Genetic analysis of MraY inhibition by the phiX174 protein E.
Protein E, the lysis protein of bacteriophage phiX174, is a specific inhibitor of MraY, the phospho-MurNAc-pentapeptide translocase that catalyzes the synthesis of lipid I in the conserved pathway for peptidoglycan biosynthesis. The original evidence for this inhibition was the isolation of two spontaneous E-resistance mraY mutants. Here we report further genetic studies aimed at dissecting the interaction between E and MraY, using a genetic strategy that is facile, rapid, and does not depend on the availability of purified E, purified MraY, or its substrates. This system relies on the ability of mraY or its enzymatically inactive D267N allele to protect cells from lysis after induction of a chimeric lambda :: E prophage. Using this approach, the MraY protein from Bacillus subtilis, which shares 43% sequence identity with the Escherichia coli enzyme, was found to interact weakly, if at all, with E. A potential E binding site defined by transmembrane domains 5 and 9 has been identified by isolating more mraY mutants resistant to E inhibition. Genetic analysis indicates that these E-resistant alleles fall into three classes on the basis of the affinity of the encoded proteins for MraY.


Theoretical proof of edge search strategy applied to power plant start-up scheduling.
Power plant start-up scheduling is aimed at minimizing the start-up time while limiting maximum turbine rotor stresses. This scheduling problem is highly nonlinear and has a number of local optima. In our previous research, we proposed an efficient search model: genetic algorithms (GAs) with enforcement operation to focus the search along the edge of the feasible space where the optimal schedule is supposed to stay. Based on a nonlinear dynamic simulation and a linear inverse calculation with the iteration method, the enforcement operation is applied to move schedules generated by GA toward the edge. We prove that the optimal schedule lies on the edge, ensuring that searching along the edge instead of the entire space can improve the search efficiency significantly without missing the optimum. Furthermore, we provide a theoretical setting equation for the inverse enforcement gains of the linear inverse calculation, intended to move schedules closer to the edge at each iteration of the enforcement operation. The theoretical setting equation is verified and discussed with the test results. We propose the theoretical setting equation with the test results as a guideline for the use of our proposed search model: GA with enforcement operation.


Crystalloid versus cold blood cardioplegia in patients operated on for myocardial revascularisation.
Post-ischemic reperfusion phenomenon has been studied in two methods of myocardial protection: a crystalloid cardioplegia (St Thomas no.2) and a cold blood cardioplegia (Buckberg) during cardiopulmonary bypass for myocardial revascularisation in patients. Myocardial protection has been assessed from the evolution of hemodynamic parameters, reperfusion arrhythmias and biochemical analysis of the coronary flow after cross-clamp removal: creatinine phosphokinase (CPK_MB) and nucleotide adenine metabolites (adenosine, inosine, hypoxanthine, xanthine and uric acid). The study was performed in two groups of 14 patients. Hemodynamic conditions were similar in both groups during reperfusion in order to avoid different coronary flow. In those conditions, myocardial protection by cold blood cardioplegia reduced reperfusion arrhythmias, and resulted in a loss of CPK-MB release. Furthermore, the reduction of metabolites release, purine bases and oxypurine bases into coronary sinus after cold blood cardioplegia suggest a better protection of myocardial high energy phosphates in this group than after crystalloid cardioplegia. Our results also show that hypoxanthine is probably the final product of ATP degradation in human myocardial tissue.


Regulation of yeast protein kinase C activity by interaction with the small GTPase Rho1p through its amino-terminal HR1 domain.
Protein kinase C from Saccharomyces cerevisiae (Pkc1p) constitutes a prototypic member of the protein kinase C superfamily, as it shares all the conserved regions scattered among the isoenzymes of higher eukaryotes. The functional significance of some of the conserved domains in the yeast enzyme has not yet been investigated. We examined strains carrying a partial deletion in the amino-terminal region of the enzyme, which is homologous to the HR1 of the protein kinase C-related kinases. This strain was sensitive to the presence of caffeine, Calcofluor white and Congo red, all drugs known to affect mutants defective in the signal transduction pathway ensuring cellular integrity in which Pkc1p is a central component. Isolation of a single point mutation in HR1A, which shares the sensitivity to the drugs mentioned, confirmed the importance of this region for proper regulation of protein kinase C activity in vivo. Two-hybrid analysis provided evidence for an interaction of the small GTPase Rho1p with the HR1A region, in addition to the reported interaction of this protein with the C1 region of Pkc1p. MAP kinase phosphorylation assays indicate that this Rho1p-Pkc1p/HR1A interaction does not result in an activation of the kinase cascade. The intragenic lethality of mutants affected in both HR1A and the C1 domain reported in this work implies an essential role for Rho1p-Pkc1p interaction in yeast.


Supramolecular Assemblies in Silver Complexes: Phase Transitions and the Role of the Halogen Bond.
Weak interactions (hydrogen bonds, halogen bonds, CH···π and π-π stacking) can play a significant role in the formation of supramolecular assemblies with desired structural features. In this contribution, we report a systematic investigation on how a halogen bond (XB) can modulate the structural arrangement of silver supramolecular complexes. The complexes are composed of X-phenyl(bispyrazolyl)methane (X = Br, I) and I-alkynophenyl(bispyrazolyl)methane ligands functionalized in meta (L3Br, L3I) and para (L4Br, L4I, L4CCI) positions on a phenyl ring with the purpose of providing different directionalities of the X function with respect to the N,N coordination system. The obtained [Ag(L)2]+ moieties show remarkable geometric similarities, and the L4Br, L4I, and L4CCI ligands exhibit the most conserved types of supramolecular arrangement that are sustained by XB. The increased σ-hole in L4CCI with respect to L4I leads to an occurrence of short (and strong) XB interactions with the anions. [Ag(L4I)2]PF6 and [Ag(L4I)2]CF3SO3 are characterized by the presence of three different phases, and the single-crystal evolution from phase-1 (a honeycomb structure with large 1D cavities) to phase-3 (solventless) occurs by a stepwise decrease in the crystallization solvent content, which promotes an increase in XB interactions in the lattice. The present paper aims to provide useful tools for the selection of appropriate components for the use of coordination compounds to build supramolecular systems based on the halogen bond.


Bone marrow expression and plasma concentration of basic fibroblast growth factor in patients with idiopathic thrombocytopenic purpura.
Basic fibroblast growth factor (bFGF) is one of main regulators of hematopoiesis, including megakaryopoiesis. The main bone marrow finding of patients with idiopathic thrombocytopenic purpura (ITP) is increased megakaryopoiesis. The purposes of this study were to evaluate the change in the production of bFGF and its expression pattern in the bone marrow of patients with ITP and to correlate these characteristics with the plasma concentration of bFGF. Paraffin sections of bone marrow biopsies from 17 patients with ITP and 5 healthy control subjects without pathologic alterations were investigated by immunohistochemistry for bFGF and CD68. bFGF messenger RNA (mRNA) in situ hybridization was performed with bone marrow biopsy sections, and the plasma levels of bFGF were evaluated by enzyme immunoassay. bFGF was expressed strongly in stromal cells and weakly in megakaryocytes. The density of bFGF-expressing stromal cells was decreased in 70% (12/17) of the patients with ITP but in none of the control subjects. The numbers of stromal cells and the cellular distributions of bFGF mRNA in patients with ITP were similar to those of the control subjects. The plasma levels of bFGF were significantly lower in almost all of the ITP patients relative to those of the control group. The results indicate that the concentrations of bFGF in plasma and bone marrow stromal cells in ITP cases are decreased, whereas the production of bFGF remains unchanged. Although the mechanism of low cellular and plasma concentrations of bFGF needs to be elucidated, these findings may complement the serologic and morphologic diagnosis of ITP.


Depressed baroreflex in heart failure is not due to structural change in carotid sinus nerve fibers.
It is well known that the baroreceptor reflex is blunted in the heart failure state. However, the mechanisms for this depression are not well understood. The aim of the present study was to determine if carotid sinus nerve fiber density is decreased in the heart failure state. Experiments were carried out in pacing-induced heart failure and normal dogs. The carotid sinus nerve (CSN) was dissected and the CSN discharge responses to changes in arterial pressure with nitroglycerin (25 micrograms/kg, i.v.) or phenylephrine (10 micrograms/kg, i.v.) were recorded. Thereafter, the carotid sinus area was isolated and perfused with oxygenated Krebs-Henseleit solution. Carotid sinus baroreceptor single-unit activity was recorded and a carotid sinus pressure-discharge curve was constructed using either static or pulsatile pressure. Finally, the carotid sinus nerve was removed and fixed at its in situ length in 3% glutaraldehyde. The fixed carotid sinus nerve was cut transversely in 0.5-1.0-micron sections and prepared for electron microscopy. A photographic collage of the CSN was then analyzed at 4000 x magnification. The total number, diameter and area of myelinated and non-myelinated fibers were measured with a digitizer and the density and diameter distribution were calculated. Carotid sinus nerve discharge responses to change in arterial pressure were significantly blunted in dogs with pacing-induced heart failure. Furthermore, single-unit baroreceptor responses to both static and pulsatile pressurization were markedly depressed in dogs with heart failure. However, there was no change in either fiber density or the ratio of myelinated fibers to unmyelinated fibers in the carotid sinus nerve in heart failure. In addition, there was no change in the distribution of either fiber diameter or cross-sectional area in the carotid sinus nerve in dogs with heart failure. These data indicate that there is no significant change in the number or type of fibers in the CSN of dogs with heart failure. Therefore, the depressed baroreceptor reflex in heart failure is not due to structural changes in fibers of the CSN. The depressed baroreflex is most likely due to desensitization of individual baroreceptors.


Developing a Two-Photon "AND" Logic Probe and Its Application in Alzheimer's Disease Differentiation.
In Alzheimer's disease, hypochlorous acid involved in the clearance of invading bacteria or pathogens and butyrylcholinesterase engaged in the hydrolysis of the neurotransmitter acetylcholine are relatively significantly altered. However, there are few dual detection probes for hypochlorous acid and butyrylcholinesterase. In addition, single-response probes suffer from serious off-target effects and near-infrared probes do not easily penetrate the blood-brain barrier due to their excessive molecular weight. In this work, we constructed a two-photon fluorescent probe that recognizes hypochlorous acid and butyrylcholinesterase based on a dual-lock strategy. The thiocarbonyl group is oxidized in the presence of hypochlorous acid, and the hydrolysis occurs at the 7-position ester bond in the existence of butyrylcholinesterase, releasing a strongly fluorescent fluorophore, 4-methylumbelliferone. Excellent imaging was performed in PC12 cells using this probe, and deep two-photon imaging was observed in the brains of AD mice after tail vein injection with this probe. It indicates that the probe can provide a promising tool for the more precise diagnosis of Alzheimer's disease.


