine proteases by melanoma cells and disintegration of the interendothelial junctional complex are main steps in the formation of brain metastases in malignant melanoma.

Yields and phase space distributions of φ-mesons emitted from p+p (minimum bias trigger), p+Pb (at various centralities) and central Pb+Pb collisions are reported (Ebeam=158AGeV). The decay φ→K+K− was used for identification. The φ/π ratio is found to increase by a factor of 3.0±0.7 from inelastic p+p to central Pb+Pb. Significant enhancement in this ratio is also observed in subclasses of p+p events (characterized by high charged-particle multiplicity) as well as in the forward hemisphere of central p+Pb collisions. In Pb+Pb no shift or significant broadening of the φ-peak is seen.

We present first data on event-by-event fluctuations in the average transverse momentum of charged particles produced in Pb+Pb collisions at the CERN SPS. This measurement provides previously unavailable information allowing sensitive tests of microscopic and thermodynamic collision models and to search for fluctuations expected to occur in the vicinity of the predicted QCD phase transition. We find that the observed variance of the event-by-event average transverse momentum is consistent with independent particle production modified by the known two-particle correlations due to quantum statistics and final state interactions and folded with the resolution of the NA49 apparatus. For two specific models of non-statistical fluctuations in transverse momentum limits are derived in terms of fluctuation amplitude. We show that a significant part of the parameter space for a model of isospin fluctuations predicted as a consequence of chiral symmetry restoration in a non-equilibrium scenario is excluded by our measurement.

The transverse mass m t distributions for antiprotons are measured at midrapidity for minimum bias Pb+Pb collisions at 158A GeV and for central Pb+Pb collisions at 20A, 30A, 40A, and 80A GeV beam energies in the fixed target experiment NA49 at the CERN SPS.The rapidity density dn/dy, inverse slope parameter T, and mean transverse mass m t derived from the m t distributions are studied as a function of the incident energy and the collision centrality and compared to the relevant data on proton production.The shapes of the m t distributions of p and p are very similar.The ratios of the particle yields, p/p and ¯ / p, are also analyzed.The p/p ratio exhibits an increase with decreasing centrality and a steep rise with increasing beam energy.The ¯ / p ratio increases beyond unity with decreasing beam energy.

Three alkaloids, lycorine, homolycorine and 2-O-acetyllycorine, were isolated from the bulbs of Leucojum vernum (Amaryllidaceae) and identified by means of NMR analysis. The alkaloids obtained from L. vernum and from other Amaryllidaceae species were studied in vitro for HIV-1 replication inhibitory activity on MT4 cells. The cytotoxicity of the compounds in uninfected cells was evaluated by using the MTT assay and the [3 H]thymidine incorporation test. The antiviral activities were determined by means of the p24 antigen assay and solid-phase reverse transcriptase testing. The results demonstrate that trisphaeridine, lycorine, homolycorine, and haemanthamine possess high antiretroviral activities (IC50 = 0.4 - 7.3 μg/mL), accompanied by low therapeutic indices (TI50 = 1.3 - 1.9).

The transverse mass m t distributions for deuterons and protons are measured in Pb+ Pb reactions near midrapidity and in the range 0 Ͻ m t -m Ͻ 1.0 ͑1.5͒ GeV/ c 2 for minimum bias collisions at 158A GeV and for central collisions at 40 and 80 A GeV beam energies.The rapidity density dn / dy, inverse slope parameter T and mean transverse mass ͗m t ͘ derived from m t distributions as well as the coalescence parameter B 2 are studied as a function of the incident energy and the collision centrality.The deuteron m t spectra are significantly harder than those of protons, especially in central collisions.The coalescence factor B 2 shows three systematic trends.First, it decreases strongly with increasing centrality reflecting an enlargement of the deuteron coalescence volume in central Pb+ Pb collisions.Second, it increases with m t .Finally, B 2 shows an increase with decreasing incident beam energy even within the SPS energy range.The results are discussed and compared to the predictions of models that include the collective expansion of the source created in Pb+ Pb collisions.

With its large acceptance and particle identification coverage the NA49 experiment (Fig. 1) can study hadron production in a wide range of high energy reactions [1]. Originally aimed at examining central Pb+Pb collisions for signatures of quark-gluon plasma formation, the scope of the experiment has been enhanced with a systematic study of impact parameter and projectile size dependence, as well as the inclusion of the more elementary p+p and p+A interactions. The question is: are predicted signals of the quark-gluon plasma observed and are there discontinuities which would support the concept of hadronic phase transition?

The nucleus 106Rh was populated using the reaction 96Zr(13C, p2n) at a beam energy of 51 MeV. γ-ray transitions were identified using the EUROBALL-IV γ-ray spectrometer and the DIAMANT charged particle array. The yrast band, which is based upon a πg9/2−1⊗νh11/2 configuration, has been extended to Iπ=(22−). A new ΔI=1 band has been identified which resides ∼300 keV above the yrast band. Core–quasiparticle coupling model calculations show reasonably good agreement with the data. The properties of the two pairs of strongly coupled bands are consistent with a chiral interpretation for these states.

Results on $\Lambda$, $\bar{\Lambda}}$, $\Xi^{-}$, and $\bar{\Xi}^{+}$ production in central Pb+Pb reactions at 20A, 30A, 40A, 80A, and 158A GeV are presented. The energy dependence of transverse mass spectra, rapidity spectra, and multiplicities is discussed. Comparisons to string hadronic models (UrQMD and HSD) and statistical hadron gas models are shown. While the latter provide a reasonable description of all particle yields, the first class of models fails to match the $\Xi^{-}$, and $\bar{\Xi}^{+}$ multiplicities.

The renin-angiotensin-aldosterone system (RAAS) has emerged as an important hormonal system in the initiation and pathogenesis of atrial fibrillation (AF). Therefore, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are emerging as novel drugs for the prevention of AF. A meta-analysis of 11 randomized, controlled, parallel-design clinical trials evaluating effect of ACEIs or ARBs on the development of AF was performed. Treatment with ACEIs or ARBs reduced the relative risk (RR) of AF in patients with hypertension by 23% [RR 0.769, P < 0.001, 95% confidence interval (CI) 0.686-0.862] and by 11% in patients after myocardial infarction (RR 0.898, P < 0.05, 95% CI 0.814-0.992). Reduction in AF was greatest in patients after electrical cardioversion (RR 0.491, P < 0.001, 95% CI 0.334-0.720) and in patients with heart failure (RR 0.684, P < 0.001, 95% CI 0.594-0.787). Overall, inhibition of the RAAS reduced the RR of AF by 19% (RR 0.810, P < 0.001, 95% CI 0.759-0.865).

Radioactive sugar-nucleotides reacted with the microsomal fractions of rat and rabbit liver to form glycoproteins with endogenous acceptors. Triton X-100 caused 2- to 3-fold enhancement of incorporation, but the transfer enzyme system lost activity very rapidly under such conditions. Higher concentrations of sugar-nucleotides somewhat protected the enzymes. The transfer of hexosamine-N-acetyl from UDP-hexosamine-NAc was noncompetitively inhibited by UDP and UMP. Cyclic UMP, uridine, ADP, and AMP had no significant effect. The incorporation of mannose from GDP-mannose was inhibited by GDP, but UMP and UDP had only very slight inhibitory action. Snake venom phosphodiesterase also caused marked inhibition under conditions where it hydrolized only a fraction of UDP-hexosamine-NAc. Two products were observed in the reactions with UDP-galactose, UDP-hexosamine-NAc, and GDP-mannose; one was very labile to acid hydrolysis and could be extracted with lipid solvents, while the other was protein-bound sugar. The incorporation of hexosamine-NAc into the lipid was initially rapid then reached a plateau after about 10 min of reaction. The incorporation into protein was slower initially but proceeded longer at a steady rate. When microsomal fractions labeled previously with hexosamine-NAc-14C were treated with UMP or UDP, the radioactivity of the sugar-lipid decreased rather rapidly. Phosphodiesterase had a similar action. In a pulse-chase experiment the radioactivity of the sugar-lipid decreased, as expected from a precursor of the protein-bound sugar, and the activity of the protein increased concomitantly. The incorporation of UDP-3H and UMP-3H into UDP-glucosamine-NAc was also measured. Under the conditions of the tests only a minute amount of 3H could be detected in UDP-glucosamine-NAc.

Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-β, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-β1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, β1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-β signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-β-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-β-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAttachment of Glucosamine to Protein at the Ribosomal Site of Rat Liver*Janos Molnar and Dalisay SyCite this: Biochemistry 1967, 6, 7, 1941–1947Publication Date (Print):July 1, 1967Publication History Published online1 May 2002Published inissue 1 July 1967https://doi.org/10.1021/bi00859a009RIGHTS & PERMISSIONSArticle Views34Altmetric-Citations59LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (548 KB) Get e-Alerts Get e-Alerts

Cerebral endothelial cells (CECs) forming the blood-brain barrier are at the interface of the immune and the central nervous systems and thus may play an important role in the functional integration of the two systems. Here, we investigated how CECs recognize and respond to pathogen- and damage-associated molecular patterns to regulate the functions of the neurovascular unit. First we detected the expression of several NOD-like receptors (NLRs) - including NOD1, NOD2, NLRC4, NLRC5, NLRP1, NLRP3, NLRP5, NLRP9, NLRP10, NLRP12, NLRA, and NLRX - in human brain endothelial cells. Inflammatory cytokines, such as interferon-γ, tumor necrosis factor-α, and IL-1β had stimulatory effects on the transcription of many of these receptors. Expression of key inflammasome components (NOD2, NLRP3, and caspase 1) along with caspase-cleaved interleukins IL-1β and IL-33 could be induced by priming with lipopolysaccharide and activation with muramyl dipeptide. In addition, combined treatment with lipopolysaccharide and muramyl dipeptide resulted in IL-1β secretion in a caspase- and ERK1/2 kinase-dependent manner. Our findings demonstrate that NLRs and inflammasomes can be activated in cerebral endothelial cells, which may confer a yet unexplored role to the blood-brain barrier in neuroimmune and neuroinflammatory processes.

Polyethylene glycol (PEG) coating has been frequently used to improve the pharmacokinetic behavior of nanoparticles.Studies which contribute to better unravel the effects of PEGylation on the toxicity of nanoparticle formulation are therefore highly relevant.In the present study, reduced graphene oxide (rGO) was functionalized with PEG and its effects on key components of the blood-brain barrier, such as Page 1 of 39 ACS Paragon Plus Environment Molecular Pharmaceutics astrocytes and endothelial cells, were analyzed in culture and in an in vivo rat model.The in vitro studies demonstrated concentration-dependent toxicity.The highest concentration (100 µg/ml) of non-PEGylated rGO had a lower toxic influence on cell viability in primary cultures of astrocytes and rat brain endothelial cells (RBECs), while PEGylated rGO induced deleterious effects and cell death.We assessed hippocampal BBB integrity in vivo by evaluating astrocyte activation and the expression of the endothelial tight and adherens junctions proteins.From 1 h to 7 days post-rGO-PEG systemic injection, a notable and progressive down-regulation of protein markers of astrocytes (GFAP, connexin-43), the endothelial tight (occludin) and adherens (βcatenin) junctions, and basal lamina (laminin) were observed.The formation of intracellular ROS demonstrated by increases in the enzymatic antioxidant system in the PEGylated rGO samples was indicative of oxidative stress-mediated damage.Under the experimental conditions and design of the present study the PEGylation of rGO did not improve interaction with components of the blood-brain barrier.In contrast, the attachment of PEG to rGO induced deleterious effects in comparison with the effects caused by non-PEGylated rGO.

Pre-eclampsia is the leading cause of fetal and maternal morbidity and mortality. Early onset pre-eclampsia (EOPE) is a disorder that has severe maternal and fetal outcomes, whilst its etiology is poorly understood. We hypothesize that epigenetics plays an important role to mediate the development of EOPE and conducted a case-control study to compare the genome-wide methylome difference between chorioamniotic membranes from 30 EOPE and 17 full-term pregnancies using the Infinium Human Methylation 450 BeadChip arrays. Bioinformatics analysis tested differential methylation (DM) at CpG site level, gene level, and pathway and network level. A striking genome-wide hypermethylation pattern coupled with hypomethylation in promoters was observed. Out of 385 184 CpG sites, 9995 showed DM (2.6%). Of those DM sites, 91.9% showed hypermethylation (9186 of 9995). Over 900 genes had DM associated with promoters. Promoter-based DM analysis revealed that genes in canonical cancer-related pathways such as Rac, Ras, PI3K/Akt, NFκB and ErBB4 were enriched, and represented biological functional alterations that involve cell cycle, apoptosis, cancer signaling and inflammation. A group of genes previously found to be up-regulated in pre-eclampsia, including GRB2, ATF3, NFKB2, as well as genes in proteasome subunits (PSMA1, PMSE1, PSMD1 and PMSD8), harbored hypomethylated promoters. Contrarily, a cluster of microRNAs, including mir-519a1, mir-301a, mir-487a, mir-185, mir-329, mir-194, mir-376a1, mir-486 and mir-744 were all hypermethylated in their promoters in the EOPE samples. These findings collectively reveal new avenues of research regarding the vast epigenetic modifications in EOPE.

The emergence of multidrug resistant (MDR) cancer phenotypes dramatically attenuates the efficiency of antineoplastic drug treatments often leading to the failure of chemotherapy. Therefore there is an urgent need to engineer new therapeutically useful agents and propose innovative approaches able to defeat resistant cancer cells. Although the remarkable anti-cancer features of silver nanoparticles (AgNPs) have already been delineated their impact on MDR cancer has never been investigated. Herein, we report that AgNPs have notable anti-proliferative effect and induce apoptosis mediated cell death both in drug sensitive and in MDR cancer cells. Furthermore we show evidence that AgNPs exert an inhibitory action on the efflux activity of MDR cancer cells which feature could be exploited to enhance drug accumulation. We verified synergistic interactions of AgNPs with six different antineoplastic agents on drug resistant cells which emphasizes the excellent potential of AgNPs as combinational partners in the chemotherapy of MDR cancer.The treatment of cancer often fails due to the development of multidrug resistant (MDR) cancer cells. Hence, novel approaches are being investigated to combat drug resistant cancer cells. One particular method studied here uses silver nanoparticles (AgNPs). The authors showed that AgNPs had anti-proliferative effect and ?exerted an inhibitory action on ABC transporter. The findings could suggest the possible use of AgNPs in combination with other chemotherapeutic agents in the clinical setting.

As virus diseases cannot be controlled by traditional plant protection methods, the risk of their spread have to be minimized on vegetatively propagated plants, such as grapevine. Metagenomic approaches used for virus diagnostics offer a unique opportunity to reveal the presence of all viral pathogens in the investigated plant, which is why their application can reduce the risk of using infected material for a new plantation. Here we used a special branch, deep sequencing of virus-derived small RNAs, of this high-throughput method for virus diagnostics, and determined viromes of vineyards in Hungary. With NGS of virus-derived small RNAs we could detect not only the viruses tested routinely, but also new ones, which had never been described in Hungary before. Virus presence did not correlate with the age of the plantation, moreover phylogenetic analysis of the identified virus isolates suggests that infections are mostly caused by the use of infected propagating material. Our results, validated by other molecular methods, raised further questions to be answered before this method can be introduced as a routine, reliable test for grapevine virus diagnostics.

Transmembrane protein coding genes are commonly associated with human diseases. We characterized disease causing mutations and natural polymorphisms in transmembrane proteins by mapping missense genetic variations from the UniProt database on the transmembrane protein topology listed in the Human Transmembrane Proteome database. We found characteristic differences in the spectrum of amino acid changes within transmembrane regions: in the case of disease associated mutations the non-polar to non-polar and non-polar to charged amino acid changes are equally frequent. In contrast, in the case of natural polymorphisms non-polar to charged amino acid changes are rare while non-polar to non-polar changes are common. The majority of disease associated mutations result in glycine to arginine and leucine to proline substitutions. Mutations to positively charged amino acids are more common in the center of the lipid bilayer, where they cause more severe structural and functional anomalies. Our analysis contributes to the better understanding of the effect of disease associated mutations in transmembrane proteins, which can help prioritize genetic variations in personal genomic investigations.

New rotational bands built on the $\nu$$(h_{11/2})$ configuration have been identified in $^{105}$Pd. Two bands built on this configuration show the characteristics of transverse wobbling: the $\Delta$$I$=1 transitions between them have a predominant E2 component and the wobbling energy decreases with increasing spin. The properties of the observed wobbling bands are in good agreement with theoretical results obtained using constrained triaxial covariant density functional theory and quantum particle rotor model calculations. This provides the first experimental evidence for transverse wobbling bands based on a one-neutron configuration, and also represents the first observation of wobbling motion in the $A$$\sim$100 mass region.

Preliminary inclusive spectra of negative hadrons, net protons and neutral strange particles are presented, measured by the NA49 experiment in central Pb+Pb collisions at 158 GeV per nucleon. Comparison of their yields with those from the lighter S+S system suggests that the yields scale approximately with the number of participating nucleons.

Production of Lambda and Antilambda hyperons was measured in central Pb-Pb collisions at 40, 80, and 158 A$\cdot$GeV beam energy on a fixed target. Transverse mass spectra and rapidity distributions are given for all three energies. The $\Lambda/\pi$ ratio at mid-rapidity and in full phase space shows a pronounced maximum between the highest AGS and 40 A$\cdot$GeV SPS energies, whereas the $\bar{\Lambda}/\pi$ ratio exhibits a monotonic increase.

High-spin states in 105Rh were populated by the 96Zr(13C, p3n) reaction at beam energies of 51 and 58 MeV, and studied using the EUROBALL IV γ-ray spectrometer and the DIAMANT charged particle array. A pair of nearly degenerate ΔI=1 three-quasiparticle bands with the same spins and parity have been observed. Comparison of the experimental results with tilted axis cranking calculations confirms the chiral character of the two bands, while arguments based on the excitation of particles within the πg9/2ν(h11/2)2 configuration of the yrast band and comparison with the previously observed γ band exclude the other possible interpretations. This is the first experimental evidence for three-quasiparticle chiral structure in the A ∼ 100 region, and the first simultaneous observation of a γ band and chiral partner bands in one nucleus.

