Shared tumor antigens in colorectal carcinoma and neuroendocrine tumors.
ND4 monoclonal antibody recognizes a tumor marker found on poorly differentiated colorectal cancer. We demonstrate its expression in 25% of gastrointestinal neuroendocrine tumors, which also express CEA in 37% of cases. As in colorectal cancer the ND4 marker is predominantly membrane bound in a colonic neuroendocrine tumor cell line, LCC-18 (p < 0.05). The ND4 marker is absent in a poorly differentiated colorectal cancer cell line that does not express CEA or other tumor antigens. Shed antigen in the serum of patients with neuroendocrine tumors is detected in only five of seven patients with the carcinoid syndrome and two of four of those without evidence of the syndrome. However, the reactivity was less in the patients with localized disease, and this test is unlikely to be of diagnostic utility in this group of patients. The sharing of this antigen in colorectal cancer and neuroendocrine tumors is not universal, but does support the common-cell progenitor theory for the origin of these tumors.


Contrast enhanced sonothrombolysis using streptokinase loaded phase change nano-droplets for potential treatment of deep venous thrombosis.
Current thrombolytic therapies for deep venous thrombosis are limited due to the wide side effect profile. Contrast mediated sonothrombolysis is a promising approach for thrombus treatment. The current study examines the effectiveness of in vitro streptokinase (SK) loaded phase-change nanodroplet (PCND) mediated sonothrombolysis at 7 MHz for the diagnosis of deep venous thrombosis. Lecithin shell and perfluorohexane core nanodroplets were prepared via the thin-film hydration method and morphologically characterized. Sonothrombolysis was performed at 7 MHz at different mechanical indexes of samples i.e., only sonothrombolysis, PCND mediated sonothrombolysis, sonothrombolysis with SK and SK loaded PCND mediated sonothrombolysis. Thrombolysis efficacy was assessed by measuring clot weight changes during 30 min US exposure, recording the mean gray intensity from the US images of the clot by computer software ImageJ, and spectrophotometric quantification of the hemoglobin in the clot lysate. In 15 minutes of sonothrombolysis performed at high mechanical index (0.9 and 1.2), SK loaded PCNDs showed a 48.61% and 74.29% reduction of mean gray intensity. At 0.9 and 1.2 MI, 86% and 92% weight loss was noted for SK-loaded PCNDs in confidence with spectrophotometric results. A significant difference (P < 0.05) was noted for SK-loaded PCND mediated sonothrombolysis compared to other groups. Loading of SK inside the PCNDs enhanced the efficacy of sonothrombolysis. An increase in MI and time also increased the efficacy of sonothrombolysis. This in vitro study showed the potential use of SK-loaded perfluorohexane core PCNDs as sonothrombolytic agents for deep venous thrombosis.


[A questionnaire study of the relationship between gender and chronic pain].
The aim of this study was to assess the relationship between gender role orientation and the prevalence of chronic pain. The individual gender role orientation in a sample of 45 chronic pain patients (ICD 10 diagnosis, F 45.4) was compared to gender role orientation in a matched, pain-free control group. Gender role orientation was assessed by questionnaires on the self-attribution of stereotypic gender traits (GEPAQ) and on the extent of agreement with traditional feminine and masculine role norms (MRNS, FRNS). Group differences were compared by multivariate analysis. In accordance with the hypothesis, results confirmed that pain patients showed stronger feminine and weaker masculine role orientations than healthy controls. Pain patients additionally ascribed to themselves more 'feminine' (e.g. worried, nervous) and less 'masculine' (e.g. aggressive, cynical) traits. Sociopsychological variables of gender role orientation were related to chronic pain in the groups observed. An integrated model consisting of psychodynamic, sociological, and sociopsychological factors is proposed.


[Prostatic adenomectomy in dialysis patients].
A case of a 55-year old patient is presented with terminal renal insufficiency and a massive prostatic adenoma causing urinary tract obstruction. The case history of the patient on mandatory dialysis was complicated by recurrent, therapy resistant urinary tract infections accompanied by septic fever outbreaks and anemic relapses. Following suprapubic transvesical adenomectomy, no fever episodes, negative urine cultures and improvement in the anemic condition were all noted. Due to the fact that the upper age limit for acceptance into a hemodialysis program and possible kidney transplantation has been raised, it is important to note that patients with prostatic adenomas may be frequently encountered. Dialysis patients require successful treatment of urinary tract obstructions prior to transplantation. Immunosuppressive therapy which follows transplantation increases risk of infection which can endanger the graft and the patient's life.


Hospital transfer of patients with acute myocardial infarction: the effects of age, race, and insurance type.
Many factors precipitate the transfer of patients hospitalized for acute myocardial infarction, including clinical status and the need for diagnostic testing and therapeutic interventions not available at the admitting hospital. The objectives of this study were to assess the frequency of transfer to another hospital and to determine whether nonmedical factors, such as age, sex, race, and insurance status, are associated with transfer. We conducted a prospective study of patients with acute myocardial infarction who were enrolled in the National Registry of Myocardial Infarction 2 from June 1994 through March 1998. The Registry involves 1674 hospitals in the United States. All patients survived to the time of hospital discharge or until transfer. Multivariable logistic regression models, with transfer as the outcome variable, were developed for the entire sample, as well as for subgroups determined by the interventional capabilities of the admitting hospital. Of 537,283 patients with acute myocardial infarction, 152,310 (28%) were transferred to another hospital after admission. After adjustment for differences in clinical and hospital characteristics, factors that were most associated with a reduced odds of transfer included older age (odds ratio [OR] = 0.43; 95% confidence interval [CI]: 0.42 to 0.44 for those aged >75 vs. <65 years), African-American race (OR = 0.69; 95% CI: 0.67 to 0.71 for African Americans vs. whites), and Medicaid/self-pay insurance status (OR = 0.68; 95% CI: 0.66 to 0.70 for Medicaid/self-pay vs. commercial insurance). These effects were most apparent for patients admitted to hospitals without full invasive diagnostic and therapeutic capabilities, but persisted to some extent among those admitted to hospitals with full invasive services. Our findings suggest that nonmedical factors, including age, race, and insurance type, affect decisions regarding the transfer of patients hospitalized with acute myocardial infarction. As only a minority of the nation's hospitals offers a full range of cardiovascular diagnostic and therapeutic procedures, these findings reinforce ongoing concerns about disparities in access to health care services for some patients.


[Interaction of the HSM3 gene with genes initiating homologous recombination repair in yeast Saccharomyces cerevisiae].
It was assumed previously that the mutator phenotype of the hms3 mutant was determined by processes taking place in the D-loop. As a next step, genetic analysis was performed to study the interactions between the hsm3 mutation and mutations of the genes that control the initial steps of the D-loop formation. The mutations of the MMS4 and XRS2 genes, which initiate the double-strand break formation and subsequent repair, were shown to completely block HSM3-dependent UV-induced mutagenesis. Mutations of the RAD51, RAD52, and RAD54 genes, which are also involved in the D-loop formation, only slightly decreased the level of UV-induced mutagenesis in the hsm3 mutant. Similar results were observed for the interaction of hsm3 with the mph1 mutation, which stabilizes the D-loop. In contrast, the shu1 mutation, which destabilizes the D-loop structure, led to an extremely high level of UV-induced mutagenesis and displayed epistatic interactions with the hsm3 mutation. The results made it possible to assume that the hsm3 mutation destabilizes the D-loop, which is a key substrate of both Rad5- and Rad52-dependent postreplicative repair pathways.


Binding of busulfan to plasma proteins and blood cells.
The reversible and non-reversible binding of busulfan to plasma proteins and to blood cells has been evaluated in man. The reversible binding to plasma proteins was insignificant in both healthy subjects and in patients with chronic myelocytic leukaemia. The percentage of busulfan irreversibly bound to plasma ligands was 32.4. Busulfan was distributed evenly between blood cells and plasma. The fraction of busulfan irreversibly bound to the blood cells was 46.9%. The major portion of busulfan that is degraded in whole blood reacts with the blood cells and the main part of that binds to macromolecular components in the cells.


[EBV/KSHV co-infection: an effective partnership].
Kaposi's sarcoma human herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL) in which Epstein-Barr virus (EBV) is also very often present. By using a humanized mouse model, Pr. Münz's team has been able to demonstrate that EBV/KSHV co-infection increases KSHV persistence and cell transformation through the stimulation of EBV replication. This is the first model of PEL in small animals, opening up exciting prospects for future studies on this unique lymphoma.


Expression of antigenic determinants of the hemagglutinin gene of a human influenza virus in Escherichia coli.
Antigenic determinants of influenza virus hemagglutinin were expressed in Escherichia coli. DNA coding for presequences of hemagglutinin were removed and an ATG codon was placed before DNA coding for mature hemagglutinin. A number of expression plasmids were constructed in which various segments of this reconstructed hemagglutinin DNA were fused to DNA coding for bacterial beta-galactosidase. The fusion proteins exhibited specific binding to antiviral antibodies. This binding could be competitively inhibited by excess viral hemagglutinin, demonstrating that these fusion proteins contained antigenic determinants of hemagglutinin.


Ability of thermophilic lactic acid bacteria to produce aroma compounds from amino acids.
Although a large number of key odorants of Swiss-type cheese result from amino acid catabolism, the amino acid catabolic pathways in the bacteria present in these cheeses are not well known. In this study, we compared the in vitro abilities of Lactobacillus delbrueckii subsp. lactis, Lactobacillus helveticus, and Streptococcus thermophilus to produce aroma compounds from three amino acids, leucine, phenylalanine, and methionine, under mid-pH conditions of cheese ripening (pH 5.5), and we investigated the catabolic pathways used by these bacteria. In the three lactic acid bacterial species, amino acid catabolism was initiated by a transamination step, which requires the presence of an alpha-keto acid such as alpha-ketoglutarate (alpha-KG) as the amino group acceptor, and produced alpha-keto acids. Only S. thermophilus exhibited glutamate dehydrogenase activity, which produces alpha-KG from glutamate, and consequently only S. thermophilus was capable of catabolizing amino acids in the reaction medium without alpha-KG addition. In the presence of alpha-KG, lactobacilli produced much more varied aroma compounds such as acids, aldehydes, and alcohols than S. thermophilus, which mainly produced alpha-keto acids and a small amount of hydroxy acids and acids. L. helveticus mainly produced acids from phenylalanine and leucine, while L. delbrueckii subsp. lactis produced larger amounts of alcohols and/or aldehydes. Formation of aldehydes, alcohols, and acids from alpha-keto acids by L. delbrueckii subsp. lactis mainly results from the action of an alpha-keto acid decarboxylase, which produces aldehydes that are then oxidized or reduced to acids or alcohols. In contrast, the enzyme involved in the alpha-keto acid conversion to acids in L. helveticus and S. thermophilus is an alpha-keto acid dehydrogenase that produces acyl coenzymes A.