GC-MS and GC-IR Analyses of the Methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles: Regioisomeric Designer Cannabinoids.
The indole ring regioisomeric methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles represent indole ring-substituted analogs of the synthetic cannabinoid JWH-018. The electron ionization mass spectra show equivalent regioisomeric major fragments resulting from cleavage of the groups attached to the central indole nucleus. The characteristic (M-17)+ fragment ion at m/z 354 resulting from the loss of OH group is significant in the mass spectra of all four compounds. Fragmentation of the naphthoyl and/or pentyl groups yields the cations at m/z 314, 300, 244 and 216. The vapor-phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers. Gas chromatographic separations on a capillary column containing a film of trifluoropropylmethyl polysiloxane (Rtx-200) provided excellent resolution of these compounds, their precursor indoles and intermediate pentylindoles. The elution order appears related to the degree of crowding of indole ring substituents.


Orthopaedic Trauma and Anemia: Conservative versus Liberal Transfusion Strategy: A Prospective Randomized Study.
To determine whether it is safe to use a conservative packed red blood cell transfusion hemoglobin (Hgb) threshold (5.5 g/dL) compared with a liberal transfusion threshold (7.0 g/dL) for asymptomatic musculoskeletal injured trauma patients who are no longer in the initial resuscitative period. Design: Prospective, randomized, multicenter trial. Three level 1 trauma centers. Patients aged 18-50 with an associated musculoskeletal injury with Hgb less than 9 g/dL or expected drop below 9 g/dL with planned surgery who were stable and no longer being actively resuscitated were randomized once their Hgb dropped below 7 g/dL to a conservative transfusion threshold of 5.5 g/dL versus a liberal threshold of 7.0 g/dL. Postoperative infection, other post-operative complications and Musculoskeletal Functional Assessment scores obtained at baseline, 6 months, and 1 year were compared for liberal and conservative transfusion thresholds. Sixty-five patients completed 1 year follow-up. There was a significant association between a liberal transfusion strategy and higher rate of infection (P = 0.01), with no difference in functional outcomes at 6 months or 1 year. This study was adequately powered at 92% to detect a difference in superficial infection (7% for liberal group, 0% for conservative, P < 0.01) but underpowered to detect a difference for deep infection (14% for liberal group, 6% for conservative group, P = 0.2). A conservative transfusion threshold of 5.5 g/dL in an asymptomatic young trauma patient with associated musculoskeletal injuries leads to a lower infection rate without an increase in adverse outcomes and no difference in functional outcomes at 6 months or 1 year. Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


A facile tetrahydrothiophene-catalyzed ylide route to vinyloxiranes.
Access to vinyloxiranes using aldehydes and allylic bromides in the presence of 1-5 mol% tetrahydrothiophene is reported. Both aliphatic and aromatic aldehydes work well in this reaction and the catalyst loading could be reduced as low as 0.5 mol%.


Development of high-throughput glass inkjet devices for pharmaceutical applications.
The application of the inkjet method to pharmaceutical products is promising. To make this realistic, not only does the throughput of this method need to be increased, but also the components should be inert to pharmaceutical preparations. We present designs of glass-based inkjet devices that are capable of producing droplets at high rates. To achieve this, inkjet devices from glass capillary tubes were manufactured with orifice diameters of 5, 10 and 20 μm and were actuated with diaphragm piezoelectric disks. Also, a pressure capsule was formed by creating a manifold at a distance from the orifice tip. Placing the piezoelectric disk at 0.5 mm distance from the tip allowed the formation of a jet at 3.2 MHz in certain designs, but for a short period of time because of overheating. The length of the pressure capsule, its inlet diameter, and the nozzle tip geometry were crucial to lower the required power. Actuating an inkjet device with 10 μm orifice diameter comfortably at 900 kHz and drying the droplets from 1% salbutamol sulphate solution allowed the formation of particles with diameters of 1.76 ± 0.15 μm and the geometric standard deviation of 1.08. In conclusion, optimising internal design of glass inkjet devices allowed the production of high-throughput droplet ejectors.


Providing multilingual access to health-related content.
Finding health-related content is not an easy task. People have to know what to search for, which medical terms to use, and where to find accurate information. This task becomes even harder when people such as immigrants wish to find information in their country of residence and do not speak the national language very well. In this paper, we present a new health information system that allows users to search for health information using natural language queries composed of multiple languages. We present the technical details of the system and outline the results of a preliminary user study to demonstrate the usability of the system.


Acoustic characterization in whole blood and plasma of site-targeted nanoparticle ultrasound contrast agent for molecular imaging.
The ability to enhance specific molecular markers of pathology with ultrasound has been previously demonstrated by our group employing a nanoparticle contrast agent [Lanza et al., Invest. Radiol. 35, 227-234 (2000); Ultrasound Med. Biol. 23, 863-870 (1997)]. One of the advantages of this agent is very low echogenicity in the blood pool that allows increased contrast between the blood pool and the bound, site-targeted agent. We measured acoustic backscatter and attenuation coefficient as a function of the contrast agent concentration, ambient pressure, peak acoustic pressure, and as an effect of duty cycle and wave form shape. Measurements were performed while the nanoparticles were suspended in either whole porcine blood or plasma. The nanoparticles were only detectable when insonified within plasma devoid of red blood cells and were shown to exhibit backscatter levels more than 30 dB below the backscatter from whole blood. Attenuation of nanoparticles in whole porcine blood was not measurably different from that of whole blood alone over a range of concentrations up to eight times the maximum in vivo dose. The resulting data provide upper bounds on blood pool attenuation coefficient and backscatter and will be needed to more precisely define levels of molecular contrast enhancement that may be obtained in vivo.


[The intensity of respiration in pea and corn seedlings under high-altitude hypoxia].
Dynamics of CO2 gas-exchange and enzymatic activity of the respiratory metabolism of pea (Pisum sativum L.) and maize (Zea mays L.) seedlings during hypobaric hypoxia simulating the altitude of 5000 m above the sea level was studied. In the 48-hour chamber experiment (total barometric pressure is 54 kPa, partial O2 pressure is 11 kPa), the relative intensity of CO2 emission was found to increase and be essentially higher for pea than maize. Periodic reactions with small upward spikes and time offset were recorded in the pea plants. The initial increase of CO2 emission velocity by maize rapidly reached the level of saturation and since then remained constant. High velocity of the main catabolic ways and carboxylating activity in maize seedlings was the effect of hypoxic stress. Utilisation of respiratory substrates by pea seedlings was blocked at the Krebs cycle level, whereas glycolysis and oxidizing pentose phosphate pathways were activated. Weak activity of the carboxylate system does not provide refixation of endogenous carbon dioxide, excessive quantities of which invade the environment.


Cognitive function in patients with epidermolysis bullosa: social adjustment and emotional problems.
Children with Epidermolysis bullosa (EB) suffer from an intractable, burdensome skin disease that may result in cognitive as well as social and emotional problems. To assess cognitive problems in patients with EB, we investigated 20 affected children and adolescents, 6-17 years of age (mean: 10.8 years; SD: 3.4 years), and 24 healthy controls (6-15 years, mean: 10.9 years; SD: 3.0 years) for cognitive abilities. Additionally, parents were asked to assess social and emotional problems of their children. Patients and controls were assessed using the Wechsler Intelligence Scales. Parents completed Achenbach's Child Behaviour Checklist (CBCL), a parent-report measure on emotional and behavioural symptoms in children. The mean scores of the young patients tested with WISC-R and WAIS-R showed no significant left shift if compared to healthy controls. Analyzing the subtypes of EB, however, considerable cognitive deficits were associated with recessive dystrophic EB (RDEB), severe generalized. Less social competence and more social and emotional problems were reported for the entire patient group. Functional rehabilitation is required to increase not only the physical but the cognitive development of the severely affected children with RDEB. Children and adolescents with all subtypes of EB require therapeutic support regarding their social and emotional life.


RME: influences on the nasal septum.
The aim of this work consists in analyzing the consequences of RME on the nasal septum. The sample included 140 patients presenting a skeletal maxillary transverse constriction. Two groups were constructed. The first group containing 100 patients presenting a septal deviation more than 1 mm was treated by a Hyrax expander, to correct the transverse dimension. The second group containing 40 patients was not treated because the patients were under pharmacological treatment for neurovascular headache. The protocol of activation in group 1 consisted by activation of the transverse screw one-quarter turn twice a day for 15 days. Then the appliance was left in place for passive retention. The skeletal variations induced by RME have been made through cephalometric evaluations obtained before therapy (T0), at the removal of the appliance (T1) and after 6 months of manteinance (T2). A lapse of time of six months passed between T0 and T1. This study demonstrates how RME can increase the length of the septum, improving its possible deviations and growth disturbance. Palatal expansion technique is a valid therapeutic option, which allows to increase nasal cavity volume and it can also have a favorable effects on the growth of the maxillary complex.


Adherence of streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa to fibronectin-coated and uncoated epithelial cells.
The relationship between the variability in the fibronectin (Fn) content on human buccal epithelial cells and the capacity of the cells to bind gram-positive (Streptococcus pyogenes) or gram-negative (Escherichia coli or Pseudomonas aeruginosa) bacteria was investigated. Adhesion experiments performed with mixtures of epithelial cells and mixed suspensions of either S. pyogenes and E. coli or S. pyogenes and P. aeruginosa exhibited three major populations of buccal cells: one of these was able to bind S. pyogenes (gram positive) but neither of the gram-negative bacteria; a second population was able to bind the gram-negative but not the gram-positive bacteria; and a third was able to bind various numbers of both types of organisms. Further adhesion experiments performed with a mixture of epithelial cells and a mixed suspension of S. pyrogens, E. coli, and fluoresceinconjugated methacrylate beads coated with immune immunoglobulin G directed against Fn revealed that the epithelial cells recognizing the gram-positive bacteria were rich in Fn, whereas those recognizing the gram-negative organisms were poor in Fn. Immunoelectron microscopy confirmed that cells of S. pyogenes bound to epithelial cells coated with Fn, whereas cells of E. coli bound to epithelial cells lacking Fn. These results suggest that Fn on the surfaces of epithelial cells may modulate the ecology of the human oropharyngeal cavity, especially with respect to the colonization of these surfaces by pathogenic gram-negative or gram-positive bacteria.