Abstract Mean arterial pressure (MAP) has traditionally been derived from systolic and diastolic pressures, weighted 1/3 systolic and 2/3 diastolic. No correction is made for the increasing time dominance of systole with increasing heart rates. In a previous study, we developed a new and more accurate heart rate‐corrected MAP formula from central aorta pressure determinations in a large number of patients: MAP = DP + [0.33 + (HR × 0.0012)] × [PP] where SP and DP are systolic and diastolic pressure and HR is heart rate. The current study validates the new MAP formula in the same patient at increasing paced heart rates. A central aorta catheter was used to obtain computer‐determined systolic, diastolic, and MAP in 12 patients. Values were obtained at baseline and then at increasing right atrial paced heart rates. The new and standard MAP formula‐derived values were compared with computer‐determined values. The new formula showed a much closer correlation with the computer‐derived values for MAP. Standard MAP calculations for MAP can easily be improved by inclusion of a heart rate factor. Catheter Cardiovasc Interv 2004;63:419–425. © 2004 Wiley‐Liss, Inc.

This study evaluated the correlation of left ventricular hypertrophy and QT dispersion in patients with systemic hypertension. QT dispersion, determined using the standard electrocardiogram, showed an increase as left ventricular mass determined by echocardiography increased in hypertensive patients.

Results are presented on event-by-event fluctuations in transverse momentum of charged particles, produced at forward rapidities in p+p, C+C, Si+Si and Pb+Pb collisions at 158 AGeV. Three different characteristics are discussed: the average transverse momentum of the event, the Phi_pT fluctuation measure and two-particle transverse momentum correlations. In the kinematic region explored, the dynamical fluctuations are found to be small. However, a significant system size dependence of Phi_pT is observed, with the largest value measured in peripheral Pb+Pb interactions. The data are compared with predictions of several models.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPurification of opsonically active human and rat cold-insoluble globulin (plasma fibronectin)Janos Molnar, Frank B. Gelder, Lai Ming Zong, Gerald E. Siefring, Jr., R. Bruce Credo, and Laszlo LorandCite this: Biochemistry 1979, 18, 18, 3909–3916Publication Date (Print):September 4, 1979Publication History Published online1 May 2002Published inissue 4 September 1979https://doi.org/10.1021/bi00585a010Request reuse permissionsArticle Views36Altmetric-Citations45LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (2 MB) Get e-Alertsclose Get e-Alerts

The preparation of [β-32P]UDP-N-acetyl[1-14C]glucosamine is described. This compound was used in reactions with microsomes of rabbit liver to investigate the pathway of glycoprotein synthesis in this system. The 32P and 14C were incorporated into a lipid component while only the 14C was found in the protein products. The lipid material was purified by ion exchange and two dimensional thin layer chromatography. In both of these systems the 32P and 14C migrated together. These results suggested that a single microsomal lipid component contained the β-phosphoryl and N-acetylglucosamine residues of the nucleotide-sugar and therefore UMP had to be the other product in the reaction. The “lipid-sugar” had properties similar to the “lipid intermediates” described for microorganisms. The results presented in this and previous papers suggested that this “lipid-sugar” may serve as an intermediate in glycoprotein synthesis.

Background: Niacin or nicotinic acid (vitamin B3) raises the levels of high-density lipoprotein cholesterol (HDL) by about 30% to 35%. In patients with prior coronary disease, 7 trials have been published on clinical cardiovascular disease outcomes and the results, not surprisingly, are inconsistent. Hence, we performed this meta-analysis of randomized placebo-controlled trials (RCTs) to evaluate the effect of niacin on cardiovascular outcomes in patients with coronary artery disease. Methods: A systematic search using PubMed, EMBASE, and Cochrane library databases was performed. Seven studies with a total of 5137 patients met our inclusion criteria. Heterogeneity of the studies was analyzed by the Cochran Q statistics. The significance of common treatment effect was assessed by computing the combined relative risks using the Mantel-Haenszel fixed-effect model. A 2-sided alpha error of less than .05 was considered statistically significant (P &lt; .05). Results: Compared to placebo group, niacin therapy significantly reduced coronary artery revascularization (RR [relative risk]: 0.307 with 95% CI: 0.150-0.628; P = .001), nonfatal myocardial infarction ([MI]; RR: 0.719; 95% CI: 0.603-0.856; P = .000), stroke, and TIA ([transient ischemic attack] RR: 0.759; 95%CI: 0.613-0.940; P = .012), as well as a possible but nonsignificant decrease in cardiac mortality (RR: 0.883: 95% CI: 0.773-1.008; p= 0.066). Conclusions: In a meta-analysis of seven trials of secondary prevention, niacin was associated with a significant reduction in cardiovascular events and possible small but non-significant decreases in coronary and cardiovascular mortality.

There are a handful of studies that have been done investigating the effect of music on various vital signs, namely systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). Many studies have also assessed effects of music on self-reported anxiety level, attributing some degree of music-induced anxiety relief to the beneficial impacts of music on vital signs. Several randomised studies have shown varying effects of music on these vital parameters and so a metaanalysis was done to compare the effect of music on them. The fixed effects model was used as studies were homogenous. A two-sided alpha error < 0.05 was considered to be statistically significant. Compared to those who did not receive music therapy, those who did receive music therapy had a significantly greater decrease in SBP before and after (difference in means, −2.629, confidence interval (CI), −3.914 to −1.344, P < 0.001), a significantly greater decrease in DBP (difference in means, −1.112, CI, −1.692 to −0.532, P < 0.001), and a significantly greater decrease in HR (difference in means, −3.422, CI, −5.032 to −1.812, P < 0.001).

Bioassay-guided fractionation of the chloroform extract of Centaurea jacea L. afforded the isolation of cirsiliol, apigenin, hispidulin, eupatorin, isokaempferide, axillarin, centaureidin, 6-methoxykaempferol 3-methyl ether, trachelogenin, cnicin, 4'-acetylcnicin and three aliphatic glucose diesters, including the new natural product 1β-isobutanoyl-2-angeloyl-glucose. The structures of the compounds were established on the basis of spectroscopic analyses (UV, MS and NMR). All compounds were isolated for the first time from this species. The compounds were evaluated for their tumour cell growth inhibitory activities on HeLa, MCF-7 and A431 cells. Different types of secondary metabolites (flavonoids, sesquiterpenes) were found to be responsible for the antitumour effects of the extracts; the highest activity was exerted by centaureidin, in addition to moderately active compounds (cirsiliol, isokaempferide, apigenin, hispidulin, cnicin and 4'-acetylcnicin).

Abstract Background Data regarding the associations between sleep duration and clinical cardiovascular ( CV ) events are limited. We aimed to analyze any associations between self‐reported sleep duration and CV events. Hypothesis Methods This is a cross‐sectional analysis of nationally representative population of noninstitutionalized US civilians recruited in the 2007 to 2008 National Health and Nutrition Examination Survey. This is a questionnaire‐based study including only those subjects who answered questions on sleep duration and CV events. The main outcome measures were prevalence of congestive heart failure, myocardial infarction, stroke, coronary artery disease, and angina. Results After logistic regression analysis, significant associations between sleep duration and prevalence of stroke, myocardial infarction, congestive heart failure, coronary artery disease, and angina were found. There was a statistically significant increase in stroke in those with &lt;6 hours of sleep (odds ratio [ OR ]: 2.0111, 95% confidence interval [ CI ]: 1.4356‐2.8174), in myocardial infarction in those with &lt;6 hours of sleep ( OR : 2.0489, 95% CI : 1.4878‐2.8216), in congestive heart failure in those with &lt;6 hours of sleep ( OR : 1.6702, 95% CI : 1.1555 to 2.4142), in coronary artery disease in those with &gt;8 hours of sleep ( OR : 1.1914, 95% CI : 1.0712‐3.4231), and in angina in those with &gt;8 hours of sleep ( OR : 2.0717, 95% CI : 1.0497‐4.0887). Conclusions The results of this cross‐sectional analysis suggest that sleep duration may be associated with the prevalence of various CV events.

The smooth and rough microsomal fractions of rat and rabbit liver were shown to carry out transfer of N-acetylhexosamine, galactose and mannose to endogenous protein acceptors from corresponding sugar-nucleotides. The rough microsomal fraction was more active than the smooth microsomal fraction for the incorporation of hexosamine and mannose, but only one-third as active for the incorporation of galactose. Data also are presented which suggest that among the subcellular fractions only the microsomal fractions are active in the hexosamine and mannose transfer reactions.