Stereoprogrammed direct synthesis of calixarene-based [3]rotaxanes.
Directional calixarene wheels were threaded along a bis(benzylalkylammonium) axle in a stereoprogrammed way to obtain the first examples of calixarene-based [3]rotaxanes. The base/acid treatment demonstrated that these systems act as nanosized molecular shuttles. An unprecedented switching between the tail-to-tail and head-to-head relative orientation of the calix-wheels was observed.


Human factor observations of the Biosphere 2, 1991-1993, closed life support human experiment and its application to a long-term manned mission to Mars.
Human factors are a key component to the success of long-term space missions such as those necessitated by the human exploration of Mars and the development of bioregenerative and eventually self-sufficient life support systems for permanent space outposts. Observations by participants living inside the 1991-1993 Biosphere 2 closed system experiment provide the following insights. (1) Crew members should be involved in the design and construction of their life support systems to gain maximum knowledge about the systems. (2) Individuals living in closed life support systems should expect a process of physiological and psychological adaptation to their new environment. (3) Far from simply being a workplace, the participants in such extended missions will discover the importance of creating a cohesive and satisfying life style. (4) The crew will be dependent on the use of varied crops to create satisfying cuisine, a social life with sufficient outlets of expression such as art and music, and to have down-time from purely task-driven work. (5) The success of the Biosphere 2 first 2-year mission suggests that crews with high cultural diversity, high commitment to task, and work democracy principles for individual responsibility may increase the probability of both mission success and personal satisfaction. (6) Remaining challenges are many, including the need for far more comprehensive real-time modeling and information systems (a "cybersphere") operating to provide real-time data necessary for decision-making in a complex life support system. (7) And, the aim will be to create a noosphere, or sphere of intelligence, where the people and their living systems are in sustainable balance.


Comparison of different calibration approaches for chloramphenicol quantification in chicken muscle by ultra-high pressure liquid chromatography tandem mass spectrometry.
Matrix-dependent signal suppression often occurs in quantitative analysis by ultra-high pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In this study, we investigated three calibration methods for compensation of signal suppression on chloramphenicol (CAP) quantification in chicken muscle. The data showed that the spiking recoveries by solvent standard calibration with a stable isotope labelled internal standard (SIL-IS) and matrix-matched standard calibration with a SIL-IS were significantly higher than by external matrix-matched standard calibration (P < 0.05). When the SIL-IS was used, standards prepared in the mobile phase solvent showed no significant difference as those prepared in the matrix (P > 0.05). The limit of detection (LOD) for external matrix matched standard calibration was 0.1 μg kg(-1), and that for SIL-IS calibration (including matrix matched and solvent dissolved standard) was 0.03 μg kg(-1).


[Identification of quantitative trait loci controlling F2 sterility and heading date in rice].
Ninety-six F2 lines derived from a cross between a japonica cultivar Taichung 65 and an indica cultivar Bhadua were developed. At the first step, an RFLP linkage map based on the F2 lines was constructed. The RFLP map contained 94 RFLP makers. F2 sterility and heading date are important agronomic traits of rice; meanwhile heading date is related to many characters of agronomic importance including sterility. Quantitative trait locus (QTL) analysis was carried out to identify genes controlling F2 sterility and heading date. Both single factor analysis and interval analysis were applied for QTL analysis. Two QTLs for F2 spikelet sterility were newly detected on Chromosome 1 and 8. Five QTLs for heading date were detected on Chromosome 1, 4, 6, 8 and 10. Two of them on chromosome 1 and 10 were newly detected. Near-isogenic lines are now under construction for further QTL analysis and gene mapping of these QTLs newly identified in this paper.


Early Relief of Pruritus in Atopic Dermatitis with Crisaborole Ointment, A Non-steroidal, Phosphodiesterase 4 Inhibitor.
Pruritus occurs in all patients with atopic dermatitis and requires quick relief to reduce disease exacerbation and improve quality of life. Crisaborole ointment is a non-steroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis explores crisaborole ointment for early relief of pruritus in patients with mild to moderate atopic dermatitis from 2 phase III studies. Patients received crisaborole or vehicle twice daily for 28 days. Pruritus was graded on a 4-point scale of none (0) to severe (3). Early improvement in pruritus required a score of none (0) or mild (1), with a ≥ 1-grade improvement from baseline on day 6. Significantly more patients experienced early improvement in pruritus with crisaborole than with vehicle (56.6% vs 39.5%; p< 0.001), including at earliest assessment (day 2, 34.3% vs 27.3%; p = 0.013). Crisaborole is a topical treatment option that can rapidly relieve atopic dermatitis-associated pruritus.


Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2-Metabolome, immunome, synaptome.
The second part of this paper builds upon and expands the epigenomic-aging perspective presented in Part 1 to describe the metabolomic and immunomic bases of the epigenomic-aging changes and then considers in some detail the application of these insights to neurotoxicity, neuronal epigenotoxicity, and synaptopathy. Cannabinoids are well-known to have bidirectional immunomodulatory activities on numerous parts of the immune system. Immune perturbations are well-known to impact the aging process, the epigenome, and intermediate metabolism. Cannabinoids also impact metabolism via many pathways. Metabolism directly impacts immune, genetic, and epigenetic processes. Synaptic activity, synaptic pruning, and, thus, the sculpting of neural circuits are based upon metabolic, immune, and epigenomic networks at the synapse, around the synapse, and in the cell body. Many neuropsychiatric disorders including depression, anxiety, schizophrenia, bipolar affective disorder, and autistic spectrum disorder have been linked with cannabis. Therefore, it is important to consider these features and their complex interrelationships in reaching a comprehensive understanding of cannabinoid dependence. Together these findings indicate that cannabinoid perturbations of the immunome and metabolome are important to consider alongside the well-recognized genomic and epigenomic perturbations and it is important to understand their interdependence and interconnectedness in reaching a comprehensive appreciation of the true nature of cannabinoid pathophysiology. For these reasons, a comprehensive appreciation of cannabinoid pathophysiology necessitates a coordinated multiomics investigation of cannabinoid genome-epigenome-transcriptome-metabolome-immunome, chromatin conformation, and 3D nuclear architecture which therefore form the proper mechanistic underpinning for major new and concerning epidemiological findings relating to cannabis exposure.


Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy. Several SMN-independent pathways that could impinge upon the SMA phenotype have been examined with varied success. To identify disease-modifying pathways that could serve as stand-alone therapeutic targets or could be used in combination with an SMN-inducing compound, we investigated adeno-associated virus-mediated (AAV-mediated) gene therapy using plastin-3 (PLS3). Here, we report that AAV9-PLS3 extends survival in an intermediate model of SMA mice as well as in a pharmacologically induced model of SMA using a splice-switching ASO that increases SMN production. PLS3 coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways.


Quantitative characterization of hemozoin in Plasmodium berghei and vivax.
The incidence and global distribution of chloroquine resistant (CR) Plasmodium vivax infection has increased since emerging in 1989. The mechanism of resistance in CR P. vivax has not been defined. The resistance likely relates to the formation and disposition of hemozoin as chloroquine's primary mechanism of action involves disruption of hemozoin formation. CR P. berghei strains, like CR P. vivax strains, are confined to reticulocyte host cells and reportedly they do not accumulate appreciable intraerythrocytic hemozoin. Reports comparing hemozoin production between P. vivax strains and CR to chloroquine sensitive (CS) P. berghei are absent. Here we compare in vivo patterns of hemozoin formation and distribution in blood, spleen and liver tissue of male Swiss mice infected with CS or CR P. berghei not treated with chloroquine and CR P. berghei also treated with chloroquine. Light microscopy, laser desorption mass spectrometry and a colorimetric hemozoin assay detect trace hemozoin in the blood of CR P. berghei infected mice but significant hemozoin accumulation in liver and spleen tissue. Field emission in lens scanning electron microscopy reveals CR P. berghei hemozoin crystals are morphologically smaller but similar to those formed by CS parasites. CR P. berghei produces approximately five-fold less total hemozoin than CS strain. Lipid analysis of CS and CR P. berghei sucrose gradient purified bloodstage hemozoin indicates a similar lipid environment around the isolated hemozoin, predominately monopalmitic glycerol and monostearic glycerol. In contrast to CR and CS P. berghei, colorimetric hemozoin analysis of P. vivax strains indicates similar amounts of hemozoin are produced despite differing chloroquine sensitivities. These results suggest CR P. berghei forms significant hemozoin which accumulates in liver and spleen tissues and that the P. vivax chloroquine resistance mechanism differs from P. berghei.


Capecitabine: indications and future perspectives in the treatment of metastatic colorectal and breast cancer.
Fluoropyrimidines remain the most important drugs in the treatment of breast and colorectal carcinoma, but response rates and survival time have been disappointing. Optimal administration is by continuous intravenous infusion, which makes it cumbersome to use and compromises patient independence. Recently, a number of new agents, including fluorouracil prodrugs and selective dihydropyrimidine dehydrogenase inhibitors, have been studied, with promising results. Capecitabine is the first in a new class of fluoropyrimidines. It is an oral, tumor-activated anticancer drug whose activity mimics that of continuously infused 5-fluorouracil. Capecitabine circumvents dihydropyrimidine dehydrogenase catabolism and appears to be at least as active against metastatic colorectal and breast cancer as conventionally administered intravenous 5-fluorouracil, with significantly less toxicity, an improved quality of life, and lesser cost. Capecitabine may ultimately provide enhanced antitumor activity to fluorouracil-containing regimes for advanced colorectal and breast cancer.