Characterization of Ile,Ser-bradykinin-induced changes in short-circuit current across rat colon.
The effects of Ile,Ser-bradykinin (TK) on electrolyte secretion across mucosa of rat distal colon were determined and compared to those of bradykinin (BK). A segment of colon stripped of muscularis was mounted in an Ussing chamber for monitoring short-circuit current (Isc). Serosal application of TK and BK produced a concentration-dependent and transient increase in Isc with EC50(nM) values of 2.0 +/- 0.6 and 1.7 +/- 0.7, respectively. At a concentration of 1.0 microM, TK produced a maximal response of 130 +/- 18 compared to 75 +/- 13 microA/cm2 for BK. Increases in Isc induced by BK and TK were significantly (P less than .001) inhibited (90 +/- 4% for BK and 87 +/- 5% for TK) by serosal addition of bumetanide (10 microM). The lipoxygenase/cyclooxygenase inhibitor, eicosa-5,8,11,14-tetraynoic acid (0.1 mM), inhibited (P less than .01) the response to BK by 67 +/- 9% and to TK by 51 +/- 8%. Moreover, the cyclooxygenase inhibitor indomethacin (5.0 microM) significantly (P less than .05) inhibited the Isc response to 1.0 nM BK and 1.0 nM TK. Atropine (1.0 microM) did not block the effects of either kinin. Finally, the BK antagonist D-Arg0[Hyp3,Thi5,8,DPhe7]-bradykinin (2.0 microM) competitively antagonized the effect of BK and TK, shifting the concentration curve competitively to the right by 6-fold and 16-fold respectively. Another BK antagonist, [D-Phe7]-bradykinin (20 microM), also exhibited similar blockade effects. In this model, although some differences exist, BK and TK appear to act by the same mechanism, which may involve arachidonic acid metabolites.


Chemical tailoring of gelatin to adjust its chemical and physical properties for functional bioprinting.
Double chemical functionalization of gelatin by methacrylation and acetylation of free amino groups enables control over both the viscous behavior of its solutions and the mechanical properties of the resulting hydrogels after photochemical crosslinking. The degree of methacrylation is controlled by the molar excess of methacrylic anhydride applied. Tenfold molar excess leads to highly methacrylated gelatin (GM10), resulting in solutions with low viscosities within the inkjet-printable range (10 wt%: 3.3 ± 0.5 mPa s, 37 °C) and crosslinked hydrogels with high storage moduli G' (10 wt%: 15.2 ± 6.4 kPa). Twofold excess of methacrylic anhydride leads to less methacrylated gelatin (GM2) proper for preparation of soft hydrogels (10 wt%: G' = 9.8 ± 4.6 mPa s) but its solutions are highly viscous (10 wt%: 14.2 ± 1.1 mPa s, 37 °C) and thus prone to clogging printing nozzles. Here we show that additional introduction of acetyl functionalities into GM2 results in a significant decrease in solution viscosity (10 wt%: 2.9 ± 0.2 mPa s, 37 °C) and prevention of physical gel formation. In such a manner twofold functionalized gelatin can be inkjet-printed while the degree of chemical crosslinking remains low and the resulting gels are soft. Thus, by adjustable twofold modification of gelatin, i.e. inserting photochemically reactive and inert groups, a versatile bioink for inkjet bioprinting is created, which allows for addressing ECM based hydrogel matrices with a broad range of physical properties. Moreover, bioinks are proven to be cytocompatible and proper for inkjet printing of viable mammalian cells.


Ovarian carcinoma histotype determination is highly reproducible, and is improved through the use of immunohistochemistry.
To assess the variation in ovarian carcinoma type diagnosis among gynaecological pathologists from Nordic countries, and whether a rationally designed panel of immunohistochemical markers could improve diagnostic reproducibility. Eight pathologists from four countries (Sweden, Denmark, Norway, and Finland) received an educational lecture on the diagnosis of ovarian carcinoma type. All tumour-containing slides from 54 ovarian carcinoma cases were independently reviewed by the participants, who: (i) determined type purely on the basis of histology; (ii) indicated whether they would apply immunohistochemistry in their routine practice; and (iii) determined type after reviewing the staining results. The results for six markers (WT1, p53, p16, HNF-1β, ARID1A, and progesterone receptor) were determined for all 54 cases, by staining of a tissue microarray. The median concordance with central review diagnosis was 86%, and significantly improved to 90% with the incorporation of immunostaining results (P = 0.0002). The median interobserver agreement was 78%, and significantly improved to 85% with the incorporation of immunostaining results (P = 0.0002). Use of the immunostaining results significantly improved both diagnostic accuracy and interobserver agreement. These results indicate that ovarian carcinoma type can be reliably diagnosed by pathologists from different countries, and also demonstrate that immunohistochemistry has an important role in improving diagnostic accuracy and agreement between pathologists.


A point mutation in the polymerase protein PB2 allows a reassortant H9N2 influenza isolate of wild-bird origin to replicate in human cells.
H9N2 influenza A viruses are on the list of potentially pandemic subtypes. Therefore, it is important to understand how genomic reassortment and genetic polymorphisms affect phenotypes of H9N2 viruses circulating in the wild bird reservoir. A comparative genetic analysis of North American H9N2 isolates of wild bird origin identified a naturally occurring reassortant virus containing gene segments derived from both North American and Eurasian lineage ancestors. The PB2 segment of this virus encodes 10 amino acid changes that distinguish it from other H9 strains circulating in North America. G590S, one of the 10 amino acid substitutions observed, was present in ~12% of H9 viruses worldwide. This mutation combined with R591 has been reported as a marker of pathogenicity for human pandemic 2009 H1N1 viruses. Screening by polymerase reporter assay of all the natural polymorphisms at these two positions identified G590/K591 and S590/K591 as the most active, with the highest polymerase activity recorded for the SK polymorphism. Rescued viruses containing these two polymorphic combinations replicated more efficiently in MDCK cells and they were the only ones tested that were capable of establishing productive infection in NHBE cells. A global analysis of all PB2 sequences identified the K591 signature in six viral HA/NA subtypes isolated from several hosts in seven geographic locations. Interestingly, introducing the K591 mutation into the PB2 of a human-adapted H3N2 virus did not affect its polymerase activity. Our findings demonstrate that a single point mutation in the PB2 of a low pathogenic H9N2 isolate could have a significant effect on viral phenotype and increase its propensity to infect mammals. However, this effect is not universal, warranting caution in interpreting point mutations without considering protein sequence context.


Promoter hypermethylation-related reduced somatostatin production promotes uncontrolled cell proliferation in colorectal cancer.
Somatostatin (SST) has anti-proliferative and pro-apoptotic effects. Our aims were to analyze and compare the SST expression during normal aging and colorectal carcinogenesis at mRNA and protein levels. Furthermore, we tested the methylation status of SST in biopsy samples, and the cell growth inhibitory effect of the SST analogue octreotide in human colorectal adenocarcinoma cell line. Colonic samples were collected from healthy children (n1 = 6), healthy adults (n2 = 41) and colorectal cancer patients (CRCs) (n3 = 34) for SST mRNA expression analysis, using HGU133 Plus2.0 microarrays. Results were validated both on original (n1 = 6; n2 = 6; n3 = 6) and independent samples ((n1 = 6; n2 = 6; n3 = 6) by real-time PCR. SST expressing cells were detected by immunohistochemistry on colonic biopsy samples (n1 = 14; n2 = 20; n3 = 23). The effect of octreotide on cell growth was tested on Caco-2 cell line. SST methylation percentage in biopsy samples (n1 = 5; n2 = 5; n3 = 9) was defined using methylation-sensitive restriction enzyme digestion. In case of normal aging SST mRNA expression did not alter, but decreased in cancer (p < 0.05). The ratio of SST immunoreactive cells was significantly higher in children (0.70% ± 0.79%) compared to CRC (0% ± 0%) (p < 0.05). Octreotide significantly increased the proportion of apoptotic Caco-2 cells. SST showed significantly higher methylation level in tumor samples (30.2% ± 11.6%) compared to healthy young individuals (3.5% ± 1.9%) (p < 0.05). In cancerous colonic mucosa the reduced SST production may contribute to the uncontrolled cell proliferation. Our observation that in colon cancer cells octreotide significantly enhanced cell death and attenuated cell proliferation suggests that SST may act as a regulator of epithelial cell kinetics. The inhibition of SST expression in CRC can be epigenetically regulated by promoter hypermethylation.


[Mechanical versus biological heart valves].
Since the first successful heart valve replacement procedures were performed in the 1950s, a multitude of different heart valves have been developed and implanted. This review offers a structured overview of the most important mechanical and biological heart valves with special regard to the individual indications of mechanical versus biological heart valve replacement and to possible postoperative complications.


Optical trapping of the anisotropic crystal nanorod.
We observed in the optical tweezers experiment that some anisotropic nanorod was stably trapped in an orientation tiled to the beam axis. We explain this trapping with the T-matrix calculation. As the vector spherical wave functions do not individually satisfy the anisotropic vector wave equation, we expand the incident and scattered fields in the isotropic buffer in terms of E→, and the internal field in the anisotropic nanoparticle in terms of D→, and use the boundary condition for the normal components of D→ to compute the T-matrix. We found that when the optical axes of an anisotropic nanorod are not aligned to the nanorod axis, the nanorod may be trapped stably at a tilted angle, under which the lateral torque equals to zero and the derivative of the torque is negative.


Analysis of Pneumonia Occurrence in Relation to Climate Change in Tanga, Tanzania.
In 2018, 70% of global fatalities due to pneumonia occurred in about fifteen countries, with Tanzania being among the top eight countries contributing to these deaths. Environmental and individual factors contributing to these deaths may be multifaceted, but they have not yet been explored in Tanzania. Therefore, in this study, we explore the association between climate change and the occurrence of pneumonia in the Tanga Region, Tanzania. A time series study design was employed using meteorological and health data of the Tanga Region collected from January 2016 to December 2018 from the Tanzania Meteorological Authority and Health Management Information System, respectively. The generalized negative binomial regression technique was used to explore the associations between climate indicators (i.e., precipitation, humidity, and temperature) and the occurrence of pneumonia. There were trend differences in climate indicators and the occurrence of pneumonia between the Tanga and Handeni districts. We found a positive association between humidity and increased rates of non-severe pneumonia (incidence rate ratio (IRR) = 1.01; 95% CI: 1.01-1.02; p ≤ 0.05) and severe pneumonia (IRR = 1.02; 95% CI: 1.01-1.03; p ≤ 0.05). There was also a significant association between cold temperatures and the rate of severe pneumonia in Tanga (IRR = 1.21; 95% CI: 1.11-1.33; p ≤ 0.001). Other factors that were associated with pneumonia included age and district of residence. We found a positive relationship between humidity, temperature, and incidence of pneumonia in the Tanga Region. Policies focusing on prevention and control, as well as promotion strategies relating to climate change-related health effects should be developed and implemented.