Preeclampsia is one of the leading causes of fetal and maternal morbidity and mortality worldwide. Preterm babies of mothers with early onset preeclampsia (EOPE) are at higher risks for various diseases later on in life, including cardiovascular diseases. We hypothesized that genome-wide epigenetic alterations occur in cord blood DNAs in association with EOPE and conducted a case control study to compare the genome-scale methylome differences in cord blood DNAs between 12 EOPE-associated and 8 normal births.Bioinformatics analysis of methylation data from the Infinium HumanMethylation450 BeadChip shows a genome-scale hypomethylation pattern in EOPE, with 51,486 hypomethylated CpG sites and 12,563 hypermethylated sites (adjusted P <0.05). A similar trend also exists in the proximal promoters (TSS200) associated with protein-coding genes. Using summary statistics on the CpG sites in TSS200 regions, promoters of 643 and 389 genes are hypomethylated and hypermethylated, respectively. Promoter-based differential methylation (DM) analysis reveals that genes in the farnesoid X receptor and liver X receptor (FXR/LXR) pathway are enriched, indicating dysfunction of lipid metabolism in cord blood cells. Additional biological functional alterations involve inflammation, cell growth, and hematological system development. A two-way ANOVA analysis among coupled cord blood and amniotic membrane samples shows that a group of genes involved in inflammation, lipid metabolism, and proliferation are persistently differentially methylated in both tissues, including IL12B, FAS, PIK31, and IGF1.These findings provide, for the first time, evidence of prominent genome-scale DNA methylation modifications in cord blood DNAs associated with EOPE. They may suggest a connection between inflammation and lipid dysregulation in EOPE-associated newborns and a higher risk of cardiovascular diseases later in adulthood.

The blood-brain barrier (BBB) is the main interface controlling molecular and cellular traffic between the central nervous system (CNS) and the periphery. It consists of cerebral endothelial cells (CECs) interconnected by continuous tight junctions, and closely associated pericytes and astrocytes. Different parts of the CNS have diverse functions and structures and may be subject of different pathologies, in which the BBB is actively involved. It is largely unknown, however, what are the cellular and molecular differences of the BBB in different regions of the brain. Using in silico, in vitro, and ex vivo techniques we compared the expression of BBB-associated genes and proteins (i.e., markers of CECs, brain pericytes, and astrocytes) in the cortical grey matter and white matter. In silico human database analysis (obtained from recalculated data of the Allen Brain Atlas), qPCR, Western blot, and immunofluorescence studies on porcine and mouse brain tissue indicated an increased expression of glial fibrillary acidic protein in astrocytes in the white matter compared with the grey matter. We have also found increased expression of genes of the junctional complex of CECs (occludin, claudin-5, and α-catenin) in the white matter compared with the cerebral cortex. Accordingly, occludin, claudin-5, and α-catenin proteins showed increased expression in CECs of the white matter compared with endothelial cells of the cortical grey matter. In parallel, barrier properties of white matter CECs were superior as well. These differences might be important in the pathogenesis of diseases differently affecting distinct regions of the brain.

Abstract Single cell segmentation is typically one of the first and most crucial tasks of image-based cellular analysis. We present a deep learning approach aiming towards a truly general method for localizing nuclei across a diverse range of assays and light microscopy modalities. We outperform the 739 methods submitted to the 2018 Data Science Bowl on images representing a variety of realistic conditions, some of which were not represented in the training data. The key to our approach is to adapt our model to unseen and unlabeled data using image style transfer to generate augmented training samples. This allows the model to recognize nuclei in new and different experiments without requiring expert annotations.

Abstract Patch clamp recording of neurons is a labor-intensive and time-consuming procedure. Here, we demonstrate a tool that fully automatically performs electrophysiological recordings in label-free tissue slices. The automation covers the detection of cells in label-free images, calibration of the micropipette movement, approach to the cell with the pipette, formation of the whole-cell configuration, and recording. The cell detection is based on deep learning. The model is trained on a new image database of neurons in unlabeled brain tissue slices. The pipette tip detection and approaching phase use image analysis techniques for precise movements. High-quality measurements are performed on hundreds of human and rodent neurons. We also demonstrate that further molecular and anatomical analysis can be performed on the recorded cells. The software has a diary module that automatically logs patch clamp events. Our tool can multiply the number of daily measurements to help brain research.

We present the first measurement of fluctuations from event to event in the production of strange particles in collisions of heavy nuclei. The ratio of charged kaons to charged pions is determined for individual central Pb+Pb collisions. After accounting for the fluctuations due to detector resolution and finite number statistics we derive an upper limit on genuine nonstatistical fluctuations, which could be related to a first- or second-order QCD phase transition. Such fluctuations are shown to be very small.

To evaluate and compare QT correction formulas in healthy subjects, we used 24-hour Holter monitoring because it allows the assessment of QT intervals over a large range of rates. Computer-assisted QT-interval measurements were obtained from 21 subjects. QT-RR relations for individuals and the group were fitted by regression analysis to 5 QT prediction formulas: simple Bazett's, modified Bazett's, linear (Framingham), modified Fridericia's and exponential (Sarma's). There were no significant differences in mean squared residuals between formulas. When using individually calculated regression parameters, each formula gave good or acceptable QT correction over the entire range of RR intervals. Simple Bazett's formula (which uses no regression parameters) was unreliable at high rates. Akaike information criteria rank was: Sarma's, Framingham, modified Bazett's, Fridericia's, and simple Bazett's. When group-based regression parameters were applied to individuals, no formula had a clear advantage over simple Bazett's. We conclude that any formula that invokes regression parameters unique to each individual provides satisfactory QT correction. Determination of these parameters requires long-term recording to obtain an adequate range of rates. Group-based regression parameters give poor correction. When individual parameters cannot be determined, as in a 12-lead electrocardiogram, no formula provides an advantage over the familiar simple Bazett's.

Hypotension is the most frequent adverse event reported with intravenous amiodarone. Hypotension has been attributed to the vasoactive solvents of the standard formulation (Cordarone IV) and is not dose related, but related to the rate of infusion. Drug labeling calls for intravenous amiodarone to be administered over 10 minutes. A new aqueous formulation of amiodarone (Amio-Aqueous) does not contain vasoactive excipients and may be administered safely by rapid administration without hypotension. This hypothesis was tested using combined data of 4 clinical trials; each assessed the development of hypotension prospectively. Hypotension was defined as a 25% decrease in systolic blood pressure (BP), with the development of a systolic BP of <90 mm Hg or a systolic BP that decreased to <80 mm Hg. In all, 358 Amio-Aqueous and 225 lidocaine boluses were administered to 278 patients; 246 had ventricular tachycardia (VT) during drug administration. Hypotension developed in 11% of patients on Amio-Aqueous versus 19% on lidocaine (p = NS), all during VT; most resolved spontaneously with VT termination. With both drugs, hypotension persisted after VT termination in 1% of patients; the incidence of drug-related hypotension occurred in 2% of patients (1% had hypotension requiring treatment). The Amio-Aqueous was discontinued in 1% of patients, and lidocaine was discontinued in 2% of patients because of hypotension. We conclude that Amio-Aqueous is at least as safe as lidocaine in terms of causing hypotension when administered rapidly. This is a significant advantage over the standard amiodarone formulation, because Cordarone cannot be administered by rapid bolus owing to excipient-related hypotension.

Results are presented on Omega production in central Pb+Pb collisions at 40 and 158 AGeV beam energy. Given are transverse-mass spectra, rapidity distributions, and total yields for the sum Omega+Antiomega at 40 AGeV and for Omega and Antiomega separately at 158 AGeV. The yields are strongly under-predicted by the string-hadronic UrQMD model and are in better agreement with predictions from a hadron gas models.

The energy dependence of hadron production in central Pb+Pb collisions is presented and discussed. In particular, midrapidity $m_T$-spectra for $\pi^-$, $K^-$, $K^+$, $p$, $\bar{p}$, $d$, $\phi$, $\Lambda$ and $\bar{\Lambda}$ at 40, 80 and 158 $A$GeV are shown. In addition $\Xi$ and $\Omega$ spectra are available at 158 $A$GeV. The spectra allow to determine the thermal freeze-out temperature $T$ and the transverse flow velocity $\beta_T$ at the three energies. We do not observe a significant energy dependence of these parameters; furthermore there is no indication of early thermal freeze-out of $\Xi$ and $\Omega$ at 158 $A$GeV. Rapidity spectra for $\pi^-$, $K^-$, $K^+$ and $\phi$ at 40, 80 and 158 $A$GeV are shown, as well as first results on $\Omega$ rapidity distributions at 158 $A$GeV. The chemical freeze-out parameters $T$ and $\mu_B$ at the three energies are determined from the total yields. The parameters are close to the expected phase boundary in the SPS energy range and above. Using the total yields of kaons and lambdas, the energy dependence of the strangeness to pion ratio is discussed. A maximum in this ratio is found at 40 $A$GeV. This maximum could indicate the formation of deconfined matter at energies above 40 $A$GeV. A search for open charm in a large sample of 158 $A$GeV events is presented. No signal is observed. This result is compared to several model predictions.