[Neurinoma of the vagus nerve. Description of 2 cases and review of the literature].
The Authors report two rare cases of schwannoma of the cervical and thoracic portion of the vagus nerve. Schwannomas of the vagus nerve are particularly uncommon; patients suffering from these neurogenic tumors typically exhibit a paucity of symptoms and in the majority of cases they present with an asymptomatic mass noted on incidental chest X-ray. Chest pain and cough may occur with tumors arising next to and compressing the trachea or major bronchi. In the cases observed, schwannomas appeared like a mass whose size had increased during the last months without producing any clinical symptom. Clinical features of the mass, laboratory tests, ultrasound, CT scanning, magnetic resonance imaging were useful only to define its extension and relationships with the adjacent structures. Needle aspiration of these lesions is not indicated because of the paucity of the material obtained for the exact diagnosis. Surgery, with preservation of the vagus nerve when possible, is the treatment of choice also for a correct diagnosis of nature and to prevent further growth and compression on adjacent structures. When the individual fibers of the vagus nerve are displayed over the surface of the tumor within a discrete capsule nerve preservation is possible. On the contrary, when it is technically difficult to preserve the nerve trunk microsurgical procedures allow to reanastomose the cut ends. Injury of homolateral recurrent nerve often is the complication of a radical removal. Recurrence of benign lesions is not usual; malignant tumors carry a poor prognosis with patients rarely surviving beyond 1 year.


A new automated subjective optometer.
A new optometer that utilizes optically simulated distance line and letter targets, focusable by patient or operator, is described. Refractive findings for 376 eyes tested on the new optometer were compared with the findings obtained by conventional clinical methods. Most differences were within the limits of repeatability reported for conventional refraction tests.


Mercury and sulphur among the High Medieval alchemists: from Rāzī and Avicenna to Albertus Magnus and pseudo-Roger Bacon.
This essay challenges the often expressed view that the principles of metals, namely mercury and sulphur, were generally viewed by alchemists as being of a 'metaphysical' character that made them inaccessible to the tools and operations of the laboratory. By examining a number of Arabo-Latin and Latin alchemical texts in circulation before the end of the thirteenth century, the author presents evidence that most alchemists of the period considered mercury and sulphur to be materials subject to techniques of purification in the same way that naturally occurring salts and minerals could be freed of their impurities or dross. The article also points to the immense influence of Avicenna and Albertus Magnus in formulating the theory that mercury and sulphur were compounds of different materials, containing both fixed and unfixed components. Finally, the author briefly examines the relationship between this materialist approach to the principles and the chymical atomism of early modern authors who were deeply aware of medieval alchemical literature.


The local electrostatic environment determines cysteine reactivity of tubulin.
Of the 20 cysteines of rat brain tubulin, some react rapidly with sulfhydryl reagents, and some react slowly. The fast reacting cysteines cannot be distinguished with [14C]iodoacetamide, N-[(14)C]ethylmaleimide, or IAEDANS ([5-((((2-iodoacetyl)amino)ethyl)amino) naphthalene-1-sulfonic acid]), since modification to mole ratios 1 cysteine/dimer always leads to labeling of 6-7 cysteine residues. These have been identified as Cys-305alpha, Cys-315alpha, Cys-316alpha, Cys-347alpha, Cys-376alpha, Cys-241beta, and Cys-356beta by mass spectroscopy and sequencing. This lack of specificity can be ascribed to reagents that are too reactive; only with the relatively inactive chloroacetamide could we identify Cys-347alpha as the most reactive cysteine of tubulin. Using the 3.5-A electron diffraction structure, it could be shown that the reactive cysteines were within 6.5 A of positively charged arginines and lysines or the positive edges of aromatic rings, presumably promoting dissociation of the thiol to the thiolate anion. By the same reasoning the inactivity of a number of less reactive cysteines could be ascribed to inhibition of modification by negatively charged local environments, even with some surface-exposed cysteines. We conclude that the local electrostatic environment of cysteine is an important, although not necessarily the only, determinant of its reactivity.


Suppressing Systemic Interference in fNIRS Monitoring of the Hemodynamic Cortical Response to Motor Execution and Imagery.
Hemodynamic response to motor execution (ME) and motor imagery (MI) was investigated using functional near-infrared spectroscopy (fNIRS). We used a 31 channel fNIRS system which allows non-invasive monitoring of cerebral oxygenation changes induced by cortical activation. Sixteen healthy subjects (mean-age 24.5 yeas) were recruited and the changes in concentration of hemoglobin were examined during right and left hand finger tapping tasks and kinesthetic MI. To suppress the systemic physiological interference, we developed a preprocessing procedure which prevents over-activated reporting in NIRS-SPM. In the condition of ME, more activation was observed in the anterior part of the motor cortex including the pre-motor and supplementary motor area (pre-motor and SMA), primary motor cortex (M1) and somatosensory motor cortex (SMC; t(15) > 2.27), however, in the condition of MI, more activation was found in the posterior part of motor cortex including SMC (t(15) > 1.81), which is in line with previous observations with functional magnetic resonance imaging (fMRI).


Directed glia-assisted angiogenesis in a mature neurosensory structure: pericytes mediate an adaptive response in human dental pulp that maintains blood-barrier function.
The specialized tightly controlled microcirculation of craniofacial neurosensory organs is an essential evolutionary adaptation and yet a dilemma where angiogenic remodeling occurs. Despite extreme plasticity of neurosensory structures, the capacity to reconcile barrier phenotype of the microcirculation with an angiogenic cascade is not known. Here we provide primary evidence for such a response in an elemental neurosensory structure, human dental pulp, following chronic carious insult. In response to hypoxic challenge neurosensory odontoblasts express hypoxia-inducible factor-1α and notch-1. Associated radial rearrangement of astrocyte-like telacytes that communicate through a cell-poor zone with the microvasculature is observed. Activated pericytes characterized by expression of α-smooth muscle actin are located adjacent to the telacyte attachment to the vasculature. In this location, endothelial expression of sonic hedgehog parallels expression of notch-1 by pericytes. The angiogenic response is initiated by pericyte contraction and altered endothelial polarity and proliferation leading to intussusception of endothelial cells and extensive remodeling of basement membrane with upregulation of laminin-8 and laminin-5. These responses guide intravascular loop formation that maintains both intact basement membrane and tight junctions. This initial phase is followed by formation of anastomoses that enhance the hemodynamic capacity of the intravascular loops. The formation of anastomoses is mediated by extension of cytonemes from pericytes guided by MHC-II(+)/CD-163(+) microglia aligned with the telacytes. The cytonemes seek out pericytes on adjacent intravascular loops to initiate migration of endothelial cells. These findings support a new paradigm for understanding angiogenic capacity of neurosensory structures and aberrations of this response manifest as neurovasculopathies.


A script for automated 3-dimentional structure generation and conformer search from 2- dimentional chemical drawing.
Building 3-dimensional (3D) molecules is the starting point in molecular modeling. Conformer search and identification of a global energy minimum structure are often performed computationally during spectral analysis of data from NMR, IR, and VCD or during rational drug design through ligand-based, structure-based, and QSAR approaches. I herein report a convenient script that allows for automated building of 3D structures and conformer searching from 2-dimensional (2D) drawing of chemical structures. With this Bash shell script, which runs on Mac OS X and the Linux platform, the tasks are consecutively and iteratively executed without a 3D molecule builder via the command line interface of the free (academic) software OpenBabel, Balloon, and MOPAC2012. A large number of 2D chemical drawing files can be processed simultaneously, and the script functions with stereoisomers. Semi-empirical quantum chemical calculation ensures reliable ranking of the generated conformers on the basis of energy. In addition to an energy-sorted list of file names of the conformers, their Gaussian input files are provided for ab initio and density functional theory calculations to predict rigorous electronic energies, structures, and properties. This script is freely available to all scientists.


[Butanol pathway construction and promoter optimization in Escherichia coli].
Promoter optimization is a useful tool in synthetic biology. Fusing promoters of various strengths to genes is a good method to get the best gene overexpression level. Butanol can be used as an intermediate in chemical synthesis and as a solvent for a wide variety of chemical and textile industry applications. At present, multiple metabolic engineering strategies have been attempted for butanol production in non-native host Escherichia coli. But there were little work on promoter optimization. We fused thlA (thiolase) with strong promoter Alper PLTetO1 or weak promoter Alper BB, operon with strong promoter Braatsch 20 or weak promoter Braatsch 10 by fast assemble method DNA assembler in Escherichia coli. The experimental results showed thlA with strong promoter Alper PLTetO1, operon with weak promoter Braatsch 10 got best butanol concentration 28 mg/L, which increased at least 3-5 fold compared with other combination.


The role of sensitization in musculoskeletal shoulder pain.
Peripheral and central sensitization are neurophysiological processes that can prolong painful conditions. Painful shoulder conditions are often persistent, perhaps due to the presence of sensitization. This manuscript summarizes six studies that have evaluated those with musculoskeletal shoulder pain for the presence of sensitization. All six manuscripts report evidence of peripheral sensitization, while central sensitization was described in five of the studies. The chronicity of symptoms in subjects who were included in the studies is probably influencing this finding. The primary somatosensory test used to assess sensitization in these studies was Pressure Pain Threshold, a test for lowered nociceptive thresholds. It appears that peripheral sensitization manifests consistently in those with musculoskeletal shoulder pathology, probably due to the inflammatory processes related to tissue injury. Central sensitization, while not universally present, was reported in a majority of the manuscripts. Because central sensitization is thought to be a key step on the pathway to chronic pain, evidence for its presence in those with shoulder pain is significant. Clinicians should expect the presence of sensitization with shoulder pathology and make appropriate choices about interventions so as not to exacerbate pain.