Ligand binding properties of myoglobin reconstituted with iron porphycene: unusual O2 binding selectivity against CO binding.
Sperm whale myoglobin, an oxygen storage hemoprotein, was successfully reconstituted with the iron porphycene having two propionates, 2,7-diethyl-3,6,12,17-tetramethyl-13,16-bis(carboxyethyl)porphycenatoiron. The physicochemical properties and ligand bindings of the reconstituted myoglobin were investigated. The ferric reconstituted myoglobin shows the remarkable stability against acid denaturation and only a low-spin characteristic in its EPR spectrum. The Fe(III)/Fe(II) redox potential (-190 mV vs NHE) determined by the spectroelectrochemical measurements was much lower than that of the wild-type. These results can be attributed to the strong coordination of His93 to the porphycene iron, which is induced by the nature of the porphycene ring symmetry. The O2 affinity of the ferrous reconstituted myoglobin is 2600-fold higher than that of the wild-type, mainly due to the decrease in the O2 dissociation rate, whereas the CO affinity is not so significantly enhanced. As a result, the O2 affinity of the reconstituted myoglobin exceeds its CO affinity (M' = K(CO)/K(O2) < 1). The ligand binding studies on H64A mutants support the fact that the slow O2 dissociation of the reconstituted myoglobin is primarily caused by the stabilization of the Fe-O2 sigma-bonding. The IR spectra for the carbon monoxide (CO) complex of the reconstituted myoglobin suggest several structural and/or electrostatic conformations of the Fe-C-O bond, but this is not directly correlated with the CO dissociation rate. The high O2 affinity and the unique characteristics of the myoglobin with the iron porphycene indicate that reconstitution with a synthesized heme is a useful method not only to understand the physiological function of myoglobin but also to create a tailor-made function on the protein.


Twelve-month suicidal ideation, incidence and persistence among college students pre-pandemic and during the pandemic: A longitudinal study.
The present study explored whether there had been significant changes in 12-month suicidal thoughts, incidence, and persistence of suicidal ideation among college students prior to and during the COVID-19 pandemic. Data were drawn from the French portion of the World Mental Health International College student Survey Initiative (WMH-ICS), a prospective cohort survey initiated in 2017. Students who completed both the baseline and one-year follow-up surveys were included (n = 1,216). Lifetime suicidal ideation and behaviors and mental disorders were assessed at baseline, and 12-month suicidal ideation and behaviors were also assessed at one-year follow-up. Logistic regressions were used to determine whether the odds of 12-month suicidal ideation at follow-up was associated with COVID-19 pandemic period while adjusting for lifetime psychopathology. No significant change in the odds of 12-month suicidal ideation was observed during the pandemic when compared to pre-pandemic times. Adjusting for prior psychopathology, 12-month suicidal ideation was not significantly associated with pandemic times, nor was incidence or persistence. No evidence of a significant increase in suicidal thoughts during the pandemic was observed. Longer follow-up periods and larger samples are needed in order to determine whether suicidal ideation and behaviors remain stable in the future.


Toward an integrated public health approach for epilepsy in the 21st century.
Epilepsy, a complex spectrum of disorders, merits enhanced public health action. In 2012, the Institute of Medicine (IOM) released a seminal report on the public health dimensions of the epilepsies, recommending actions in 7 domains. The report urged a more integrated and coordinated national approach for care centering on the whole patient, including heightened attention to comorbidities and quality of life; more timely referral and access to treatments; and improved community resources, education, stakeholder collaboration, and public communication. The US Department of Health and Human Services responded to this report by accelerating and integrating ongoing initiatives and beginning new ones. This article summarizes recent federally supported activities promoting an integrated public health approach for epilepsy, highlighting progress in response to the landmark 2012 IOM report and identifying opportunities for continued public health action.


Two pathways can activate the interleukin-5 gene and induce binding to the conserved lymphokine element 0.
Eosinophilia is a uniquely specific phenomenon regulated by interleukin-5 (IL-5), suggesting specific control for IL-5 gene expression. Using a transient-transfection reporter assay and DNA mobility-shift experiments in EL4 mouse lymphoma cells, reporter expression and binding of transcription factors to the conserved lymphokine element 0 (CLE0) in the mouse (mIL-5) promoter was investigated. Activation of the IL-5 promoter required costimulation of T cells with phorbol ester (phorbol 12-myristate 13-acetate [PMA]) and cyclic adenosine 3',5'-monophosphate (cAMP), but was blocked by the immunosuppressive drug, cyclosporin A (CsA). Binding to CLE0 was induced under conditions optimal for IL-5 transcription but was not blocked by CsA. CD28-induced signals could partly substitute for cAMP. However, the effects of cAMP, but not of CD28, were sensitive to the cAMP-dependent protein kinase inhibitor, H89, suggesting that CD28 does not involve a cAMP mechanism. It therefore appears that IL-5 expression can be induced by at least two distinct stimulatory pathways. Although CLE0 contains sequences similar to AP-1 and NF-AT, only the AP-1 moiety of the CLE0 element could be demonstrated to have inducible binding. Experiments with antisera to the AP-1 family of transcription factors indicated that c-fos and JunB bind to the IL-5 CLE0 in activated lymphoma cells. The role of the NF-AT-like element was less clear. A constitutively expressed protein showed a weak band that was inhibited by mIL-2 NF-AT competitor sequences. However, this protein did not react with an anti-NF-ATp antiserum. On the other hand, transcription was partially inhibited by an oligonucleotide containing the intact NF-AT-like element from CLE0, suggesting that the element is important for optimal transcription, but the nature of the protein binding to it remains unknown. The fact that these factors are induced in a subclone of EL4 that does not express IL-5 and bind to a number of other cytokine gene promoters suggests that although binding to CLE0 appears to be necessary for IL-5 transcription, other factors must control the specific expression of the gene.


Assessment of cellular immune responses of healthy and diseased Tasmanian devils (Sarcophilus harrisii).
The Tasmanian devil (TD) (Sarcophilus harrisii) is under threat from devil facial tumour disease (DFTD), a cancer that is transmitted between devils by direct cell implantation. As no devil is known to have rejected the tumour allograft, an understanding of the immune status of this species is essential to help explain the unique infectious nature of this cancer. We analysed differential white blood cell counts, the phagocytic response of neutrophils as well as mitogen-induced lymphocyte proliferation. Devils analysed included healthy TDs kept in captivity, healthy devils from disease-free and diseased areas as well as diseased devils. Neutrophils isolated from the peripheral blood of healthy devils showed competent phagocytosis and peripheral blood mononuclear cells from healthy and diseased devils proliferated in response to Con A, PHA and PWM stimulation. Although a wide range of responses was observed and relatively high doses of mitogens were required, there was no significant difference between males and females, adults and juveniles or between normal and diseased animals, suggesting that transmission of DFTD is not a consequence of a severely impaired immune system. As lymphocytes from all TDs appear to require strong stimulation for activation, this threshold may contribute to all devils being susceptible to DFTD.


Effects of n-butyrate on Epstein-Barr virus-carrying lymphoma lines.
n-Butyrate has been shown to induce Epstein-Barr virus (EBV) antigen synthesis in certain EBV-carrying lymphoma lines (Luka et al., 1979). We have studied the effect of n-butyrate on two EBV-positive Burkitt lymphoma lines by immuno-fluorescence and electron microscopy. In the producer line P3HR-1, the drug induced not only early antigen (EA) and virus capsid antigen (VCA) synthesis, as shown before, but also increased the number of cells containing virus particles. The transition from VCA expression to the formation of virus particles was much more effective in treated cells than in EBV antigen-producing cells of the same line. The productive cycle was associated with the development of characteristic morphological changes. In the non-producer Raji cells, n-butyrate induced EA in only a minor fraction of the cells. There were, however, clear signs of differentiation in the direction of plasma cells. Two days after the addition of n-butyrate 80% of the Raji cells could be classified as plasmablasts. After 72 h, 20% of the cells appeared as typical plasma cells.


Role of fat-derived substrates in the regulation of gluconeogenesis during fasting.
To determine the role of fat-derived substrates in the regulation of glucose metabolism during fasting, glucose turnover, urea nitrogen production, alanine conversion to glucose, and substrate oxidation rates were measured in 34 normal 4-day-fasted volunteers treated with the antilipolytic drug acipimox or placebo for 8 h. The approximately 50% inhibition of lipolysis induced by acipimox increased glucose concentration and production, respectively, by approximately 35 and approximately 30%, whereas the protein breakdown and the amount of alanine converted to glucose were increased, respectively, by approximately 70 and approximately 85%. Insulin levels were reduced by approximately 40%, cortisol levels doubled, and growth hormone concentration increased sevenfold. The relative contribution of free fatty acid (FFA) and ketone body lowering to the observed response was evaluated in nine acipimox-treated subjects in whom ketone body concentration was clamped with an intravenous beta-hydroxybutyrate infusion. The results of these experiments suggest that, during fasting, both FFA and ketone bodies tend to suppress gluconceogenesis and to protect the protein stores. FFA seem to exert their effects mainly through their ability to modulate the hormonal milieu (especially insulin), whereas ketone bodies seem to act mainly by other mechanisms. Thus the widespread view according to which FFA exert a stimulatory role on gluconeogenesis does not apply to the fasting state in vivo.