Results of the production of Xi and Xi-bar hyperons in central Pb+Pb interactions at 158 GeV/c per nucleon are presented. This analysis utilises a global reconstruction procedure, which allows a measurement of 4pi integrated yields to be made for the first time. Inverse slope paramters, which are determined from an exponential fit to the transverse mass spectra, are shown. Central rapidity densities are found to be 1.49 +- 0.08 and 0.33 +- 0.04 per event per unit of rapidity for Xi and Xi-bar respectively. Yields integrated to full phase space are 4.12 +- 0.02 and 0.77 +- 0.04 for Xi and Xi-bar. The ratio of Xi-bar/Xi at mid-rapidity is 0.22 +- 0.03.

Bullous pemphigoid (BP) is an IgG-mediated autoimmune blistering disease that targets the hemidesmosomal proteins BP230 and BP180. To investigate the pathogenic role of anti-BP230 antibodies, rabbit polyclonal antibodies were generated against an antigenic sequence of the human BP230 antigen (BPAG 1, 2479–2499), which shows 67% homology in the human and the mouse BP230. Purified IgG from the rabbit anti-serum was transferred subcutaneously into the dorsal skin of neonatal isogeneic CBA/Ca (CBA) mice in a dose of 5 mg (n = 7) or 1.2 mg IgG/50 μl (n = 16). After 24 h, 1 of the mice injected with 5 mg IgG exhibited blisters, but the dorsal skin of all 7 of them was erythematous, and gentle friction produced a fine persistent wrinkling of the epidermis in 4 mice. The mice injected with 1.2 mg IgG developed less severe symptoms. Immunohistological examinations revealed linear rabbit IgG and mouse C3 depositions along the basement membrane of the perilesional skin and subepidermal blister formation. An intradermal inflammatory reaction (granulocyte infiltration) was also detected. None of these symptoms was seen in mice injected with IgG from a control rabbit anti-serum. These findings demonstrate that antibodies against BP230 can elicit the clinical and immunopathological features of BP in neonatal mice, suggesting that anti-BP230 antibodies may possibly play a pathogenic role in this disease.

The authors have previously identified a peptide of the human muscarinic acetylcholine receptor-3 (m3AChR) as a suitable antigen for the immunodetection of antimuscarinic acetylcholine receptor autoantibodies in primary Sjögren's syndrome (pSS). The aim of this study was to assess the clinical correlations and disease specificity of these antibodies.Seventy-three pSS, 40 rheumatoid arthritis (RA), 19 systemic lupus erythematosus (SLE), 14 secondary Sjögren's syndrome (sSS) patients, 22 subjects in whom pSS was suspected but in whom the diagnosis not could eventually be established (suspSS) and 40 healthy subjects were investigated. An enzyme-linked immunosorbent assay system developed by the authors using a 16-mer peptide of the m3AChR (m3AChR(213-228)) in a recombinant fusion peptide form was used as the antigen.Anti-m3AChR(213-228) antibody positivity was observed in 66 (90%) of the pSS patients. The antibody levels correlated positively with the number of extraglandular organ manifestations. Both the mean antibody levels and the occurrence of anti-m3AChR(213-228) positivity were significantly higher in pSS than in the comparison groups. The test discriminated the pSS patients from the various comparison groups with specificities of 65, 68, 71 and 50% for RA, SLE, sSS and suspSS, respectively.The presence of m3AChR(213-228) antibodies is a common feature in pSS. Although it is significantly more common in pSS than in the comparison groups, anti-m3AChR(213-228) positivity is not exclusive to pSS.

[corrected] The effectiveness of chemotherapy is limited by the emergence of multidrug resistance (MDR). MDR is caused by the activity of various ATP binding cassette (ABC) transporters that pump anticancer drugs out of the cells in an ATP-dependent manner. Additionally some other cellular mechanisms of MDR have been reported. The purpose of this study was to investigate mechanisms of MDR in drug resistant MCF-7 cell lines and to modulate P-glycoprotein (P-gp) and MRP1-based MDR.Paclitaxel (MCF-7/Pac), docetaxel (MCF-7/Doc), doxorubicin (MCF-7/Dox) and vincristine (MCF-7/Vinc) resistant sublines were developed from the parent MCF-7 cell line (MCF-7/S) by stepwise selection in dose increments over two years. Flow cytometry, MTT cytotoxicity assay, RT-PCR, caspase-3 activity assay and checkerboard combination assay were performed to investigate the degree of resistance developed in sublines and to reverse drug resistance phenotype.The flow cytometry histograms of drug accumulation assays demonstrated that the drug-resistant cell lines are P-gp and MRPI positive. RT-PCR results showed that the resistant sublines express both MDR1 and MRP1 genes. Resistance indices of each subline to each anticancer drug were determined using the MTT cytotoxicity assay and it was found that all the sublines were resistant to their respective agents. Caspase-3 activities of the cell lines were also determined. Caspase-3 activity is an important indicator of apoptosis in the cell. The reversal of MDR was attempted by two cinnamylidene ketone and two organosilicon compounds. The results indicated that these compounds modulated P-gp effectively, but they were not very effective at reversing MRP1 activity in the MCF-7 sublines. Four selective anticancer drugs (paclitaxel, docetaxel, doxorubicin and vincristine) and four synthetic MDR modulators [2-(2-methoxycinnamylidene) indan-1-one (cinnamylidene-1), 2-(2- methoxycinnamylidene)-3, 4-dihydro-2H-naphthelen-1-one) (cinnamylidene-2), ALIS 409 and ALIS 421] were applied to the sublines in combination. The fractional inhibitory indices illustrated that combined applications of cinnamylidene ketones and organosilicon compounds with paclitaxel, docetaxel or vincristine exerted significant antiproliferative effects on the resistant sublines.This report demonstrates the development of rational models for drug resistance MCF-7 cell lines and reversal of acquired drug resistance.

Nesiritide (recombinant human B-type natriuretic peptide) has been shown to provide symptomatic and hemodynamic improvement in acute decompensated heart failure. A previous meta-analysis of 3 randomized controlled trials has suggested an increased short-term risk of death with nesiritide use. We performed a meta-analysis of 7 available randomized controlled trials to evaluate the short- and long-term risk of death with nesiritide use for acute decompensated heart failure.Seven large randomized controlled nonmortality trials on nesiritide with available data on 30-day mortality were included. Data on 180-day mortality were available only in 4 trials. Mortality data in nesiritide and control arms were extracted from the selected trials and the nesiritide database (Scios Inc, Fremont, CA).The pooled estimate of the relative risks (RRs) for unadjusted 30- and 180-day mortality revealed no significant differences between the nesiritide arm (RR 1.243, 95% CI 0.798-1.935) and control arm (RR, 0.002, 95% CI 0.798-1.259), respectively).Unlike a previous analysis, our meta-analysis indicates that nesiritide is not associated with a higher 30- or 180-day mortality. Further analysis of mortality adjusted for confounding variables such as nesiritide dose, duration of infusion, concurrent use of inotropes, heart failure stage, and arrhythmias may reveal subgroups in jeopardy. Large-scale randomized controlled trials powered to evaluate mortality are required to conclusively address these findings.

The extracellular matrix (ECM) plays a critical role during the development and invasion of primary brain tumours. However, the function of ECM components and signalling between a permissive ECM and invasive astrocytes is not fully understood. We have recently reported the ECM enzyme, lysyl oxidase (LOX), in the central nervous system and observed up-regulation of LOX in anaplastic astrocytoma cells. While the catalytic function of LOX is essential for cross-linking of ECM proteins, we also reported that LOX induced invasive and metastatic properties in breast tumour epithelial cells through hydrogen peroxide-mediated FAK/Src activation. In this study, we tested the hypothesis that active LOX is expressed in anaplastic astrocytes and promotes FAK activation and invasive/migratory behaviour. Results demonstrate that increased expression and activity of LOX positively correlated with invasive phenotype of malignant astrocytoma cell lines. Immunohistochemistry detected increased LOX within tumour cells and ECM in grade I-IV astrocytic neoplasm compared with normal brain and coincidence of increased LOX with the loss of glial fibrillary acidic protein in higher-grade tumours. Increased active LOX in invasive astrocytes was accompanied by phosphorylation of FAK[Tyr576] and paxillin[Tyr118]; furthermore, both FAK and paxillin tyrosine phosphorylation were diminished by beta-aminopropionitrile inhibition of LOX activity and depletion of H(2)O(2) via catalase treatment. Additionally, we provide evidence that in astrocytes, LOX is likely processed by bone morphogenic protein-1 and LOX activity might be further stimulated by the expression of fibronectin in these cells. These results demonstrate an important LOX-mediated mechanism that promotes migratory/invasive behaviour of malignant astrocytes.