Endometrial expression of β3 integrin, calcitonin and plexin-B1 in the window of implantation in women with unexplained infertility.
Endometrial receptivity plays a key role in the establishment of successful implantation and its impairment may contribute to subfertility and limit the assisted reproduction techniques (ART) success. The aim of present study was to investigate endometrial receptivity in terms of β3 integrin, calcitonin and plexin-B1 expression in women with unexplained infertility. We evaluated expression of β3 integrin, calcitonin and plexin-B1 through mRNA level measurement with real-time RT-PCR, in the endometrium of 16 infertile women with unexplained infertility and 10 fertile women. Endometrial biopsies were collected during a single menstrual cycle on postovulatory day LH+7 in each subject. Significant differences regarding β3 integrin and calcitonin expression levels found between patients with unexplained infertility and the fertile women. Endometrial plexin-B1 expression levels showed no significant difference between fertile and infertile women. There were significant correlations between expression of β3 integrin with calcitonin and plexin-B1 in fertile and infertile women. Reduced in endometrial expression of β3 integrin and calcitonin alone or together may contribute to unexplained infertility and these genes could account as the potential molecular markers of infertility.


Cells of the human respiratory tract support the replication of pathogenic Old World orthohantavirus Puumala.
Transmission of all known pathogenic orthohantaviruses (family Hantaviridae) usually occurs via inhalation of aerosols contaminated with viral particles derived from infected rodents and organ manifestation of infections is characterized by lung and kidney involvement. Orthohantaviruses found in Eurasia cause hemorrhagic fever with renal syndrome (HFRS) and New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS). However, cases of infection with Old World orthohantaviruses with severe pulmonary manifestations have also been observed. Therefore, human airway cells may represent initial targets for orthohantavirus infection and may also play a role in the pathogenesis of infections with Eurasian orthohantaviruses. We analyzed the permissiveness of primary endothelial cells of the human pulmonary microvasculature and of primary human epithelial cells derived from bronchi, bronchioles and alveoli for Old World orthohantavirus Puumala virus (PUUV) in vitro. In addition, we examined the expression of orthohantaviral receptors in these cell types. To minimize donor-specific effects, cells from two different donors were tested for each cell type. Productive infection with PUUV was observed for endothelial cells of the microvasculature and for the three tested epithelial cell types derived from different sites of the respiratory tract. Interestingly, infection and particle release were also detected in bronchial and bronchiolar epithelial cells although expression of the orthohantaviral receptor integrin β3 was not detectable in these cell types. In addition, replication kinetics and viral release demonstrate enormous donor-specific variations. The human respiratory epithelium is among the first targets of orthohantaviral infection and may contribute to virus replication, dissemination and pathogenesis of HFRS-causing orthohantaviruses. Differences in initial pulmonary infection due to donor-specific factors may play a role in the observed broad variance of severity and symptoms of orthohantavirus disease in patients. The absence of detectable levels of integrin αVβ3 surface expression on bronchial and small airway epithelial cells indicates an alternate mode of orthohantaviral entry in these cells that is independent from integrin β3.


The effect of cryotherapy on total antioxidative capacity in patients with active seropositive rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) have increased oxidative stress, decreased antioxidant levels, and impaired antioxidant capacity. Cold treatments are used to relieve joint inflammation and pain. Therefore, we measured the effect of cold treatments on the antioxidative capacity of RA patients with active disease. Sixty patients were randomized to (1) whole body cryotherapy at -110 °C, (2) whole body cryotherapy at -60 °C, or (3) local cryotherapy. Each treatment was given three times daily for 7 consecutive days in addition to the conventional rehabilitation. Blinded rheumatologist evaluated disease activity before the first and after the last cryotherapy. We collected plasma samples daily immediately before the first and after the second cryotherapy and measured total peroxyl radical trapping antioxidant capacity of plasma (TRAP), which reflects global combined antioxidant capacity of all individual antioxidants in plasma. Baseline morning TRAP levels (mean, 95% CI), adjusted for age, body mass index, disease activity, and dose of prednisolone, were 1244 (1098-1391) µM/l in the local cryotherapy, 1133 (1022-1245) µM/l in the cryotherapy at -60 °C, and 989 (895-1082) µM/l in the cryotherapy at -110 °C groups (p = 0.006). After the first treatment, there was a rise in 1-h TRAP of 14.2 (-4.2 to 32.6) µM/l, 16.1 (-7.4 to 39.6) µM/l, and 23.6 (4.1-43.2) µM/l, respectively. The increase was significant in the whole-body cryotherapy -110 °C group (p < 0.001) but not significant between the groups (p = 0.78). When analyzed for the whole week, the daily morning TRAP values differed significantly between the treatment groups (p = 0.021), but there was no significant change within each treatment group. Whole-body cryotherapy at -110 °C induced a short-term increase in TRAP during the first treatment session with but not during other treatment modalities. The effect was short and the cold treatments did not cause a significant oxidative stress or adaptation during 1 week.


Nasopharyngeal brain heterotopia--a cause of upper airway obstruction in infancy.
The finding of mature neuroglial tissue in a mass from the head and neck region of a child raises four differential diagnostic possibilities: teratoma, encephalocele, glioma, and heterotopic brain tissue. We present a review of the literature and discuss the clinical, radiographical, and pathological features of a rare nasopharyngeal brain heterotopia in an infant causing upper airway obstruction.


[Coronary bypass surgery in patients 70 years of age and older].
Twenty-six patients 70 years of age and older who underwent elective coronary artery bypass grafting were analyzed. These patients were compared with 76 patients under 70 years of age. The results obtained were as follows. The aged group had significantly greater incidences of preoperative pulmonary and renal complications. Preoperative cardiac function in the aged group was not different from that in the younger one. The incidence of left main trunk stenosis among the aged group (31%) was twice that in the younger one (15%). Then mean number of grafts was 3.0 in both groups. There were no significant differences in the operation time, anoxic arrest time, and extracorporeal circulation time between these two groups. Although the operative mortality rate in the aged group (11.5%) was higher than that (2.6%) in the younger one, the difference was not significant. Postoperative cerebral, respiratory and renal complications were more common in the aged group. However, the incidences of these complications were not different between these two groups. Surgical mortality and morbidity were improved in the latter half of the patients of the aged group, in whom only one operative death was observed and there was no life-threatening postoperative complication. Symptomatic improvements in survivors were remarkable. Thus, we conclude that coronary artery bypass grafting can be performed with acceptable risk in patients 70 years of age and older.


Fibrinogen Dusart presenting as recurrent thromboses in the hepatic portal system.
Dysfibrogenemias are characterized by the production of abnormally functioning fibrinogen, occurring in the presence of liver disease, medication toxicity, malignancy, or genetic mutation. Here, we report a patient with multiple, separate episodes of hepatic portal system thromboses associated with dysfibrinogenemia. Molecular studies identified the presence of a 554Arg→Cys mutation in the fibrinogen Aα gene, previously identified as Fibrinogen Dusart (also known as Fibrinogen Paris V and Fibrinogen Chapel Hill). This case further illustrates the association of this dysfibrinogenemia with a unique thrombophilic manifestation.


Role of toll-like receptors in multiple sclerosis.
Multiple Sclerosis (MS) is an autoimmune disease in which Central Nervous System (CNS) lesions result from perivascular immune cell infiltration associated with damage to myelin, oligodendrocytes and neurons. CNS autoimmunity and its regulation are dominated by the inflammatory cytokines IL17 and IFNγ, and the opposing regulatory cytokines IL10 and the type I IFNs. Toll-like receptors (TLR) play a critical role in modulating cytokine and chemokine secretion in response to exogenous Pathogen Associated to Molecular Patterns and endogenous Danger-Associated to Molecular Patterns. Here, we systematically examine the evidence that TLR play a major role in the initiation disease, the triggering of relapses, and regulation of CNS damage. Data from human studies are supported analyses of a variety of animal models, including Experimental Autoimmune Encephalomyelitis in TLR-deficient mice.


Noble-Metal-Free Janus-like Structures by Cation Exchange for Z-Scheme Photocatalytic Water Splitting under Broadband Light Irradiation.
Z-scheme water splitting is a promising approach based on high-performance photocatalysis by harvesting broadband solar energy. Its efficiency depends on the well-defined interfaces between two semiconductors for the charge kinetics and their exposed surfaces for chemical reactions. Herein, we report a facile cation-exchange approach to obtain compounds with both properties without the need for noble metals by forming Janus-like structures consisting of γ-MnS and Cu7 S4 with high-quality interfaces. The Janus-like γ-MnS/Cu7 S4 structures displayed dramatically enhanced photocatalytic hydrogen production rates of up to 718 μmol g-1 h-1 under full-spectrum irradiation. Upon further integration with an MnOx oxygen-evolution cocatalyst, overall water splitting was accomplished with the Janus structures. This work provides insight into the surface and interface design of hybrid photocatalysts, and offers a noble-metal-free approach to broadband photocatalytic hydrogen production.


Two common, often coexisting grassland plant species differ in their evolutionary potential in response to experimental drought.
For terrestrial plant communities, the increase in frequency and intensity of drought events is considered as one of the most severe consequences of climate change. While single-species studies demonstrate that drought can lead to relatively rapid adaptive genetic changes, the evolutionary potential and constraints to selection need to be assessed in comparative approaches to draw more general conclusions. In a greenhouse experiment, we compare the phenotypic response and evolutionary potential of two co-occurring grassland plant species, Bromus erectus and Trifolium pratense, in two environments differing in water availability. We quantified variation in functional traits and reproductive fitness in response to drought and compared multivariate genetic variance-covariance matrices and predicted evolutionary responses between species. Species showed different drought adaptation strategies, reflected in both their species-specific phenotypic plasticity and predicted responses to selection indicating contrasting evolutionary potential under drought. In T. pratense we found evidence for stronger genetic constraints under drought compared to more favourable conditions, and for some traits plastic and predicted evolutionary responses to drought had opposing directions, likely limiting the potential for adaptive change. Our study contributes to a more detailed understanding of the evolutionary potential of species with different adaptive strategies in response to climate change and may help to inform future scenarios for semi-natural grassland ecosystems.