Photocontrol of the polypeptide composition ofEuglena : Analysis by two-dimensional gel electrophoresis.
Two-dimensional gel electrophoresis resolved total cellular protein fromEuglena gracilis Klebs var.bacillaris Cori into 650 polypeptides detectable by silver staining. Exposure of dark-grown restingEuglena to light for 72 h increased the relative amounts of 79 polypeptides and decreased the relative amounts of 72 polypeptides. Four polypeptides whose level increased upon light exposure were undetectable in the bleached mutant W3BUL. Since W3BUL has lost most if not all of its chloroplast genome, these polypeptides may be coded by the chloroplast genome. Although the majority of the polypeptides studied appear to be coded by the nuclear or mitochondrial genomes, seven polypeptides which were present in W3BUL were not detectable in another chloroplast-DNA-deficient, bleached mutant, W10BSmL. It appears that a number of nonchloroplast genes are no longer expressed in this mutant. Exposure of dark-grown resting cells of the bleached mutant, W3BUL, to light increased the relative amounts of 12 polypeptides and decreased the relative amounts of 14 polypeptides. Since W3BUL lacks detectable protochlorophyll(ide), the chloroplast photoreceptor, the levels of these polypeptides are regulated by light acting through a nonchloroplast photoreceptor. Exposure of cells to light had no detectable effect on the relative amounts of those polypeptides which were present in W10BSmL, even though W10BSmL has a nonchloroplast photoreceptor. EitherEuglena contains multiple nonchloroplast photoreceptors, some of which are absent from W10BSmL, or the nonchloroplast photoreceptor present in W10BSmL is uncoupled from some of the events normally controlled by that photoreceptor.


[Effect of various extrusion conditions on the protein quality of soybean and whole rye meal].
Using a Creusot-Loire twin-screw extruder (Type BC 45), ground soy bean and whole rye meal were extruded under various processing conditions (12% and 18% water content in the raw material, 129 degrees C and 165 degrees C product temperature in the case of soy bean, 12% and 18% water content, 165 degrees C product temperature in the case of rye, screw speed of 150 R/min, for all samples). The nutritional protein quality (apparent protein digestibility PV, net protein utilization NPU, and biological value BW) of the extrudates was determined by the nitrogen balance technique in growing rats. Compared to the untreated raw material no decrease in PV or NPU was noted for extrudates made from soy bean or rye. Extrusion of ground soy bean at 165 degrees C and 18% water content caused a significant decrease of BW from 68% to 64%. The lower water content (12%) induced a slight improvement of PV in soy extrudates and of NPU and BW in rye extrudates. The results indicate that the extrusion at low water content and moderate temperature can safely be used to process ground soy bean and whole rye meal without and damage to the nutritional protein quality.


ADT2FHIR - A Tool for Converting ADT/GEKID Oncology Data to HL7 FHIR Resources.
Harmonized and interoperable data management is a core requirement for federated infrastructures in clinical research. Institutions participating in such infrastructures often have to invest large degrees of time and resources in implementing necessary data integration processes to convert their local data to the required target structure. If the data is already available in an alternative shared data structure, the transformation from source to the desired target structure can be implemented once and then be distributed to all participants to reduce effort and harmonize results. The HL7® FHIR® standard is used as a basis for the shared data model of several medical consortia like DKTK and GBA. It is based on so-called resources which can be represented in XML. Oncological data in German university hospitals is commonly available in the ADT/GEKID format. From this common basis we conceptualized and implemented a transformation which accepts ADT/GEKID XML files and returns FHIR resources. We identified several problems with using the general ADT/GEKID structure in federated research infrastructures, as well as some possible pitfalls relating to the FHIR need for resource ids and focus on semantic coding which differs from the approach in the ADT/GEKID standard. To facilitate participation in federated infrastructures, we propose the ADT2FHIR transformation tool for partners with oncological data in the ADT/GEKID format.


Neuroprotective effects of ginsenosides Rh1 and Rg2 on neuronal cells.
The present study investigates the effects of ginsenosides Rh1 and Rg2 against 6-hydroxydopamine (6-OHDA), a neurotoxin on SH-SY5Y cells and PC-12 cells. The effects of these two ginsenosides on neuronal differentiation are also examined. LDH assay was used to measure cell viability after exposure to 6-OHDA and ginsenosides. Neuronal differentiation was evaluated by changes in cell morphology and density of neurite outgrowths. Western blotting was used to determine the ginsenosides' effects on activation of extracellular signal-regulated protein kinases (ERKs). Rh1 and Rg2 attenuated 6-OHDA toxicity in SH-SY5Y cells and induced neurite outgrowths in PC-12 cells. 6-OHDA-induced ERK phosphorylation was decreased by Rh1 and Rg2. 20(R)-form and 20(S)-form of the ginsenosides exerted similar effects in inducing neurite outgrowths in PC-12 cells. The present study demonstrates neuroprotective effects of ginsenosides Rh1 and Rg2 on neuronal cell lines. These results suggest potential Chinese medicine treatment for neurodegenerative disorders (eg Parkinson's disease).


Laparoscopic adjustable gastric banding versus Roux-en-Y gastric bypass: 5-year results of a prospective randomized trial.
To perform a prospective, randomized comparison of laparoscopic adjustable gastric banding (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB). LAGB, using the pars flaccida technique, and standard LRYGB were performed. From January 2000 to November 2000, 51 patients (mean age 34.0 +/- 8.9 years, range 20-49) were randomly allocated to undergo either LAGB (n = 27, 5 men and 22 women, mean age 33.3 years, mean weight 120 kg, mean body mass index [BMI] 43.4 kg/m(2); percentage of excess weight loss 83.8%) or LRYGB (n = 24, 4 men and 20 women, mean age 34.7, mean weight 120 kg, mean BMI 43.8 kg/m(2), percentage of excess weight loss 83.3). Data on the operative time, complications, reoperations with hospital stay, weight, BMI, percentage of excess weight loss, and co-morbidities were collected yearly. Failure was considered a BMI of >35 at 5 years postoperatively. The data were analyzed using Student's t test and Fisher's exact test, with P <.05 considered significant. The mean operative time was 60 +/- 20 minutes for the LAGB group and 220 +/- 100 minutes for the LRYGB group (P <.001). One patient in the LAGB group was lost to follow-up. No patient died. Conversion to laparotomy was performed in 1 (4.2%) of 24 LRYGB patients because of a posterior leak of the gastrojejunal anastomosis. Reoperations were required in 4 (15.2%) of 26 LAGB patients, 2 because of gastric pouch dilation and 2 because of unsatisfactory weight loss. One of these patients required conversion to biliopancreatic diversion; the remaining 3 patients were on the waiting list for LRYGB. Reoperations were required in 3 (12.5%) of the 24 LRYGB patients, and each was because of a potentially lethal complication. No LAGB patient required reoperation because of an early complication. Of the 27 LAGB patients, 3 had hypertension and 1 had sleep apnea. Of the 24 LRYGB patients, 2 had hyperlipemia, 1 had hypertension, and 1 had type 2 diabetes. Five years after surgery, the diabetes, sleep apnea, and hyperlipemia had resolved. At the 5-year (range 60-66 months) follow-up visit, the LRYGB patients had significantly lower weight and BMI and a greater percentage of excess weight loss than did the LAGB patients. Weight loss failure (BMI >35 kg/m(2) at 5 yr) was observed in 9 (34.6%) of 26 LAGB patients and in 1 (4.2%) of 24 LRYGB patients (P <.001). Of the 26 patients in the LAGB group and 24 in the LRYGB group, 3 (11.5%) and 15 (62.5%) had a BMI of <30 kg/m(2), respectively (P <.001). The results of our study have shown that LRYGB results in better weight loss and a reduced number of failures compared with LAGB, despite the significantly longer operative time and life-threatening complications.


Conversion Rules for Weyl Points and Nodal Lines in Topological Media.
According to a widely held paradigm, a pair of Weyl points with opposite chirality mutually annihilate when brought together. In contrast, we show that such a process is strictly forbidden for Weyl points related by a mirror symmetry, provided that an effective two-band description exists in terms of orbitals with opposite mirror eigenvalue. Instead, such a pair of Weyl points convert into a nodal loop inside a symmetric plane upon the collision. Similar constraints are identified for systems with multiple mirrors, facilitating previously unreported nodal-line and nodal-chain semimetals that exhibit both Fermi-arc and drumhead surface states. We further find that Weyl points in systems symmetric under a π rotation composed with time reversal are characterized by an additional integer charge that we call helicity. A pair of Weyl points with opposite chirality can annihilate only if their helicities also cancel out. We base our predictions on topological crystalline invariants derived from relative homotopy theory, and we test our predictions on simple tight-binding models. The outlined homotopy description can be directly generalized to systems with multiple bands and other choices of symmetry.


Lack of sex-specific movement patterns in an alien species at its invasion front - consequences for invasion speed.
Efficient targeting of actions to reduce the spread of invasive alien species relies on understanding the spatial, temporal, and individual variation of movement, in particular related to dispersal. Such patterns may differ between individuals at the invasion front compared to individuals in established and dense populations due to differences in environmental and ecological conditions such as abundance of conspecifics or sex-specific dispersal affecting the encounter rate of potential mates. We assessed seasonal and diurnal variation in movement pattern (step length and turning angle) of adult male and female raccoon dog at their invasion front in northern Sweden using data from Global Positioning System (GPS)-marked adult individuals and assessed whether male and female raccoon dog differed in their movement behavior. There were few consistent sex differences in movement. The rate of dispersal was rather similar over the months, suggesting that both male and female raccoon dog disperse during most of the year, but with higher speed during spring and summer. There were diurnal movement patterns in both sexes with more directional and faster movement during the dark hours. However, the short summer nights may limit such movement patterns, and long-distance displacement was best explained by fine-scale movement patterns from 18:00 to 05:00, rather than by movement patterns only from twilight and night. Simulation of dispersing raccoon dogs suggested a higher frequency of male-female encounters that were further away from the source population for the empirical data compared to a scenario with sex differences in movement pattern. The lack of sex differences in movement pattern at the invasion front results in an increased likelihood for reproductive events far from the source population. Animals outside the source population should be considered potential reproducing individuals, and a high effort to capture such individuals is needed throughout the year to prevent further spread.


Surface plasmon polaritons in metal stripes and wires.
Surface plasmon polaritons (SPPs) are collective electron oscillations coupled to a light field which are propagating along the interface of a metal and a dielectric. As a surface wave, SPP modes feature properties essentially different from light-field modes in all dielectric structures. These properties could allow the realization of novel photonic devices that overcome certain limitations of conventional devices. Specifically, the realization of two-dimensional optics and light-field transport in sub-wavelength SPP waveguides seems feasible. In this review we discuss recent experimental advances regarding SPP waveguides, i.e. laterally confined metal thin films that guide SPPs. Electron-beam lithography is applied to tailor these films with widths ranging from a few micrometres (stripes) to nanoscopic values (wires). We investigate SPP properties such as propagation length, mode field profile and reflection or scattering at interfaces. Various techniques for SPP excitation and detection are discussed.