Background: Carotid intimal—medial thickness (CIMT) as measured by B-mode ultrasonography is a surrogate marker for carotid atherosclerosis. Studies have found conflicting results for the effect of statins on carotid atherosclerosis progression by measuring CIMT. Hence, this meta-analysis was conducted to evaluate the impact of statin therapy on CIMT progression. Methods: A systematic search using PubMed, EMBASE, and Cochrane library databases was performed. Heterogeneity of the studies was analyzed by the Cochran Q statistics. The significance of common treatment effect was assessed by computing common mean difference between the control and treatment groups. A 2-sided alpha error of less than 0.05 was considered to be statistically significant. Results: In all, 11 trials (N = 3806) fulfilled the criteria for inclusion in the analysis. The study population included 67.2% males and 22.8% females. The mean age was 58.7 years. Treatment with statins (mean treatment duration of 25.6 months) resulted in a significant reduction in the mean low-density lipoprotein ([LDL]; mg/dL, before treatment 168.6 ± 33.3, after treatment 102.33 ± 27.9, P &lt; .05). No significant changes in the levels of LDL cholesterol were noted in the control group. A total of 7 trials showed regression and 4 trials showed slowing of progression of CIMT. Pooled analysis of all 11 trials showed that there was a statistically significant benefit with statin therapy in slowing down the progression of CIMT and the common mean difference between statin therapy arm and placebo arm was -0.040 (CI: -0.052--0.028; P value &lt; .001). Conclusions: Statins therapy slows down the progression of carotid atherosclerosis as measured by CIMT, indicating benefits at subclinical stage of the disease process.

&lt;i&gt;Background:&lt;/i&gt; Ineffectiveness of anticancer drugs is frequently observed in cancer chemotherapy. The resistance of tumor cells to various cytotoxic drugs is defined as multidrug resistance (MDR). The purpose of this study is to investigate the potential reversal effect of some synthetic and natural chemicals on drug-resistant MCF-7 cell lines. The effects of potential MDR modulators combined with some anticancer drugs were also studied. &lt;i&gt;Methods:&lt;/i&gt; Flow cytometry, MTT cytotoxicity assays and checkerboard combination assays were performed to study the reversal of drug resistance and to investigate the antiproliferative effects of the combination of anticancer drugs and the potential modulators. The results indicated that verapamil, capsanthin, zeaxanthin and promethazine inhibited P-gp effectively, but chrysin was not effective at reversing the resistance in MCF-7 sublines. Four selective anticancer drugs (paclitaxel, docetaxel, doxorubicin and vincristine) and 4 effective MDR modulators (verapamil, capsanthin, zeaxanthin and promethazine) were applied to the sublines in combination. &lt;i&gt;Results and Conclusion:&lt;/i&gt; Fractional inhibitory indices show that verapamil and zeaxanthin seem to be the most effective MDR reversal agents that may be used together with paclitaxel, docetaxel, vincristine and doxorubicin in drug-resistant mammary carcinoma sublines. In conclusion, this report represents the importance to find out active and efficient drug resistance modulators for improving the efficacy of chemotherapy.

In these studies an α1-an α2-macroglobulin were isolated from rat serum. The α2 protein had all the opsonic activity, promoting phagocytosis of various colloidal particles by rat liver slices. The opsonin was stable in the lyophilized form or in solution kept in ice. The opsonic activity was lost slowly at 37 °C at all pH values between 3.5 and 9.5. The activity increased when the protein was preincubated at 37 °C for 20 min. Measurement of optical rotatory dispersion suggested that no major change of conformation occurred when the temperature was raised to 37 °C. The protein dissociated, however, into two subunits at 37 °C. The activity was lost when the protein was incubated at 60 °C. The opsonin contained 6.5% carbohydrate comprised of hexosamine, hexose and sialic acid. Neuraminidase treatment released all the sialic acid without affecting the opsonic activity. Trypsin treatment inactivated the protein after prolonged incubation. The α2-opsonic promoted phagocytosis of the test lipid emulsion of the reticuloendothelial system, colloidal gold and sulfur. It also stimulated the uptake of membrane fragments from heart, liver, skeletal muscle, skin and cancer cells. It is suggested that one of the most important physiological roles of the opsonin is to promote clearance of tissue debris produced under various adverse conditions. The uptake of two species of bacteria was also enhanced by the protein. The opsonin did not bind trypsin, all the trypsin binding activity was associated with the α1-macroglobulin fraction. In this respect the α2-opsonin is not related to the α2-macroglobulin of human serum or to the α2 acute phase macroglobulin of rat serum, both of which are known to bind proteolytic enzymes. Furthermore, an antiserum prepared against human α2-macroglobulin did not show a precipitin line when tested against the opsonin even though it reacted weakly with rat serum indicating the presence of a cross-reacting antigen in rat serum. These data showed that the human α2-macroglobulin and the rat α2-opsonin are not related antigenically. The uptake of colloids in vitro required heparin as an obligatory cofactor, 5 units of heparin were optimal. Polyethylene sulfonate could replace heparin but chondroitin sulfate A and C were without effects.

Results are presented on event-by-event fluctuations of transverse momenta pT in central Pb+Pb interactions at 20A, 30A, 40A, 80A, and 158A GeV. The analysis was performed for charged particles at forward center-of-mass rapidity (1.1<yπ*<2.6). Three fluctuation measures were studied: the distribution of average transverse momentum M(pT) in the event, the ΦpT fluctuation measure, and two-particle transverse momentum correlations. Fluctuations of pT are small and show no significant energy dependence in the energy range of the CERN Super Proton Synchrotron. Results are compared with QCD-inspired predictions for the critical point, and with the UrQMD model. Transverse momentum fluctuations, similar to multiplicity fluctuations, do not show the increase expected for freeze-out near the critical point of QCD.18 MoreReceived 10 November 2008DOI:https://doi.org/10.1103/PhysRevC.79.044904©2009 American Physical Society

Multidrug resistance (MDR) is a major cause of failure of cancer chemotherapy. Fifty-eight ecdysteroids, herbal analogues of the insect molting hormone and their semisynthetic derivatives, were tested for their activity against L5178 mouse T-cell lymphoma cells (non-MDR) and their subcell line transfected with pHa MDR1/A retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line). The compounds showed very low antiproliferative activities but modulated the efflux of rhodamine 123 mediated by the ABCB1 transporter. Roughly depending on the polarity, mild to strong synergism or antagonism was observed by combining ecdysteroids with doxorubicin, and specific structure-activity relationships were also found. Our results show the effect of ecdysteroids on MDR cancer cells for the first time. Less polar derivatives may serve as valuable leads toward a potent and safe resistance modulator. Biological significance of the resistance-increasing activity of the most abundant phytoecdysteroids including 20-hydroxyecdysone is yet to be clarified.

Bioassay-guided fractionation of the N-hexane and CHCl₃ phases of the methanol extract of the roots of Conyza canadensis (L.) Cronquist led to the isolation of two new dihydropyranones named conyzapyranone A (1) and B (2), and the known 4 Z,8 Z-matricaria- γ-lactone (3), 4 E,8 Z-matricaria- γ-lactone (4), 9,12,13-trihydroxy-10(E)-octadecenoic acid (5), epifriedelanol (6), friedeline (7), taraxerol (8), simiarenol (9), spinasterol (10), stigmasterol, β-sitosterol, and apigenin. The structures were determined by means of ESIMS and 1D and 2D NMR spectroscopy, including ¹H-¹H COSY, NOESY, HSQC, and HMBC experiments. The isolated compounds were evaluated for their antiproliferative activities and were demonstrated to exert considerable cell growth-inhibitory activity against human cervix adenocarcinoma (HeLa), skin carcinoma (A431), and breast adenocarcinoma (MCF-7) cells. Some of the active components, including 2, 4, and 10, proved to be substantially more potent against these cell lines than against noncancerous human foetal fibroblasts (MRC-5) and can therefore be considered selective antiproliferative natural products.

Background Bisphosphonates are used for the prevention and treatment of osteoporosis, but there have been concerns about a potential link between bisphosphonate therapy and atrial fibrillation. Data on the effects of bisphosphonate on the risk of atrial fibrillation are conflicting and the association of serious atrial fibrillation (defined as events resulting in hospitalization or disability or judged to be life-threatening) with the use of bisphosphonates is uncertain. Hypothesis We aimed to systematically evaluate the association of bisphosphonate use with the risk of atrial fibrillation. Methods We performed a systematic literature search for clinical trials using bisphosphonates and providing data on the outcome of atrial fibrillation. Four randomized controlled trials and 3 population based case-control studies were included in the final analysis. A meta-analysis was performed with the 4 randomized controlled trials to determine the risk of serious atrial fibrillation. Results For the purpose of meta-analysis, the studies were homogenous; therefore the Mantel-Haenszel fixed-effect model was used to calculate combined relative risk (RR). A two-sided alpha error of less than 0.05 was considered to be statistically significant (p<0.05). Four studies with 26126 postmenopausal women were included in the meta-analysis. Meta-analysis revealed that serious atrial fibrillation occurred more frequently in the bisphosphonate group compared to the placebo group (RR 1.525; 95% CI, 1.166 to 1.997; p=0.002). Two out of 3 observational studies indicated a statistically significant increase in the risk of atrial fibrillation with bisphosphonate therapy. Conclusions Bisphosphonate use is associated with a significant increase in the risk of serious atrial fibrillation in postmenopausal women.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTGlycoproteins of Ehrlich Ascites Carcinoma Cells. Incorporation of [14C]Glucosamine and [14C]Sialic Acid into Membrane Proteins*Janos MolnarCite this: Biochemistry 1967, 6, 10, 3064–3076Publication Date (Print):October 1, 1967Publication History Published online1 May 2002Published inissue 1 October 1967https://doi.org/10.1021/bi00862a013RIGHTS & PERMISSIONSArticle Views32Altmetric-Citations39LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (5 MB) Get e-Alerts Get e-Alerts