[The findings and value of computed tomography in pleural empyema].
Chest radiographs and CT images of 25 patients with pleural empyemas were compared retrospectively with those of 20 patients with pleural exudates and transudates in order to determine criteria for differential diagnosis and to define the place of CT in the diagnosis of pleural empyemas. The sign which was most suggestive of an empyema on a chest radiograph was an encapsulated effusion in an atypical position (18/25); this was found in only 4 out of 20 exudates and in none of the transudates. On CT, changes in the pleura, the subcostal tissues and the configuration and position of the fluid were suggestive of an empyema. In nearly all patients with a pleural empyema there was thickening and increased contrast uptake of the parietal pleura (22/25) and thickening and increased density oft the subcostal tissues (23/25). Usually, empyemas were encapsulated and biconvex (20/25). None of the patients with pleural transudates showed any of these changes. In the presence of some pleural exudates, pleural (14/20) or thoracic (11/20) changes were noted. In part, these changes were due to previous treatment (sclerotherapy) or tumour infiltration (7/20). An attempt to correlate the CT findings with changes in the pleura and subcostal tissues with the clinical empyema stages I-III, according to Light, showed that CT was unable to distinguish between early and late empyemas. Consequently, diagnostic aspiration remains necessary for correct treatment.


Ambiguities and Asymmetries in Consent and Refusal: Reply to Manson.
John Harris claims that is it 'palpable nonsense' to suggest that 'a child (or anyone) might competently consent to a treatment but not be competent to refuse it.' In 'Transitional Paternalism: How Shared Normative Powers Give Rise to the Asymmetry of Adolescent Consent and Refusal' Neil Manson aims to explain away the apparent oddness of this asymmetry of consent and refusal, by appealing to the idea of shared normative powers, presenting joint bank accounts as an example. In this article, I will argue that Manson's account fails to explain away the oddness. Rather, I will argue that there are ambiguities to which Manson has not paid sufficient attention. In fact, as odd as it may sound, I argue that Manson actually agrees with Harris (at least in relation to the asymmetry of competence). He fails to recognize that he agrees with Harris because he is not careful enough to distinguish between different asymmetries, which I have labelled the asymmetries of choice, permissibility and competence.


Characterization of Ovarian Granulosa Cell Tumors using Magnetic Resonance Imaging.
To identify the MRI features that aid in the characterization of ovarian granulosa cell tumors. 11 MR pelvis of an adult woman with pathology-proven ovarian granulosa cell tumors with surgical pathology.We evaluated the patient's age, Ca-125, size, laterality, and with MRI features such as indirect signs (i.e., thickened endometrium > 0.9 cm), morphology (cystic, solid-cystic, or solid), subacute hemorrhage, T2 signal (low or intermediate-to-high), restricted diffusion (B values: 0, 50, 1000 sec/mm3/ADC), and dynamic enhancement (intense or similar to myometrium). Also, the presence of ascites, peritoneal implants, or adenopathy. The final cohort included 11 women with a surgical-pathological diagnosis of granulosa cell tumors. The median age was 52.4 years (range, 17-80). The Ca-125 level was with a median within normal limits. The median size was 9.4 cm. Most cases were unilateral (81.8%) and more frequent on the left (54.5%). 36.4% had endometrial thickening. Ovarian granulosa cell tumors were polymorphous: cystic (54.6%), mixed solid-cystic (9.1%), and solid (36.3%). Most GC had intermediate to high signal on T2 (90.9%), restricted diffusion (81.8%), intense enhancement (81.8%), and 36.4% had intraparenchymal bleeding. 9.1% had associated implants/adenopathy/ascites at diagnosis. The MRI features characteristic of ovarian granulosa cell tumors were the polymorphous morphology, an intense enhancement to the myometrium, restricted diffusion, and the presence of intraparenchymal hemorrhage.


Prevalence, incidence, and persistence or recurrence of trichomoniasis among human immunodeficiency virus (HIV)-positive women and among HIV-negative women at high risk for HIV infection.
Trichomoniasis has been implicated in the acquisition and transmission of human immunodeficiency virus (HIV) infection. The prevalence, incidence, and persistence or recurrence of trichomoniasis were assessed among HIV-positive women and among HIV-negative women at high risk for HIV infection. A total of 871 HIV-seropositive women and 439 HIV-seronegative women enrolled in the HIV Epidemiology Study (HERS) were seen biannually. The prevalence of trichomoniasis was 9.4%-29.5% among HIV-seropositive women and 8.2%-23.4% among HIV-seronegative women. Prevalence decreased over time, did not vary according to HIV status or CD4 cell count, and was higher among women who reported crack use (P=.02) or cigarette use (P=.02), women who had bacterial vaginosis (P=.02), and those who were black (compared with white women, P<.001). There were no differences, according to HIV status or CD4 cell count, in the adjusted incidence, unadjusted incidence, or persistence or recurrence of trichomoniasis. HIV infection does not make a woman more likely to have prevalent, incident, or persistent or recurrent trichomoniasis.


Helix Sense-Selective Supramolecular Polymerization Seeded by a One-Handed Helical Polymeric Assembly.
Helix sense-selective supramolecular polymerization was achieved using a one-handed helical nanotubular polymeric assembly as a seed. First, bipyridine (BPY)-appended achiral hexabenzocoronene ((BPY)HBC) was copolymerized noncovalently with chiral (BPY)HBC(S) (or (BPY)HBC(R)) at a molar ratio of 9:1, which, via the sergeants-and-soldiers effect, afforded a P-helical (or M-helical) nanotube, which was then treated with Cu(2+) to transform into structurally robust ((BPY)Cu)NT(P) (or ((BPY)Cu)NT(M)) with a Cu(2+)/BPY coordination polymer shell. Helical seeds ((BPY)Cu)NT(P) and ((BPY)Cu)NT(M) brought about the controlled assembly of fluorinated chiral FHBC(S) and FHBC(R) as well as achiral FHBC to yield one-handed helical nanotubular supramolecular block copolymers, in which the helical senses of the newly formed block segments were solely determined by those of the helical seeds employed. Noteworthy, FHBC(S) and FHBC(R) alone without the helical seeds form ill-defined agglomerates. Attempted supramolecular polymerization of a racemic mixture of FHBC(S) and FHBC(R) from ((BPY)Cu)NT(P) (or ((BPY)Cu)NT(M)) resulted in its chiral separation, affording P-helical (or M-helical) diastereomeric block segments composed of FHBC(S)and FHBC(R) with different thermodynamic properties.


Effect of methylprednisolone injection speed on the perception of intramuscular injection pain.
Pain originating from intramuscular (IM) injection should not be underestimated, because a painful injection might incite severe fear of injection, which may lead a patient to delay seeking medical help. The aim of this study was to determine the impact of two different IM methylprednisolone injection speeds on pain intensity and pain duration. A one-group quasiexperimental design was used to study 10-second versus 30-second injection durations. According to the formula for one sample using average values, 25 patients were recruited from a dermatology clinic. Data were collected using the "Patient Characteristics Form" and the visual analog scale (VAS). The mean difference in pain levels according to the VAS in the postinjection period was significantly higher with administration of IM methylprednisolone in 10 seconds compared with 30-second administration (VAS 1.9 vs. 1.3; p < .05). The severity of pain peaked at 0 minutes for both injection speeds, but the duration of pain was longer with 10-second injections. The data showed that at multiple time points after 10-second injections, men and patients >40 years old experienced greater pain severity. Pain severity after 30-second injections was greater for patients of normal or low weight who had completed higher levels of education. In conclusion, slow IM injection of steroids improves pain management.


Quantification of interventions and outcomes in an outpatient telemanagement and care management congestive heart failure program.
The congestive heart failure continuum was developed in collaboration with the medical management committee of our hospital in response to a need to decrease readmissions for this chronic and progressive disease. This is accomplished via a multidisciplinary team that provides education and long-term telemanagement, as well as care management to assist these patients in maintaining an optimum level of functioning and the ability to remain in their homes for as long as possible. Since October 1996 there have been 375 patients referred with a decrease in the 31-day readmission rate from 21% to an average of 5%. Costs are presently $55.00 per month per patient. Evaluation of the congestive heart failure phone management tool revealed a strong 77% positive correlation between the patient's score and the number of interventions needed to stabilize the patient. Care management visits, when necessary, help reduce the need for hospitalization. (c)2000 by CHF, Inc.


[Bipolar disorders, challenges and innovations].
The treatment of patients suffering from bipolar disorders is a public healthcare challenge. While the clinical profile of these disorders remains complex, it has clearly evolved over the last few years. The healthcare provision has consequently expanded, particularly with regard to psychoeducational programmes. In this context, the FondaMental Foundation is an example of collaborative work acting for the benefit of the patient.


Modified Transseptal Puncture Technique in Challenging Septa: A Randomized Comparison to Conventional Technique.
Background. Transseptal puncture (TSP) can be challenging. We compared safety and efficacy of a modified TSP technique ("mosquito" technique, MOSQ-TSP) to conventional TSP (CONV-TSP). Method. Patients undergoing AF ablation in whom first attempt of TSP did not result in left atrial (LA) pressure (failure to cross, FTC) were randomized to MOSQ-TSP (i.e., puncture of the fossa via a wafer-thin inner stylet) or CONV-TSP (i.e., additional punctures at different positions). Primary endpoint was LA access. Secondary endpoints were safety, time, fluoroscopic dose (dose-area product, DAP), and number of additional punctures from FTC to final LA access. Result. Of 384 patients, 68 had FTC (MOSQ-TSP, n = 34 versus CONV-TSP, n = 34). No complications were reported. In MOSQ-TSP, primary endpoint was 100% (versus 73.5%, p < 0.002), median time to LA access was 72 s [from 37 to 384 s] (versus 326 s [from 75 s to 1936 s], p < 0.002), mean DAP to LA access was 1778 ± 2315 mGy/cm2 (versus 9347 ± 10690 mGy/cm2, p < 0.002), and median number of additional punctures was 2 [1 to 3] (versus 0, p < 0.002). Conclusion. In AF patients in whom the first attempt of TSP fails, the "mosquito" technique allows effective, safe, and time sparing LA access. This approach might facilitate TSP in elastic, aneurysmatic, or fibrosed septa.


Animalistic slurs increase harm by changing perceptions of social desirability.
In propaganda and hate speech, target groups are often compared to dangerous and disgusting animals. Exposure to these animalistic slurs is thought to increase endorsement of intergroup harm but the mechanism by which this happens remains unclear. Across two pre-registered and highly powered studies, we examined how animalistic language influences the cultural transmission of beliefs about target groups. In line with previous work, we found that describing a novel political group with animalistic slurs increased the extent to which participants endorsed harm towards them. Importantly, reading animalistic slurs did not influence the extent to which participants believed the target group possessed uniquely human qualities. Rather, the animalistic slurs influenced endorsement of harm by making the target group appear more undesirable. These findings offer a novel perspective into the nature of dehumanization and new insights into how hate speech functions.