Differential transferrin expression in placentae from normal and abnormal pregnancies: a pilot study.
The placenta is an important site for iron metabolism in humans. It transfers iron from the mother to the fetus. One of the major iron transport proteins is transferrin, which is a blood plasma protein crucial for iron uptake. Its localization and expression may be one of the markers to distinguish placental dysfunction. In the experimental study we used antibody preparation, mass spectrometric analysis, biochemical and immunocytochemical methods for characterization of transferrin expression on the human choriocarcinoma cell line JAR (JAR cells), placental lysates, and cryostat sections. Newly designed monoclonal antibody TRO-tf-01 to human transferrin was applied on human placentae from normal (n = 3) and abnormal (n = 9) pregnancies. Variations of transferrin expression were detected in villous syncytiotrophoblast, which is in direct contact with maternal blood. In placentae from normal pregnancies, the expression of transferrin in the syncytium was significantly lower (p < 0.001) when compared to placentae from abnormal ones (gestational diabetes, pregnancy induced hypertension, drug abuse). These observations suggest that in the case of abnormal pregnancies, the fetus may require higher levels of transferrin in order to prevent iron depletion due to the stress from the placental dysfunction.


[Androgen insensitivity syndrome in adolescents].
21 patients aged 16-20 with the kariotype 46, XY were studied. In 20 cases complete androgen insensitivity syndrome was diagnosed. All patients had normal female appearance and psychosexuality, well-developed breasts, sparse pubic and auxiliary hair, normal female external genitalia and short pseudovagina. In 15 patients unilateral (3) and bilateral (7) herniotomy in their childhood was described. Ultrasound examination in all cases revealed the absence of uterus. In 14 patients gonads were visualized in the pelvic area, unilaterally or bilaterally. In one patient with the kariotype 46, XY and following clinical characteristics: masculine build, normal female like pubic hair and psychosexuality, clitoromegaly, slightly developed breast and pseudovagina, incomplete androgen insensitivity syndrome was diagnosed. In all cases of complete androgen insensitivity syndrome after finishing puberty gonadectomy procedure was carried out, with a subsequent estrogen replacement therapy. Diagnostic of rare genetic pathologies, such as androgen insensitivity syndrome, with female phenotype and primary amenorrhea, is very important for avoiding developing of gonadoblastoma and the timely therapy.


Dissection of Two Complex Clusters of Resistance Genes in Lettuce (Lactuca sativa).
Of the over 50 phenotypic resistance genes mapped in lettuce, 25 colocalize to three major resistance clusters (MRC) on chromosomes 1, 2, and 4. Similarly, the majority of candidate resistance genes encoding nucleotide binding-leucine rich repeat (NLR) proteins genetically colocalize with phenotypic resistance loci. MRC1 and MRC4 span over 66 and 63 Mb containing 84 and 21 NLR-encoding genes, respectively, as well as 765 and 627 genes that are not related to NLR genes. Forward and reverse genetic approaches were applied to dissect MRC1 and MRC4. Transgenic lines exhibiting silencing were selected using silencing of β-glucuronidase as a reporter. Silencing of two of five NLR-encoding gene families resulted in abrogation of nine of 14 tested resistance phenotypes mapping to these two regions. At MRC1, members of the coiled coil-NLR-encoding RGC1 gene family were implicated in host and nonhost resistance through requirement for Dm5/8- and Dm45-mediated resistance to downy mildew caused by Bremia lactucae as well as the hypersensitive response to effectors AvrB, AvrRpm1, and AvrRpt2 of the nonpathogen Pseudomonas syringae. At MRC4, RGC12 family members, which encode toll interleukin receptor-NLR proteins, were implicated in Dm4-, Dm7-, Dm11-, and Dm44-mediated resistance to B. lactucae. Lesions were identified in the sequence of a candidate gene within dm7 loss-of-resistance mutant lines, confirming that RGC12G confers Dm7.


SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies.
The variable clinical features of hereditary sensory and autonomic neuropathy (HSAN I) suggest heterogeneity. Some cases of idiopathic sensory neuropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be recognised as familial. To screen persons with dominantly inherited HSAN I and others with idiopathic sensory neuropathies for known mutations of SPTLC1 and RAB7. DNA was examined from well characterised individuals of 25 kindreds with adult onset HSAN I for mutations of SPTLC1 and RAB7; 92 patients with idiopathic sensory neuropathy were also screened for known mutations of these genes. Of the 25 kindreds, only one had a mutation (SPTLC1 399T-->G). This kindred, and 10 without identified mutations, had prominent mutilating foot injuries with peroneal weakness. Of the remainder, 12 had foot insensitivity with injuries but no weakness, one had restless legs and burning feet, and one had dementia with hearing loss. No mutation of RAB7 was found in any of these. No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy. Adult onset HSAN I is clinically and genetically heterogeneous and further work is required to identify additional genetic causes. Known SPTLC1or RAB7 mutations were not found in idiopathic sensory neuropathy.


Movement-related EEG potentials are force or end-effector dependent: evidence from a multi-finger experiment.
This study examined behavioral and electrocortical responses in producing 3 levels of force (25, 50 and 75% of MVC) at a constant rate of force development with each of 4 fingers both during the achievement of the desired force (ramp phase) and its maintenance (static phase). We were particularly interested in describing in more detail the interaction between nominal force and finger on various components of movement-related potential (MRP) associated with preparation and execution of isometric force production tasks. Our experimental design systematically controlled the rate of force development while nominal force level was experimentally manipulated during isometric force production tasks. We applied time-domain averaging of EEG single trials in order to extract 3 components of MRP (BP(-600 to -500); MP(-100 to 0); MMP) preceding and accompanying behavioral responses. Overall, as in our previous research the effect of force per se was not reflected in the EEG components. However, we did find an interaction between finger and force level in both the Bereitshaftspotential (BP) and motor potential (MP) components of the movement-related potentials. While the middle, ring and little finger produced no differences in EEG components at any of the 3 force levels, the index finger did. We further correlated the force trajectory and the EEG time series with the highest correlations found in the lowest force level with the index finger. As the force level was increased, the correlation was significantly reduced. Overall, the whole complex of MRP components and evolution of EEG time series during multi-finger isometric force production tasks reflect a combination of factors including the primary end-effector performing the task and interaction of end-effector and the amount of nominal force.


Training-Induced Changes in Mitochondrial Content and Respiratory Function in Human Skeletal Muscle.
A sedentary lifestyle has been linked to a number of metabolic disorders that have been associated with sub-optimal mitochondrial characteristics and an increased risk of premature death. Endurance training can induce an increase in mitochondrial content and/or mitochondrial functional qualities, which are associated with improved health and well-being and longer life expectancy. It is therefore important to better define how manipulating key parameters of an endurance training intervention can influence the content and functionality of the mitochondrial pool. This review focuses on mitochondrial changes taking place following a series of exercise sessions (training-induced mitochondrial adaptations), providing an in-depth analysis of the effects of exercise intensity and training volume on changes in mitochondrial protein synthesis, mitochondrial content and mitochondrial respiratory function. We provide evidence that manipulation of different exercise training variables promotes specific and diverse mitochondrial adaptations. Specifically, we report that training volume may be a critical factor affecting changes in mitochondrial content, whereas relative exercise intensity is an important determinant of changes in mitochondrial respiratory function. As a consequence, a dissociation between training-induced changes in mitochondrial content and mitochondrial respiratory function is often observed. We also provide evidence that exercise-induced changes are not necessarily predictive of training-induced adaptations, we propose possible explanations for the above discrepancies and suggestions for future research.


The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats: a temperature-controlled histological study.
Activation of cation channels conducting Ca2+, Na+ and K+ is involved in the pathogenesis of infarction in experimental focal cerebral ischaemia. Pinokalant (LOE 908 MS) is a novel broad-spectrum inhibitor of several subtypes of such channels and has previously been shown to improve the metabolic and electrophysiologic status of the ischemic penumbra and to reduce lesion size on magnetic resonance images in the acute phase following middle cerebral artery occlusion in rats. The purpose of the present study was to investigate whether these beneficial effects of pinokalant are translated into permanent neuroprotection in terms of a reduction in infarct size one week after middle cerebral artery occlusion in rats. Halothane-anaesthetized male Wistar rats subjected to permanent distal middle cerebral artery occlusion were randomly assigned to one of two treatment groups: 1) Control (vehicle intravenous loading dose followed by infusion); 2) Pinokalant (0.5 mg/kg intravenous loading dose followed by infusion of 1.25 mg/kg/hr). Infusions started 30 min. after middle cerebral artery occlusion and were continued for 24 hr. Body temperature and mean arterial blood pressure were monitored by telemetry during this period and the spontaneous temperature after course in control rats established in other experiments was imitated. Seven days later histological brain sections were prepared and the infarct volumes measured. Body temperature did not differ between the groups. Mean arterial blood pressure was slightly higher in the pinokalant group. Pinokalant treatment significantly reduced cortical infarct volume from 33.8+/-15.8 mm3 to 24.5+/-13.1 mm3 (control group versus pinokalant group, P=0.017, t-test). Taking the effective drug plasma concentration established in other experiments into account revealed that in rats with plasma concentrations within the therapeutic interval, infarct volumes were further reduced to 17.9+/-7.5 mm3 (P<0.005).


Diet and Prognosis in Women with Breast Cancer.
Women who have obesity or who have metabolic abnormalities, including diabetes, prediabetes, or hyperglycemia/insulinemia, have poorer survival compared with other women with breast cancer. Data are lacking on specific lifestyle modifications to prevent or treat these conditions to improve women's chances of survival from breast cancer. The Nurses' Health Study cohorts provide new evidence that diets with the potential to elevate circulating insulin or glucose are associated with breast cancer prognosis. The researchers found statistically significant evidence that women in the highest quintile of glycemic load had a 31% higher risk of breast cancer-specific mortality and a 26% higher risk of all-cause mortality. While a randomized controlled clinical trial testing if a reduced glycemic load diet reduces recurrence or death would be optimal, evidence from this observational study suggests that diet matters in survival from breast cancer. The dietary guidelines provided by the World Cancer Research Fund/American Institute for Cancer Research, the American Cancer Society, and the American Society for Clinical Oncology, which collectively emphasize increased intake of vegetables, fruits, whole grains, and legumes, and reduced intake of sugar, calorie-dense foods, and sugary drinks, are reasonable for most breast cancer survivors to follow for optimal health.See related article by Farvid et al., p. 335.