This chapter highlights annulate lamellae (AL) that are porous and often stacked parallel membranes that are largely confined to the cytoplasm of cells possessing them, but in a few cell types they may also be located inside the nucleus (intranuclear annulate lamellae). The chapter discusses distribution of the organelle, its generalized structure and variations in different cell types, the nature of the pore that characterizes this organelle, the relationships of annulate lamellae to other cellular organelles and cell products, postulated mechanisms involved in the morphogenesis of annulate lamellae, experimental manipulations that have been reported to either increase or decrease the amount of these membranes in cells, and consideration of the broad array of functions proposed for this organelle. AL is partially membranous like the endoplasmic reticulum (ER) and contains numerous pore complexes that are structurally similar to those in the nuclear envelope. The membranes enclose a compartment, a cisterna, and ribosomes are occasionally attached directly to the outer surface of the annulate lamellae. The AL is cyclical or transitory in some cells and variable in quantity. AL appears to be well developed in germ cells (male and female gametes), embryonic cells, and tumor and cancer cells.

A method has been developed by which the separation of plasma membrane fragments from those of the smooth and rough endoplasmic reticulum of Ehrlich ascites tumor could be achieved. The fractions were characterized by enzyme constituents, carbohydrate contents, physicochemical measurements, and electron microscopy.

Abstract Background Mangalicas are fatty type local/rare pig breeds with an increasing presence in the niche pork market in Hungary and in other countries. To explore their genetic resources, we have analysed data from next-generation sequencing of an individual male from each of three Mangalica breeds along with a local male Duroc pig. Structural variations, such as SNPs, INDELs and CNVs, were identified and particular genes with SNP variations were analysed with special emphasis on functions related to fat metabolism in pigs. Results More than 60 Gb of sequence data were generated for each of the sequenced individuals, resulting in 11× to 19× autosomal median coverage. After stringent filtering, around six million SNPs, of which approximately 10% are novel compared to the dbSNP138 database, were identified in each animal. Several hundred thousands of INDELs and about 1,000 CNV gains were also identified. The functional annotation of genes with exonic, non-synonymous SNPs, which are common in all three Mangalicas but are absent in either the reference genome or the sequenced Duroc of this study, highlighted 52 genes in lipid metabolism processes. Further analysis revealed that 41 of these genes are associated with lipid metabolic or regulatory pathways, 49 are in fat-metabolism and fatness-phenotype QTLs and, with the exception of ACACA , ANKRD23 , GM2A , KIT, MOGAT2, MTTP, FASN, SGMS1, SLC27A6 and RETSAT , have not previously been associated with fat-related phenotypes. Conclusions Genome analysis of Mangalica breeds revealed that local/rare breeds could be a rich source of sequence variations not present in cosmopolitan/industrial breeds. The identified Mangalica variations may, therefore, be a very useful resource for future studies of agronomically important traits in pigs.

Long intergenic noncoding RNAs (lincRNAs) are a relatively new class of non-coding RNAs that have the potential as cancer biomarkers. To seek a panel of lincRNAs as pan-cancer biomarkers, we have analyzed transcriptomes from over 3300 cancer samples with clinical information. Compared to mRNA, lincRNAs exhibit significantly higher tissue specificities that are then diminished in cancer tissues. Moreover, lincRNA clustering results accurately classify tumor subtypes. Using RNA-Seq data from thousands of paired tumor and adjacent normal samples in The Cancer Genome Atlas (TCGA), we identify six lincRNAs as potential pan-cancer diagnostic biomarkers (PCAN-1 to PCAN-6). These lincRNAs are robustly validated using cancer samples from four independent RNA-Seq data sets, and are verified by qPCR in both primary breast cancers and MCF-7 cell line. Interestingly, the expression levels of these six lincRNAs are also associated with prognosis in various cancers. We further experimentally explored the growth and migration dependence of breast and colon cancer cell lines on two of the identified lncRNAs. In summary, our study highlights the emerging role of lincRNAs as potentially powerful and biologically functional pan-cancer biomarkers and represents a significant leap forward in understanding the biological and clinical functions of lincRNAs in cancers.

Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in patients with chronic systolic heart failure (SHF) and a wide QRS complex. It is unclear whether the same benefit extends to patients with QRS duration (QRSd) <130 ms.Our aim was to perform a meta-analysis of all randomized controlled trial (RCTs) and to evaluate the effect of implantable CRT defibrillator(CRTD) on all-cause mortality, HF mortality, and HF hospitalization in patients with QRSd <130 ms. We performed a systematic literature search to identify all RCTs, comparing CRTD therapy with implantable cardiac defibrillator (ICD) therapy in patients with SHF (ejection fraction <35%) and QRS ≤130 ms, published in Pubmed, Medline, EMBASE, Cochrane library, and Google scholar from June 1980 through June 2013. The search terms included CRT, QRS duration, narrow QRS, clinical trial, RCT, biventricular pacing, heart failure, systolic dysfunction, dyssynchrony, left ventricular remodelling, readmission, mortality, survival, and various combinations of these terms. We studied the trends of overall mortality, SHF mortality, and hospitalizations due to SHF between the two groups. Heterogeneity of the studies was analysed by Q statistic. A fixed-effect model was used to compute the relative risk (RR) of mortality due to SHF, while a random-effects model was used to compare hospitalization due to SHF. Out of a total of 12 100 citations, four RCTs comparing CRTD vs. ICD therapy in patients with SHF and QRS ≤130 ms fulfilled the inclusion criteria. The median follow-up was 12 months and the cumulative number of patients was 1177. Relative Risk for all-cause mortality in patients treated with CRTD was 1.66 with a 95% CI of 1.096-2.515 (P = 0.017) while for SHF mortality was 1.29 with 95% CI of 0.68-2.45 (P = 0.42). Relative risk for HF hospitalization in patients treated with CRTD was 0.94 with 95% CI of 0.50-1.74 (P = 0.84) in comparison to the ICD group.Cardiac-resynchronization therapy defibrillator has no impact on SHF mortality and SHF hospitalization in patients with systolic HF with QRS duration ≤130 ms and is associated with higher all-cause mortality in comparison with ICD therapy.

Brain metastases are common and devastating complications of both breast cancer and melanoma. Although mammary carcinoma brain metastases are more frequent than those originating from melanoma, this latter has the highest tropism to the brain. Using static and dynamic in vitro approaches, here we show that melanoma cells have increased adhesion to the brain endothelium in comparison to breast cancer cells. Moreover, melanoma cells can transmigrate more rapidly and in a higher number through brain endothelial monolayers than breast cancer cells. In addition, melanoma cells have increased ability to impair tight junctions of cerebral endothelial cells. We also show that inhibition of Rac or PI3K impedes adhesion of breast cancer cells and melanoma cells to the brain endothelium. In addition, inhibition of Rac or PI3K inhibits the late phase of transmigration of breast cancer cells and the early phase of transmigration of melanoma cells. On the other hand, the Rac inhibitor EHT1864 impairs the junctional integrity of the brain endothelium, while the PI3K inhibitor LY294002 has no damaging effect on interendothelial junctions. We suggest that targeting the PI3K/Akt pathway may represent a novel opportunity in preventing the formation of brain metastases of melanoma and breast cancer.

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 ± 28 ms) than in healthy subjects (20 ± 10 ms) and control patients (15 ± 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 a.m.) than at daytime (10 a.m. to 4 p.m.) in healthy subjects (25 ± 13 vs 15 ± 8 ms, p <0.001) and control patients (18 ± 10 vs 12 ± 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 ± 31 vs 37 ± 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.

A multicounter radiocarbon dating system was developed applying the experiences of the previous one-channel low-level counting facility. The counter system consists of nine electrolytic copper proportional counters of identical diameters with sensitive volumes of 0.35–0.7dm 3 and filled with either methane at high pressure (6 bar) or CO 2 at 1 bar. The inner counters are surrounded by an anticoincidence shield consisting of five multiwire proportional flat counters filled with propane. The pulses of the detectors are handled by integrated amplifiers, discriminators and anticoincidence units interfaced to a microprocessor-controlled data evaluation unit. Software is written in BASIC using ASSEMBLER sub-routines. The overall precision of the system for modern carbon samples using high-pressure methane-filled counters (B ≍ 0.7 cpm, S ≍ 14 cpm) is better than 4 after a counting period of seven days.