2D/2D Dy2O3 Nanosheet/MoO3 Nanoflake Heterostructures for Humidity-Independent and Sensitive Ammonia Detection.
Chemiresistive ammonia gas (NH3) sensors have been playing a significant role in the fields of environmental protection, food safety monitoring, and air quality evaluation. Nevertheless, balancing the high sensitivity and humidity tolerance remains challenging. Herein, the two-dimensional (2D) heterostructures of molybdenum trioxide (MoO3) nanoflakes decorated with dysprosium oxide (Dy2O3) nanosheets (termed Dy2O3/MoO3) were synthesized via a facile probe-sonication method. With respect to pristine MoO3 counterparts, the optimal Dy2O3/MoO3 sensors possessed a 4.49-fold larger response at a lower temperature (email@example.com °C vs firstname.lastname@example.com °C toward 10 ppm of NH3), shorter response/recovery times (11.6/2.9 s vs 26.9/43.4 s), 52.6-fold higher sensitivity (17.35/ppm vs 0.33/ppm), and a lower theoretical detection limit (1.02 vs 32.82 ppb). Besides the nice reversibility, wide detection range (0.45-100 ppm) and robust long-term stability, inspiringly, the Dy2O3/MoO3 sensors showed a nearly humidity-independent response. These impressive improvements in the NH3-sensing performance were attributed to numerous heterojunctions to strengthen the carrier concentration modulation and the compensation/protection effect of Dy2O3 to mitigate the humidity effect. Moreover, the Dy2O3/MoO3 sensors showed preliminary application potential in monitoring pork freshness. This work provides a universal methodology for constructing NH3 gas sensors with high sensitivity and good humidity resistance and probably extends the application scenarios of MoO3-based sensors in the Internet of Things in the future.


Case Report: Clinicopathological characteristics of patients with gastric cancer with features of a submucosal tumour.
To investigate the clinicopathological characteristics, diagnosis and key points in the differential diagnosis of patients with gastric cancer (GC) with features of a submucosal tumour (GCSMT). The clinical presentation and imaging findings of four GCSMT cases diagnosed at our centre from 2016 to 2021 were observed and their clinicopathological outcomes were analysed. The related literature was reviewed. Based on our collected data and the related literature, a total of 31 cases of GCSMT can be summarized. 22 out of 31 cases did not present obvious symptoms and were accidentally discovered during gastroscopic examination. Only 10 patients experienced symptoms such as gastric discomfort, upper abdominal swelling and pain, haematemesis, or haematochezia. The male to female ratio was 22:9 and the age of onset ranged from 40 to 81 years (median age: 63 years). Tumours were located in the upper and middle third of the stomach (24/31), and in the lower third(7/31). The tumour diameter ranged from 0.6 to 7.3 cm, with an average value of 2.5 cm. Endoscopically, the disease manifested as SMTs, with the gastric mucosal surface appearing normal. Most patients underwent radical gastrectomy for GC (80.6%, 25/31). The pathological diagnoses of the 31 cases of GCSMT included well- and moderately-differentiated adenocarcinoma (6/31), poorly differentiated adenocarcinoma or signet ring cell carcinoma 6/31), mucinous adenocarcinoma (9/31), lymphoepithelioma-like carcinoma (7/31), gastric adenocarcinoma of the fundic gland type (3/31). Stage T1b and T2 tumours accounted for 56.7% (17/30) and 26.7% (8/30) of all cases. Lymph node metastases were found in six cases (20.0%, 6/30), whereas distant metastasis was not observed in any of the cases. For the 16 patients whose follow-up data were available, the follow-up time was 5-66 months, during which recurrence or metastasis was not observed. GCSMT is a rare disease that is often difficult to accurately diagnose through endoscopic biopsy. The importance of gaining an understanding of this disease lies in differentiating it from other SMTs (mostly mesenchymal tumours) to avoid misdiagnosis and missed diagnosis and enable the early diagnosis and treatment of patients.


The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents.
Macrophage migration inhibitory factor (MIF) is an immunoregulatory protein that is a potential therapeutic target for a number of inflammatory diseases. Evidence exists that an unexpected catalytic active site of MIF may have a biological function. To gain further insight into the role of the catalytic active site, a series of mutational, structural, and biological activity studies were performed. The insertion of an alanine between Pro-1 and Met-2 (PAM) abolishes a non-physiological catalytic activity, and this mutant is defective in the in vitro glucocorticoid counter-regulatory activity of MIF. The crystal structure of MIF complexed to (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of MIF d-dopachrome tautomerase activity, reveals that ISO-1 binds to the same position of the active site as p-hydroxyphenylpyruvic acid, a substrate of MIF. ISO-1 inhibits several MIF biological activities, further establishing a role for the catalytic active site of MIF.


Early failure of minimally invasive unicompartmental knee arthroplasty is associated with obesity.
There has been increasing use of and expanding indications for unicompartmental knee arthroplasty using minimally invasive techniques. We sought to define contraindications by examining failures. We retrospectively reviewed the early results of a consecutive series of minimally invasive medial unicompartmental knee arthroplasty using two implant designs. Seventy-nine consecutive unicompartmental knee arthroplasty cases (48 instrumented and 31 noninstrumented) with minimum 2-year followup were reviewed. Patients with radiographic involvement with or without pain referable to the lateral compartment or to the patellofemoral joint were not considered candidates. Failure was defined as revision or pending revision. The average followup was 40.2 months. There were 16 failures (six tibial loosening, three plateau fracture, four persistent medial pain, one progressive arthritis, and two sepsis). Age, gender, disease severity and implant design did not predict failure. Body mass index greater than 32 did predict failure and was associated with a reduction in survivorship by log-rank and Wilcoxon analyses. These results show reliable success if obesity is considered a contraindication and technical errors resulting in fracture are eliminated. Better defining the ideal candidate for unicompartmental knee arthroplasty, with obesity remaining a contraindication, will make this a more predictable and reliable procedure. Prognostic study, Level IV-2 (case series). See the Guidelines for Authors for a complete description of levels of evidence.


Assessment of anti-diabetic activity of an ethnopharmacological plant Nerium oleander through alloxan induced diabetes in mice.
Nerium oleander L. (syn. Nerium indicum Mill. and Nerium odorum Aiton.) is used for its anti-diabetic properties in Pakistan, Algeria, Morocco and is also recognized in Ayurveda. The present study was undertaken to investigate the anti-diabetic capacity of a standardized hydromethanolic extract of Nerium oleander in alloxan induced diabetes in mice. Nerium oleander leaf extract (NOLE) was orally administered at 50 and 200mg/kg body weight (BW) dose to alloxanized mice (blood glucose >200mg/dl). After 20 consecutive days of treatment, various diabetic parameters were studied and compared with untreated mice. Furthermore, gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) analysis was employed to reveal the phytochemical composition of the plant extract. NOLE demonstrated antihyperglycaemic activity by reducing 73.79% blood glucose level after 20 days of treatment. Oral glucose tolerance test (OGTT) revealed increase in glucose tolerance as evident by 65.72% decrease in blood glucose in 3h post treatment. Percentage decrease in different liver marker enzymes were significant along with decrease in triglyceride and cholesterol levels, displaying potent antihyperlipidemic activity. Peroxidase and catalase activity in liver, kidney and skeletal muscle were significantly restored besides marked reduction in lipid peroxidation and normalization of hepatic glycogen level in the NOLE treated alloxanized mice. Different bioactive phytocompounds with potent anti-diabetic activity were identified by GC-MS and HPLC analysis. The present investigation revealed that Nerium oleander possess potent anti-diabetic activity as claimed in different ethnopharmacological practices.


Clinical features, evaluation, and detection of colorectal cancer.
The most common presentation of colorectal carcinoma is in the symptomatic patient, most often with complaints of rectal bleeding, abdominal pain, or change in bowel habits. Symptomatic patients often have advanced disease and, because surgical resection is the only effective therapy at present, their chance for cure is poor. Until effective treatment is available, therefore, we must identify patients at high risk for lifelong screening. In addition, more effective means of surveillance of the general population need to be developed in order to diagnose patients at risk for sporadic colorectal cancer, given that this represents the majority of patients with disease. Tumor markers also would be useful to find residual disease while it is still resectable in patients who have undergone surgery for curative resection.


A brief history of galectin evolution.
Galectins are a family of carbohydrate-binding proteins found in vertebrates in great abundance and diversity in terms of both structure and ligand-binding properties as well as physiological function. Proteins with clear relationships to vertebrate galectins are already found in primitive Bilateria. The increasing amount of accessible well-annotated bilaterian genomes has allowed us to reveal, through synteny analyses, a new hypothesis about the phylogenetic history of the galectin family in this animal group. Thus, we can trace the genomic localization of the putative ancestral Bilateria galectin back to the scallops as a still very primitive slow-evolving bilaterian lineage. Intriguingly, our analyses show that the primordial galectin of the Deuterostomata most likely exhibited galectin-8-like characteristics. This basal standing galectin is characterized by a tandem-repeat type with two carbohydrate recognition domains as well as by a sialic acid binding property of the N-terminal domain, which is typical for galectin-8. With the help of synteny, the amplification of this potential primordial galectin to the broad galectin cosmos of modern jawed vertebrates can be reconstructed. Therefore, it is possible to distinguish between the paralogs resulting from small-scale duplication and the ohnologues generated by whole-genome duplication. Our findings support a substantially new hypothesis about the origin of the various members of the galectin family in vertebrates. This allows us to reveal new theories on the kinship relationships of the galectins of Gnatostomata. In addition, we focus for the first time on the galectines of the Cyclostomata, which as a sister group of jawed vertebrates providing important insights into the evolutionary history of the entire subphylum. Our studies also highlight a previously neglected member of the galectin family, galectin-related protein 2. This protein appears to be a widespread ohnologue of the original tandem-repeat ancestor within Gnathostomata that has not been the focus of galectin research due to its nonclassical galactose binding sequence motif and the fact that it was lost during mammalian evolution.