Genetic complexity of host-selection behavior in Drosophila.
Genetic variation for settling responses to different types of food and for oviposition behavior exists within natural populations of Drosophila tripunctata. After flies from two isofemale strains and F(2) derived from crosses between them were released in the wild and recaptured at either mushroom or tomato baits, the oviposition preferences of females for these foods were determined in the laboratory. Whereas settling behavior and oviposition-site preference were negatively correlated in the parental strains, there was no association of these behaviors in the F(2) generation. Furthermore, lines produced by crossing these two strains followed by inbreeding did not manifest such a negative correlation. Together, these results indicate that two important aspects of host selection are under independent genetic control. These findings caution against using a single component of the process of host selection as indicative of the probability that a particular resource will be utilized in the field, and they bear on the question of how speciation based on genetic variation for host selection may be accomplished.


Cancer during pregnancy: what is the role of maternal serum and placental biomarkers? A review and commentary.
Cancer during pregnancy, referred to as gestational cancer (GC), is infrequent but can occur in 1.0% of pregnant women. Hepatocellular carcinoma (HCC) is often lethal and is the fifth most common cancer worldwide, while breast adenocarcinoma (breast cancer) is the most common cancer seen during pregnancy. Liver and breast carcinomas are two examples of cancer types that present challenges to the obstetrician due to late and/or delayed diagnosis during pregnancy. Delays in diagnosis limit choices available to physicians regarding surgery, radiation, and chemotherapy. In view of such clinical situations, a role for maternal serum and placental biomarker (MSPB) screening results contributing to cancer diagnosis should be recognized; overlooking such data in GC could result from a lack of knowledge and understanding of MSPB biology, chemistry, and physiology. In this report, obstetricians and perinatologists seeking a diagnosis are urged to take advantage of available results from MSPB screening programs obtained from first- and second-trimester patient data. Using liver and breast cancer as examples, the present review and commentary seeks to demonstrate that MSPB levels, profiles, patterns, and cellular responses could provide foundational data in planning invasive or noninvasive methods and procedures (biopsy, imaging, scans, surgery) to attain a diagnosis as soon as possible in pregnancy. Finally, MSPB epidemiological and cancer risk studies could aid in providing baseline information for decisions regarding GC diagnosis from knowledge of their proposed roles in reducing lifetime risk of malignancies such as breast cancer.


Hydrogel microsphere encapsulation of a cell-based gene therapy system increases cell survival of injected cells, transgene expression, and bone volume in a model of heterotopic ossification.
Bone morphogenetic proteins (BMPs) are well known for their osteoinductive activity, yet harnessing this capacity remains a high-priority research focus. We present a novel technology that delivers high BMP-2 levels at targeted locations for rapid endochondral bone formation, enhancing our preexisting cell-based gene therapy system by microencapsulating adenovirus-transduced cells in nondegradable poly(ethylene glycol) diacrylate (PEGDA) hydrogels before intramuscular delivery. This study evaluates the in vitro and in vivo viability, gene expression, and bone formation from transgenic fibroblasts encapsulated in PEGDA microspheres. Fluorescent viability and cytotoxicity assays demonstrated >95% viability in microencapsulated cells. ELISA and alkaline phosphatase assays established that BMP-2 secretion and specific activity from microencapsulated AdBMP2-transduced fibroblasts were not statistically different from monolayer. Longitudinal transgene expression studies of AdDsRed-transduced fibroblasts, followed through live animal optical fluorescent imaging, showed that microencapsulated cells expressed longer than unencapsulated cells. When comparable numbers of microencapsulated AdBMP2-transduced cells were intramuscularly injected into mice, microcomputed tomography evaluation demonstrated that the resultant heterotopic bone formation was approximately twice the volume of unencapsulated cells. The data suggest that microencapsulation protects cells and prolongs and spatially distributes transgene expression. Thus, incorporation of PEGDA hydrogels significantly advances current gene therapy bone repair approaches.


A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma.
To evaluate sitravatinib, an inhibitor of multiple receptor tyrosine kinases (RTK), for the treatment of well-differentiated/dedifferentiated liposarcoma (WD/DD LPS). This multicenter, open-label, Phase II trial enrolled patients with advanced WD/DD LPS who had received at least one prior systemic regimen and had progression within 12 weeks of enrollment. Patients received sitravatinib 150 mg (later amended to 120 mg) orally daily. A Simon two-stage design was used to evaluate for an improvement in the primary endpoint, progression-free rate at 12 weeks (PFR12), from 20% to 40%. Secondary endpoints included antitumor activity and safety. A subset of patients underwent paired biopsies analyzed using reverse-phase protein array. Twenty-nine patients enrolled. Median age was 62 years and 31% had received 3 or more prior lines. Most patients (93%) had DDLPS or mixed WD/DD LPS. Overall, 12 of 29 patients (41%) were alive and progression-free at 12 weeks and the study met the primary endpoint. There were no confirmed responses. Median progression-free survival was 11.7 weeks [95% confidence interval (CI): 5.9-35.9] and median overall survival was 31.7 weeks (95% CI: 18.1-90.1). The most common treatment-related adverse events were diarrhea (59%), hypertension (52%), hoarseness (41%), mucositis (31%), and nausea (31%). Baseline expression of phospho-RTKs was not significantly different between patients with and without clinical benefit from sitravatinib, but the number of samples was small. Sitravatinib provided a PFR12 of 41% and meaningful disease control in a subset of patients with advanced, progressive WD/DD LPS.


Moderate hypoxia suppresses exercise-induced procoagulant changes.
Hypoxia has been implicated as a stimulant of coagulation. As exertion is known to affect haemostasis, we sought to control for this by using a standardized protocol. Subjects were exercised both at room air and at 12% oxygen. Exercise produced an increase in procoagulant factors, which was reduced with hypoxic exercise. Room air exercise increased fibrinolytic markers. Hypoxic exercise did not affect the increase in tissue plasminogen activator, but decreased the increase in plasminogen activator inhibitor-1 expression. Thus, it appears that hypoxia may exert an antithrombotic effect by both damping exercise-induced procoagulant changes and stimulating fibrinolysis.


Robot-assisted microsurgery for chronic orchialgia.
Chronic orchialgia is one of the most common complaints seen in the urologists office and has traditionally been considered a very difficult diagnostic and therapeutic challenge for the clinician. First line management of chronic orchialgia is conservative treatment; however, in men who fail conservative therapy, surgical intervention may be indicated. Microsurgery has been the mainstay for surgical treatment of chronic orchialgia, but the implementation of robotics to microsurgery lends itself particularly to surgical treatment of chronic orchialgia. PubMed was used to perform a current literature search on chronic orchialgia with robotic microsurgery, robotic spermatic cord denervation, robotic varicocelectomy, and robotic vasectomy reversal. Although conservative therapy is considered the first line treatment for chronic orchialgia, reported outcomes are moderate to poor, with the need to proceed to surgical intervention in select cases. Current surgical therapies in which robot assistance have been applied to microsurgery include microsurgical denervation of the spermatic cord, varicocelectomy, and vasectomy reversal. As further studies have assisted in the understanding of surgical treatment of chronic orchialgia, the application of robot assistance to this level of microsurgery has been shown to be feasible and safe with comparable outcomes to traditional microsurgery and may provide potential advantages.


An in vivo assay identifies changes in residue accessibility on mechanosensitive channel gating.
MscL is a mechanosensitive channel of large conductance that functions as an "emergency release valve," allowing bacteria to survive acute hypoosmotic stress. Although Escherichia coli MscL is the best-studied mechanosensitive channel, structural rearrangements occurring during gating remain disputed. Introduction of a charged residue into the pore of MscL was shown to result in a reduced-viability phenotype. Here, we probe for residues in the transmembrane domains that are exposed to the aqueous environment in the presence and absence of hypoosmotic shock by reacting a charged sulfhydryl reagent with substituted cysteines. Subsequent analysis of cell viability allows for an assessment of residues exposed in the closed and opening states in vivo. The results suggest that the crystal structure of MscL derived from the Mycobacterium tuberculosis orthologue may reflect a nearly closed rather than fully closed state and support a clockwise rotation of the pore-forming first transmembrane domain on gating.


Clustering of the structures by using "snakes-&-dragons" approach, or correlation matrix as a signal.
Biological, ecological, social, and technological systems are complex structures with multiple interacting parts, often represented by networks. Correlation matrices describing interdependency of the variables in such structures provide key information for comparison and classification of such systems. Classification based on correlation matrices could supplement or improve classification based on variable values, since the former reveals similarities in system structures, while the latter relies on the similarities in system states. Importantly, this approach of clustering correlation matrices is different from clustering elements of the correlation matrices, because our goal is to compare and cluster multiple networks-not the nodes within the networks. A novel approach for clustering correlation matrices, named "snakes-&-dragons," is introduced and illustrated by examples from neuroscience, human microbiome, and macroeconomics.


"Third drug" trial: comparative study of antihypertensive agents added to treatment when blood pressure remains uncontrolled by a beta blocker plus thiazide diuretic.
Hydralazine, labetalol, methyldopa, minoxidil, prazosin, and placebo were compared when added by random allocation to atenolol 100 mg and bendrofluazide 5 mg daily in a series of 238 hypertensive patients inadequately controlled by the beta blocker-diuretic combination. Atenolol was withdrawn in those allocated to labetalol, and minoxidil was given only to men. The order of acceptability was: placebo, hydralazine, prazosin, methyldopa, minoxidil, labetalol. Minoxidil was more effective than the other active drugs, which had similar potency to one another. All the active agents were more effective than placebo. Hydralazine was the most generally suitable third drug, with prazosin a close second. Minoxidil was especially effective in patients with less severe hypertension but the same regimen caused fluid retention in those with more severe disease. Labetalol should probably be introduced at a low dose (150 mg daily) even when replacing full doses of a previously administered beta blocker.


Inhaled clemastine, an H1 antihistamine inhibits airway narrowing caused by aerosols of non-isotonic saline.
Asthmatic subjects were challenged with aerosols of hyper- and hypotonic saline 15 min (Group A) and 90 min (Group B) after inhaling clemastine. Measurements were made of forced expiratory volume in one second (FEV1) before and after medication and after challenge. When the FEV1 values (% predicted) were compared on the active and placebo days they were higher 15 min after clemastine (p less than 0.05) for both challenges and higher 90 min after clemastine inhalation (p less than 0.05) for the hypertonic challenge. The % fall in FEV1 was compared after the same concentration of saline aerosol had been given on both active and placebo days. In Group A the % fall in FEV1 on the clemastine day was reduced after challenge with hypertonic (p less than 0.02) and hypotonic (p less than 0.03) aerosol. In Group B there was a reduction in the % fall in FEV1 on the clemastine day only after hypertonic challenge (p less than 0.04). The protective effect afforded by clemastine was unrelated to change in baseline lung function. We conclude that histamine is an important mediator of the airway response to non-isotonic aerosols and suggest that the aerosol route of administration may be useful for delivering antihistamines.