The dried aerial parts of Euphorbia mongolica afforded three new acylated polyhydroxy diterpenoids based on the jatrophane framework. The structures were established by means of a combination of 1D and 2D NMR techniques and mass spectrometry as (2S,3S,4R,5R,7S,8R,13S,15R)-5alpha,7beta,8alpha-triacetoxy-3beta-benzoyloxy-15beta-hydroxyjatropha-6(17),11E-diene-9,14-dione (1), (2S,3S,4R,5R,7S,8S,9S13S,15R)-5alpha,7beta,8alpha,9alpha,15beta-pentaacetoxy-3beta-benzoyloxyjatropha-6(17),11E-dien-14-one (2), and (2S,3S,4R,5R,7S,8S,9S13S,15R)-3beta,7beta,8alpha,9alpha,15beta-pentaacetoxy-5alpha-benzoyloxyjatropha-6(17),11E-dien-14-one (3). When the isolates were assayed for multidrug resistance-reversing activity in a rhodamine 123 exclusion test using L5178 mouse lymphoma cells, all compounds demonstrated a concentration-dependent effect in inhibiting the efflux pump activity of these tumor cells in the range 11.2-112 microM.

&lt;i&gt;Objectives:&lt;/i&gt; Methadone is a synthetic opioid, an analgesic and an antiaddictive. QT prolongation as well as torsade de pointes ventricular tachycardia and death have been reported with methadone. Methadone’s proarrhythmic toxicity is related to the inhibition of cardiac IKr channel and prolongation of the action potential. We hypothesized that the 2 isomers of methadone may have different effects on the IKr channel. &lt;i&gt;Methods:&lt;/i&gt; The effects of the isomers on IKr were evaluated by using an oocytes system with heterogeneously expressed human ether-a-go-go-related gene (HERG) using the 2 electrode voltage clamp technique. &lt;i&gt;r-&lt;/i&gt; and &lt;i&gt;s&lt;/i&gt;-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of –141 and +143 degrees. &lt;i&gt;Results:&lt;/i&gt; At concentrations of 0.01, 0.03, 0.1, 1 and 3 m&lt;i&gt;M&lt;/i&gt;, &lt;i&gt;r/s&lt;/i&gt;-methadone produced a dose-dependent inhibition of HERG by 17 ± 5, 23 ± 4, 40 ± 4, 57 ± 3, 69 ± 3 and 80 ± 1%, respectively. The IC&lt;sub&gt;50&lt;/sub&gt; of &lt;i&gt;r/s&lt;/i&gt;-methadone was 0.21 ± 0.02 m&lt;i&gt;M&lt;/i&gt;. At 0.1, 0.3 and 1 m&lt;i&gt;M&lt;/i&gt;, &lt;i&gt;s&lt;/i&gt;-methadone reduced HERG current by 50 ± 4, 76 ± 5 and 87 ± 5%, respectively, while &lt;i&gt;r&lt;/i&gt;-methadone reduced HERG current by 26 ± 4, 53 ± 3 and 77 ± 3%, respectively. &lt;i&gt;Conclusions:&lt;/i&gt; There was a significant difference (p &lt; 0.01) in the percentage of current inhibition between &lt;i&gt;r-&lt;/i&gt; and &lt;i&gt;s&lt;/i&gt;-methadone, at 0.1 and 0.3 m&lt;i&gt;M&lt;/i&gt; (52% reduction). Thus, &lt;i&gt;r&lt;/i&gt;-methadone may be a safer agent due to less QT effect.

The centrality and system size dependence of multiplicity fluctuations of charged particles produced in nuclear collisions at $158A$ GeV was studied by the NA49 Collaboration. Centrality selected Pb+Pb collisions, semicentral C+C and Si+Si collisions as well as inelastic $p$+$p$ interactions were analyzed. The number of projectile participants determined on an event-by-event basis was used to characterize the collision centrality. The scaled variance of the multiplicity distribution obtained in the forward rapidity region ($1.1&lt;{y}_{\mathrm{c.m.}}&lt;2.6$) shows a significant increase toward peripheral collisions. The results are similar for negatively and positively charged particles and about 50% larger for all charged particles. String-hadronic models of nuclear reactions without the fusion process do not reproduce the rise of fluctuations from central toward peripheral collisions. The measured centrality dependence can be reproduced in superposition models with the assumption of contributions from target participants to particle production in the forward hemisphere or in string models with fusion.

This paper proposes and tests an explanation as to why rational managers seeking to maximize shareholder value can pursue value-decreasing mergers. It can be optimal to overpay for a target firm and decrease shareholder value if the loss is less than in an alternative where the merger is undertaken by a product market rival. This paper presents a model based on synergies, market power and competition for merger targets. Consistent with the model the empirical results obtained here show a strong correlation between the returns of acquiring firms and close rivals around merger events.

This paper tests market power in the banking industry. Price-cost margins predicted by different oligopoly models are calculated using discrete-choice demand estimates of own-price and cross-price elasticities. These predicted price-cost margins are then compared with price-cost margins computed using observed interest rates and estimates of marginal costs. This paper is among the first to apply this methodology on a detailed, bank-level dataset from the retail banking sector. It extends on previous papers and illustrates the advantages of structural modelling by simulating a counterfactual merger experiment with a number of mergers, each of which involves two major banks, and studying the unilateral effect of the mergers on interest rates. This provides more evidence that concentration measures (such as the Herfindahl index) could be very misleading indicators of market power.

Previous clinical trials on the treatment of esophageal variceal bleeding yielded mixed results regarding the efficacy of endoscopic procedures compared with pharmacotherapy only.To compare the efficacy of endoscopic procedures with that of pharmacotherapy in the prevention of mortality and rebleeding.A systematic literature review was performed to identify randomized, controlled trials of the efficacy of pharmacotherapy and endoscopic therapy. A meta-analysis was performed by using the Comprehensive MetaAnalysis software package. A 2-sided alpha error <.05 was considered statistically significant (P < .05).Twenty-five clinical trials with a total of 2159 patients were eligible for meta-analysis.Relative risk (RR) with 95% confidence interval (CI) was computed for all-cause mortality, mortality from rebleeding, all-cause rebleeding, and rebleeding caused by varices.Pharmacotherapy was as effective as endoscopic procedures in preventing rebleeding (RR 1.067; 95% CI, 0.865-1.316; P = .546), variceal rebleeding (RR 1.143; 95% CI, 0.791-1.651; P = .476), all-cause mortality (RR 0.997; 95% CI, 0.827-1.202, P = .978), and mortality from rebleeding (RR 1.171; 95% CI, 0.816-1.679; P = .39). Pharmacotherapy combined with endoscopic procedures did not reduce all-cause mortality (RR 0.787; 95% CI, 0.587-1.054; P = .108) or mortality caused by rebleeding (RR 0.786; 95% CI, 0.445-1.387; P = .405) compared with endoscopic procedures. However, combination therapy (endoscopic procedure plus pharmacotherapy) significantly reduced the incidence of all rebleeding (RR 0.623; 95% CI, 0.523-0.741; P < .001) and variceal rebleeding (RR 0.601; 95% CI, 0.440-0.820; P < .001).Heterogeneity of patient population and different treatment protocols may have affected our meta-analysis.Pharmacotherapy may be as effective as endoscopic therapy in reducing rebleeding rates and all-cause mortality. Pharmacotherapy plus endoscopic intervention is more effective than endoscopic intervention alone.

Regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of steroidal 17α-azides with different terminal alkynes afforded novel 1,4-disubstituted triazolyl derivatives in good yields in both the estrone and the androstane series. The antiproliferative activities of the structurally related triazoles were determined in vitro on three malignant human cell lines (HeLa, MCF7 and A431), with the microculture tetrazolium assay.

Intermolecular Cu(I)-catalyzed azide-alkyne cycloadditions of 15β-azido-17β-hydroxy-5α-androstan-3β-yl acetate with different terminal alkynes under optimized reaction conditions were carried out to furnish 15β-triazolyl derivatives in good yields. Subsequent oxidation of the 'click' products with the Jones reagent afforded the corresponding 17-ketones. All the synthetized compounds were tested on three malignant human cell lines (HeLa, MCF7 and A431) in order to investigate their antiproliferative activities in vitro. Evidence of cell cycle blockade and apoptosis induction was obtained for the most effective five selected compounds by means of flow cytometry and microscopic techniques. The 15β-triazolyl-5α-androstane framework may be considered an appropriate base for the design of steroidal antiproliferative agents.

Aqueous and organic extracts of 27 selected species from five genera ( Fallopia , Oxyria , Persicaria , Polygonum and Rumex ) of the family Polygonaceae occurring in the Carpathian Basin were screened in vitro for antiproliferative activity against HeLa (cervix epithelial adenocarcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast epithelial adenocarcinoma) cells, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. A total of 196 n ‐hexane, chloroform, 50% methanol or water extracts of different plant parts were investigated. It was found that extracts of Polygonum hydropiper , Rumex acetosa , Rumex alpinus , Rumex aquaticus , Rumex scutatus and Rumex thyrsiflorus at 10 or 30 µg/mL demonstrated substantial cell growth inhibitory activity (at least 50% inhibition of cell proliferation) against one or more cell lines. R. acetosa and R. thyrsiflorus proved to be the most active and are considered worthy of activity‐guided phytochemical investigations. Copyright © 2012 John Wiley &amp; Sons, Ltd.