Current and future treatment options in non-alcoholic steatohepatitis (NASH).
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. Diagnosis of NASH requires a liver biopsy and is defined as presence of hepatic steatosis, ballooning and lobular inflammation with or without fibrosis. Although NASH is the most common cause of liver disease in the west world and among the top three indications for liver transplantation, there are no universally accepted pharmacological therapies and therapeutic advances have been slow. Areas covered: Current evidence about lifestyle interventions, bariatric surgery and pharmacotherapy is reviewed. Dietary recommendations and lifestyle interventions have shown promising results but are difficult to maintain. At the moment, there is no universally approved medical treatment for NASH. Pioglitazone and vitamin E are recommended by guidelines in selected patients. An increasing number of phase II and III trials in non-cirrhotic NASH are currently recruiting and their preliminary results discussed. Expert commentary: As NASH is classified as a medical condition of an unmet therapeutic need, it has gained an accelerated access pathway for drug approval based on surrogate endpoints. It is therefore expected that within the next five years, there will be at least one approved agent for the pharmacological treatment of pre-cirrhotic NASH.


Insulin and losartan reduce proteinuria and renal hypertrophy in the pregnant diabetic rat.
This study was designed to investigate the effect of hyperglycemia and angiotensin II (AngII) on renal hypertrophy and proteinuria in the pregnant diabetic rat. Secondary objectives were to evaluate changes in components of the renin-angiotensin axis and the effects of administration of losartan on pregnancy outcome. Fifty-three pregnant rats were allocated to 6 groups (1) nondiabetic controls (n = 12), (2) nondiabetic controls administered losartan (70-80 mg/kg/day; n = 10), (3) rats in which intravenous streptozotocin (STZ) was used to induce diabetes (55 mg/kg on day 10 of pregnancy; n = 10), (4) diabetic rats treated with losartan (n = 7), (5) diabetic rats treated with insulin (4 U/day; n = 7), and (6) diabetic rats treated with insulin and losartan (n = 7). Urinary protein excretion measured 4 days after STZ was 4 times greater in the rats with STZ-induced diabetes and significantly less in diabetic rats given losartan, insulin, or both. Postpartum kidney weight was greater in the rats with STZ-induced diabetes (2.04 +/- 0.21 g) than in the controls (1.37 +/- 0.14 g; P <.05) and reduced in the diabetic rats given losartan, insulin, or both (1.57 +/- 0.22, 1.73 +/- 0.13, and 1.51 +/- 0.14 g, respectively; P <.05). Plasma levels of angiotensin II in rats given losartan were more than 3.5 times greater than those in controls (749 +/- 436, 596 +/- 323, 567 +/- 349, and 159 +/- 28 pg/mL; P <.001). Postpartum activity of angiotensin-converting enzyme was increased in the untreated diabetic rats compared with that in control rats (162 +/- 12 vs 117 +/- 16 nmol/mL/min; P <.05). This increase was abolished by treatment with losartan or insulin. The number of newborns and mean weight of each newborn was similar in all groups. In summary, administration of losartan or insulin prevented, in part, kidney hypertrophy and protein excretion in the diabetic pregnant rat. Losartan did not affect the number or weight of newborns. Because angiotensin II receptor-blockers are contraindicated in pregnancy, good control of diabetes through the use of insulin should be advantageous.


The impact of oral contraceptives on women's periodontal health and the subgingival occurrence of aggressive periodontopathogens and Candida species.
The purpose of this study is to evaluate the influence of oral contraceptive (OC) use on the subgingival occurrence of specific periodontopathogens and the host's periodontal status. Ninety-two females aged 19 to 40 years were included in the study. They were divided into two groups, OC users and non-users, and subgrouped according to the most severe periodontal condition and duration of OC usage. A pooled subgingival sample from each subject was cultured to investigate the presence of Candida species, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), and Prevotella intermedia. OC users, particularly smokers, show a statistically significant increase in the prevalence of severe periodontitis. OC users had deeper probing depths (>or=5 mm) than non-users. Moreover, OC users had higher gingival index scores and clinical attachment loss, >or=2 and >or=5 mm, respectively, than non-users (P <0.01). Patients taking OCs had significantly higher numbers of cultures positive for Candida. Seven Candida species were isolated. Subgingival Candida was associated with P. gingivalis and P. intermedia in 82.9% and 85.4%, respectively, in patients taking OCs. A. actinomycetemcomitans was isolated in patients with moderate and severe periodontitis and was associated with subgingival P. gingivalis, P. intermedia, and Candida. OC use may increase the risk of severe periodontitis and seems to cause a selection of certain Candida species in periodontal pockets. OC users showed a higher prevalence of P. gingivalis, P. intermedia, and A. actinomycetemcomitans compared to non-users. C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata were the species with the ability to survive in the conditions created by the sex hormones after 3 years.


Estimating renal function to reduce the risk of adverse drug reactions.
The aging process is characterized by relevant changes in pharmacokinetics. Renal function is known to decline with aging. However, as a result of reduced muscle mass, older individuals frequently have a depressed glomerular filtration rate (GFR) despite normal serum creatinine, and such a concealed renal insufficiency may impact significantly on the clearance of hydrosoluble drugs, as well as the risk of adverse drug reactions (ADRs) from hydrosoluble drugs. The assessment of renal function should thus be a mandatory item in the global examination of patient characteristics. Equations for estimating GFR have become very popular in recent years. However, different equations may yield significantly different estimated glomerular filtration rate (eGFR) values, which have important implications in dosing drugs cleared by the kidney. Current knowledge suggests that eGFR based on the Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) study equation outperformed eGFR based on the Modification of Diet in Renal Disease (MDRD) study equation and creatinine clearance estimate based on the Cockcroft-Gault formula as a predictor of ADRs from kidney cleared drugs. More recently, the combined creatinine-cystatin C equation was shown to perform better than equations based on either of these markers alone in diagnosing CKD, even in older patients. However, its accuracy in predicting ADRs and usefulness in drug dosing is still to be investigated.


Hypercalcemia induced by Rosai-Dorfman disease in a hemodialysis patient: histological evidence of extrarenal calcitriol overproduction.
Rosai-Dorfman disease (RDD) is a rare disorder characterized by the proliferation of histiocytes in the sinus of the affected lymph nodes, which leads to massive lymphadenopathy. RDD usually presents as an increased inflammatory response and lymph node swelling. We herein report the case of a hemodialysis patient with a fever, hypercalcemia and increased serum calcitriol level who was histologically diagnosed to have RDD. Immunohistochemistry revealed an increased expression of 1α-hydroxylase by histiocytes in the dilated sinus, indicating the extrarenal overproduction of calcitriol. Treatment with oral prednisolone decreased the serum levels of inflammatory markers and calcitriol, normalized the serum calcium level and mitigated the systemic lymph node enlargement.


Venous thromboembolism: What pharmacists know? What do they need?
Venous thromboembolism is common in cancer. Low-molecular weight heparins are recommended for prolonged treatment (3-6 months or more if the cancer is active) and prevention of recurrence of venous thromboembolism in cancer. Community pharmacists are often faced with questions from patients. The main objective of this study was to describe the organization, practices and knowledge of pharmacists in care of venous thromboembolism in cancer patients. A descriptive survey was conducted electronically in October and November 2013 with pharmacists in the Champagne-Ardenne region. The questionnaire collected data on the general organization of the pharmacy, management of outpatients with cancer and thrombosis, and the level of knowledge regarding recommendations on the management of thrombosis in patients with cancer. The participation rate was 31.6%. In 93% of cases, pharmacists had no particular expertise in oncology and/or supportive care. In addition, 96% did not know the existence of recommendations for "thrombosis in cancer." Finally, 49% gave the correct answer to the case report (low-molecular weight heparins). Training sessions on the management of venous thromboembolism in cancer are currently available to pharmacists in the region. A new assessment of knowledge will be performed at the end of the year 2014. This regional experience is now extended to a national level (all French regions).


Tough pNAGA hydrogel hybridized porcine pericardium for the pre-mounted TAVI valve with improved anti-tearing properties and hemocompatibility.
The rate of adoption of transcatheter aortic valve implantation (TAVI) is increasing rapidly, due to the procedure being less invasive. However, TAVI still faces problems relating to durability, the potential incidence of thrombosis, and the inconvenience of storage in glutaraldehyde (Glut) solution. In this work, a tough hydrogel poly(N-acryloyl glycinamide) (pNAGA) is hybridized with Glut-crosslinked porcine pericardium (Glut-PP) via in situ polymerization and glycerolization, so as to obtain dry leafet material for the fabrication of a pre-mounted bioprosthetic heart valve (BHV). The tensile strength, anti-shearing, and anti-tearing properties of the valve are significantly improved by the process of hydrogel hybridization. Following a period of dry-state compression as a simulation for the crimping process of pre-mounted TAV, pNAGA/Glut-PP showed full recovery without structural damage when fully rehydrated. The introduction of pNAGA also improved the blood compatibility of the tissue, with less clot formation and fewer blood cells adhering to the surface of pNAGA/Glut-PP than is found with Glut-PP. Subcutaneous implantation in rats showed that pNAGA/Glut-PP induced a decreased inflammatory response compared with Glut-PP. These results indicate that the strategy for hybridization with hydrogel could be a potential method for preparing pre-mounted TAVs with an improved performance.


[Drug addiction: A link between sexuality and maternal desire].
If addictions lead to a strategy in order to delay the access to adult sexuality, addiction to heroin satisfies some needs which annihilate one's own sexual desire. This investment in addiction reduces fertility because of the difficulty of drug-addict women to care of their body. A specific taking charge with the help of drug substitutes can lead to the introduction of a sponsorship for the future parents.


Allylstannanes and vinylstannanes from stannylcupration of C-C multiple bonds. Recent advances and applications in organic synthesis.
The stannylcupration of allenes and alkynes has emerged as a powerful tool for the synthesis of allyl- and vinylorganostannanes. The regio- and stereoselectivity of this reaction depends upon the nature of the cuprate, the temperature and the structure of the allene or alkyne. The versatility and synthetic scope of the tin-synthons thus obtained is very wide. These intermediates have been employed as precursors in the key step of the stereoselective synthesis of many natural products, heterocycles or conjugated polyenes. This tutorial review shows a general survey of the recent advances in this area together with the contribution of our lab to this field.