Effects of fasting during the month of Ramadan on renal function in patients with autosomal dominant polycystic kidney disease .
In this study, we aimed to examine the impact of fasting during the month of Ramadan on autosomal dominant polycystic kidney disease (-ADPKD) patients with normal to near-normal glomerular filtration rate (GFR). This was a prospective observational study of patients with ADPKD, the majority of whom had normal or near-normal GFR. Patients were divided into two groups: the fasting group (FG) and the nonfasting group (NFG). Assessments in the NFG were performed 1 week before and 1 month after Ramadan, while FG patients were assessed on the last day of fasting in addition to the abovementioned visits. The following parameters were checked at each visit: blood pressure (BP), weight, sodium, potassium, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, glucose, lipid profile, bicarbonate, urine density, 24-hour urine volume, 24-hour urine protein, GFR, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). Kidney function tests were carried out on the 7th day of fasting in the FG for the identification of early kidney damage. Of the overall group of 54 patients, 23 were in FG (19 female) and 31 were in NFG (18 female). There were no significant differences between the two groups in terms of age, gender, ADPKD duration, and presence of hypertension. The mean estimated glomerular filtration rate (eGFR) values of FG and NFG were 86.4 ± 18.5 and 66.1 ± 36.5 mL/min/1.73m2, respectively. During the follow-up period, no significant changes occurred in BP, weight, creatinine, 24-hour urine volume, NGAL, KIM-1, or GFR in either group (p > 0.05), while 24-hour urinary protein was significantly decreased in FG (p < 0.001). A fasting duration of ~ 17 hours a day did not affect renal function negatively in patients with early-stage chronic kidney disease due to ADPKD. Also, no significant changes occurred in acute renal failure markers. .


Reporting and methodological quality of systematic reviews in the orthopaedic literature.
Properly designed and conducted systematic reviews can reliably produce valid pooled treatment-effect estimates and are an important resource for clinical decision-making. The purpose of this report was to assess the reporting and methodological quality of systematic reviews in orthopaedic journals. With use of the 2010 Institute for Scientific Information (ISI) Thomson Reuters Journal Citation Reports, the five orthopaedic surgery journals with the highest impact factors were searched by one individual over a five-year period (from 2006 to 2010) for systematic reviews and meta-analyses. The two authors separately and independently assessed the included studies. The reporting quality was assessed with use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the methodological quality was assessed with use of the Assessment of Multiple Systematic Reviews (AMSTAR) guidelines, both of which are accepted instruments. We calculated the proportions of each item reported within and across journals. Seventy-six systematic reviews and meta-analyses were included. Of the five journals that were examined, articles from The Journal of Bone and Joint Surgery (American Volume) had the best reporting. Articles from The American Journal of Sports Medicine fulfilled the most methodological quality items. The papers from all of the journals reported an average of only 68% of the PRISMA items and only 54% of the AMSTAR quality items. Both reporting and methodological quality in the top five orthopaedic journals were poor; the reporting quality was slightly superior to the methodological quality. Although there was a wide range of reporting quality and methodological quality scores across the journals, the included articles demonstrated inadequate adherence to accepted standards of quality. The use of PRISMA and AMSTAR guidelines in designing, implementing, and writing systematic reviews is recommended to improve the quality of systematic reviews and meta-analyses in orthopaedic journals. The validity of published systematic reviews in orthopaedics is questionable, and their contribution to clinical decision-making is suboptimal. Clinicians should be careful when interpreting and applying findings of current orthopaedic systematic reviews.


Enantiomeric separation of beta-blockers by HPLC using (R)-1-naphthylglycine and 3,5-dinitrobenzoic acid as chiral stationary phase.
Direct liquid chromatographic separations of the enantiomers of metoprolol and bisoprolol have been developed, using (R)-1-naphthylglycine and 3,5-dinitrobenzoic acid as chiral stationary phase (CSP). The separations were achieved in a normal phase system employing a mobile phase containing n-hexane, 1,2-dichloroethane and methanol. Column efficiency was strongly dependent on the composition of the mobile phase. The eluent contents of methanol and of 1,2-dichloroethane were optimized, and so was flow-rate and column temperature. Under the optimal conditions, linear responses for (R)-metoprolol and (S)-metoprolol are obtained in the range of 0.079-1.38 and 0.015-5.80 mg/ml, with detection limits of 0.008 and 0.002 mg/ml, respectively. As for bisoprolol, the linear ranges of (R)-isomer and (S)-isomer are 0.05-1.31 and 0.02-1.00 mg/ml with detection limits of 0.001 and 0.008 mg/ml, respectively. The relative standard deviation (R.S.D.) of each enantiomer did not exceed 0.90%. The method has been successfully applied to the determination of enantiomers in pharmaceuticals.


The pathogenicity of the M9 mutant of Semliki Forest virus in immune-compromised mice.
The role of immune mechanisms in the pathogenicity of the M9 mutant of Semliki Forest virus (SFV) has been examined by the use of immune-deficient and immune-suppressed mice. In immune-competent BALB/c and C57BL/6 mice, the lesions in the central nervous system (CNS) were characterized by acute demyelinating meningoencephalomyelitis. Myelin vacuolation and demyelination were more severe in BALB/c mice than in mice with a C57BL background. The mortality was 12% and 29% respectively. Treatment with cyclophosphamide or sodium aurothiomalate did not greatly alter the type of lesion produced, although mortality was increased. Lesions were less severe in nude (T-lymphocyte-deficient) mice and more severe in beige (natural killer cell-deficient) mice than in most immune-competent mice. Mortality was marginally increased in nude mice but not in beige mice. Demyelination in nude mice was followed rapidly by remyelination. Immune modification did not significantly alter the titres of virus in the brain at 7 days post-infection and infectious virus had been cleared from the brain by 14 days in all cases. Degenerating oligodendrocytes were detected in the CNS of all immune-modified mice examined at day 7. This study therefore suggests that both immune mechanisms and destruction of oligodendrocytes play a role in the production of demyelination by M9.


Tilt aftereffect following adaptation to translational Glass patterns.
Glass patterns (GPs) consist of randomly distributed dot pairs (dipoles) whose orientations are determined by specific geometric transforms. We assessed whether adaptation to stationary oriented translational GPs suppresses the activity of orientation selective detectors producing a tilt aftereffect (TAE). The results showed that adaptation to GPs produces a TAE similar to that reported in previous studies, though reduced in amplitude. This suggests the involvement of orientation selective mechanisms. We also measured the interocular transfer (IOT) of the GP-induced TAE and found an almost complete IOT, indicating the involvement of orientation selective and binocularly driven units. In additional experiments, we assessed the role of attention in TAE from GPs. The results showed that distraction during adaptation similarly modulates the TAE after adapting to both GPs and gratings. Moreover, in the case of GPs, distraction is likely to interfere with the adaptation process rather than with the spatial summation of local dipoles. We conclude that TAE from GPs possibly relies on visual processing levels in which the global orientation of GPs has been encoded by neurons that are mostly binocularly driven, orientation selective and whose adaptation-related neural activity is strongly modulated by attention.


Rapid spatially-resolved post-synthetic patterning of metal-organic framework films.
Reactive inkjet printing was used for fast and facile spatially-controlled post-synthetic patterning of metal-organic framework films. Here, we report use of the reactive inkjet printing technique to rapidly produce patterned electroactive MOF films by covalent attachment of redox-responsive ferrocenyl groups to UiO-66-NH2 on FTO glass. This study paves the way for the wide applicability of reactive printing to MOF film modification.


NADP+ reduction with reduced ferredoxin and NADP+ reduction with NADH are coupled via an electron-bifurcating enzyme complex in Clostridium kluyveri.
It was recently found that the cytoplasmic butyryl-coenzyme A (butyryl-CoA) dehydrogenase-EtfAB complex from Clostridium kluyveri couples the exergonic reduction of crotonyl-CoA to butyryl-CoA with NADH and the endergonic reduction of ferredoxin with NADH via flavin-based electron bifurcation. We report here on a second cytoplasmic enzyme complex in C. kluyveri capable of energetic coupling via this novel mechanism. It was found that the purified iron-sulfur flavoprotein complex NfnAB couples the exergonic reduction of NADP+ with reduced ferredoxin (Fdred) and the endergonic reduction of NADP+ with NADH in a reversible reaction: Fdred2-+NADH+2 NADP++H+=Fdox+NAD++2 NADPH. The role of this energy-converting enzyme complex in the ethanol-acetate fermentation of C. kluyveri is discussed.


Effect of prophylactic valacyclovir on the presence of human herpesvirus DNA in saliva of healthy individuals after dental treatment.
Human herpesviruses (HHVs) are ubiquitous pathogens that intermittently reactivate from latency. Transmission is believed to be facilitated by their frequent appearance in saliva. This study sought to understand the factors that influence the appearance of these viruses in saliva by examining the prevalence, pattern, and quantity of all eight HHVs in saliva of immunocompetent adults with a history of recurrent oral herpes simplex virus (HSV) infections following dental treatment and antiviral therapy. Valacyclovir or matched placebo was given (2 g twice on the day of treatment and 1 g twice the following day) to 125 patients in a randomized, double-blind controlled trial. Saliva, collected on the day of dental treatment and 3 and 7 days later, was analyzed using real-time quantitative PCR. At all visits, HHVs coinfected saliva. Over the course of the week, the DNAs of HHV-6 and HHV-7 were detected significantly more often (97% to 99% of patients) than Epstein-Barr virus (EBV; 64.8%), HSV-1 (13.0%), HHV-8 (3.2%), cytomegalovirus (2.4%), HSV-2 (0%), and varicella-zoster virus (0%), irrespective of drug treatment (P < 0.002). Mean genome copy numbers were highest for HSV-1 and HHV-6. Dental treatment did not influence asymptomatic viral shedding patterns. However, valacyclovir treatment resulted in significantly fewer patients shedding EBV at both postoperative visits compared with placebo (P < 0.008). These results suggest that HHVs are simultaneously present in the saliva of healthy adults at levels that could facilitate transmission, and valacyclovir therapy decreases the prevalence of EBV in saliva but has little effect on HHV-6 and HHV-7.