Close relationship of Crimean hemorrhagic fever-Congo (CHF-C) virus strains by neutralizing antibody assays.
Strains of Crimean hemorrhagic fever-Congo (CHF-C) virus originating in widely separated points representing diverse zoogeograhiczl and ecological areas were compared by a neutralization of fluorescent foci of infection-test, in an attempt to determine whether antigenic differences could be detected among the strains. Minor differences were found which could be confirmed by reciprocal kinetic neutralization tests with one-injection immune sera if the results were analyzed by linear regression. However, CHF-C virus strains cannot be reliably subdivided into geographic variants on the basis of the minor antigenic variations observed. In this apparent paucity of antigenic diversity over its wide distribution, CHF-C virus differs from other arboviruses with similar or even lesser distribution.


Structure-Based Design of Dendritic Peptide Bolaamphiphiles for siRNA Delivery.
Development of safe and effective delivery vectors is a critical challenge for the application of RNA interference (RNAi)-based biotechnologies. In this study we show the rational design of a series of novel dendritic peptide bolaamphiphile vectors that demonstrate high efficiency for the delivery of small interfering RNA (siRNA) while exhibiting low cytotoxicity and hemolytic activity. Systematic investigation into structure-property relationships revealed an important correlation between molecular design, self-assembled nanostructure, and biological activity. The unique bolaamphiphile architecture proved a key factor for improved complex stability and transfection efficiency. The optimal vector contains a fluorocarbon core and exhibited enhanced delivery efficiency to a variety of cell lines and improved serum resistance when compared to hydrocarbon analogues and lipofectamine RNAiMAX. In addition to introducing a promising new vector system for siRNA delivery, the structure-property relationships and "fluorocarbon effect" revealed herein offer critical insight for further development of novel materials for nucleic acid delivery and other biomaterial applications.


Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]thiazoles as cholinesterase inhibitors.
A series of novel cholinesterase inhibitors based on 2-substituted 6-fluorobenzo[d]thiazole were synthesised and characterised by IR, (1)H, (13)C and (19)F NMR spectroscopy and HRMS. Purity was checked by elemental analyses. The novel carbamates were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The toxicity of the most active compounds was investigated using a standard in vitro test with HepG2 cells, and the ratio between biological activity and toxicity was determined. In addition, the toxicity of the most active compounds was evaluated against MCF7 cells using the xCELLigence system. Structure-activity relationships reflecting the dependence of cholinesterase inhibitors on the lipophilicity of the compounds as well as on the Taft polar and steric substituent constants are discussed. The specific orientation of the inhibitors in the binding site of acetylcholinesterase was determined using molecular docking of the most active compound.


Quality of life of parents and siblings of children with inflammatory bowel disease.
Few investigators have reported on the quality of life of family members of children with inflammatory bowel disease. Psychological symptoms have been reported in parents and siblings, but the problems that which give rise to these symptoms are seldom examined. In this pilot study, some of the issues that affect the quality of life of parents and siblings of children with inflammatory bowel disease were examined. Focus group meetings were held separately with 20 parents and 7 siblings of children with inflammatory bowel disease. The participants were encouraged to identify voluntarily problems related to the disease that affected their lives, and the discussions were tape recorded. Each participant subsequently wrote down the three most important concerns. Thirteen (65%) parents were very concerned about the effect of the disease on the child's future jobs, marriage, independence) and 11 (55%) were worried about problems the ill child was encountering at school. Other issues of most concern to parents included side effects of medication (n = 7), limited job prospects (n = 3), persistent feelings of guilt (n = 3), and restricted family lifestyle (n = 1 ). Most siblings (57%) were concerned about their parents' keeping information about the illness from them, and three (43%) of them were also concerned about others bullying the ill child at school. Other issues of concern to siblings included fear about the disease and treatment (n = 3), parents overprotecting the ill child, and feelings of jealousy (n = 1). Families of children with inflammatory bowel disease experience many problems that may affect their quality of life. Resources should be made available to help families with these concerns.


Demonstration of de novo production of adipocytes in adult rats by biochemical and radioautographic techniques.
Adult rats of various strains show small increases in the number of adipocytes in the epididymal (Epi) fat pad and large increases in the retroperitoneal (RP) fat depot when they are fed a high-fat, high-sugar diet ( HFS ). In the present study, radioautographic techniques are used to demonstrate that these increases result from replication and differentiation of adipocyte precursors. In addition, both in vivo and in vitro biochemical techniques are used to demonstrate that HFS -induced acceleration of DNA synthesis differs between Epi and RP depots. Measures of levels of incorporation of radiolabeled thymidine into DNA in rats fed HFS for 4 weeks reveal significant elevation in the RP depot but not in the Epi pad. Analysis of radioautographs indicates that formation of precursors may be accelerated in the RP depot as early as the first week of HFS -feeding. Results obtained from the in vitro biochemical assay are of interest with regard to possible clinical application since current in vivo techniques for quantitative assessment of precursor synthesis cannot be applied directly to the study of adipose tissue growth in man. While data obtained from the in vitro assay contains a relatively high degree of variation, the information it provides is in general agreement with that provided by the in vivo assay.


Rigid bronchoscopy: a consultant survey.
Inhalation of foreign bodies represents a potentially fatal emergency in both adults and children. Chest x-ray, in isolation, is neither sensitive nor specific. Rigid bronchoscopy represents the gold standard to diagnose and retrieve paediatric foreign bodies. Cases are encountered infrequently, creating anxieties about their management. Little is known about the confidence in, and maintenance of, rigid bronchoscopy skills by ear, nose and throat teams. A 15-question survey was completed by 50 practising otolaryngology consultants in England. Results show that almost 40% of otolaryngology consultants covering rigid bronchoscopy have not performed bronchoscopy in more than 5 years. Consultants raised concerns about the anaesthetic support and the speed of equipment assembly. Questions on clinical practice showed disparities in practice in the same scenario. The authors advocate addressing many of the issues raised by the study with a greater availability of simulation courses and regular scheduled intradepartmental teaching days for all professionals involved. National guidelines on criteria for transfer to tertiary centres would improve the consistency of practice.


[Clinical significance of expression of enhancer of zeste homolog 2 and 53 in cervical squamous cell carcinoma and intraepithelial neoplasia].
To investigate the expression and clinical significance of enhancer of zeste homolog 2 (EZH2) and p53 proteins in cervical squamous cell carcinoma (SCC) and cervical intraepithelial neoplasia (CIN). The expression and distribution of EZH2 and p53 were determined with reference to clinicopathological features and patient survival. 168 cervical SCC, 19 CINII, 35 CINIII patients and 30 normal control cases were collected for immunohistochemical analysis. The expression of EZH2 in the normal cervix, CIN and SCC was 6.7% (2/30), 37.0% (20/54) and 75.6% (127/168), respectively, with a significant difference between them (P < 0.05). The expression of p53 was 3.3% (1/30), 20.4% (11/54) and 39.3% (66/168), respectively, also (P < 0.05). In the 168 SCC cases, the positive rate of EZH2 in the cases with lymph node metastasis was 82.9%, and that of p53 was 45.7%; the positive rate of EZH2/p53 protein expression in the cases with negative lymph nodes was 70.4%, and that of p53 was 34.7%, with a significant difference between the two subgroups (P < 0.05). Among the 143 followed-up SCC patients, the EZH2(+) p53(+) cases had a progression-free survival of (51.3 ± 3.8) months, that of EZH2(+) or p53(+) cases was (66.1 ± 2.0) months, and that of EZH2(-) p53(-) cases was (71.3 ± 1.9) months, with a very significant difference among the three subgroups (P < 0.001). The overall survival times of EZH2(-) p53(-), EZH2(+) or p53(+), and EZH(2+) p53(+) cases were (72.9 ± 1.1), (68.6 ± 1.8), and (57.4 ± 3.4) months, respectively, with a significant difference among the three subgroups (P < 0.001). The multivariate analysis showed that EZH2 expression, lymph node metastasis and tumor staging were independent prognostic factors. Both EZH2 and p53 proteins may play important roles in the occurrence and development of cervical squamous cell carcinoma. There is a close relationship between the expression of both EZH2 and p53 proteins and the prognosis of SCC patients.


gamma-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells.
Tocotrienols are naturally occurring isoprenoid compounds highly enriched in palm oil, rice bran, oat, wheat germ, barley and rye. Tocotrienols have antioxidant properties as well as potent anticancer properties. In this study, the mechanisms underlying the apoptosis of gamma-tocotrienol on human gastric adenocarcinoma SGC-7901 cells were further studied, especially in correlation with the involvement of the apoptotic pathway. gamma-Tocotrienol inhibited SGC-7901 cell growth in a concentration- and time-dependent manner. The inhibitory effects of SGC-7901 cells were correlated with the DNA damage and arresting cell cycle at G(0)/G(1) phase in a time-dependent manner at 60 mumol/L concentration of gamma-tocotrienol. gamma-Tocotrienol induced activation of caspase-3 and increased the cleavage of the downstream substrate poly(ADP-ribose) polymerase. Furthermore, gamma-tocotrienol-induced apoptosis on SGC-7901 cells was mediated by activation of caspase-9. The data in this study suggested that gamma-tocotrienol could induce the apoptosis on human gastric cancer SGC-7901 cells via mitochondria-dependent apoptosis pathway. Thus, our findings revealed gamma-tocotrienol as a potential, new chemopreventive agent for human gastric cancer.


Blocking the interaction between HIV-1 integrase and human LEDGF/p75: mutational studies, virtual screening and molecular dynamics simulations.
HIV-1 integrase (IN) mediates integration of viral cDNA into the host cell genome, an essential step in the retroviral life cycle. The human lens epithelium-derived growth factor (LEDGF/p75) is a co-factor of HIV-1 IN that plays a crucial role in viral integration. Because of its crucial role in early steps of HIV replication, the IN-LEDGF/p75 interaction represents an attractive target for anti-HIV drug discovery. In this study, the IN-LEDGF/p75 interaction was studied by in silico mutational studies and molecular dynamics simulations. The results showed that all of the key residues in the LEDGF/p75 binding pocket of IN protein are important for stabilization of the complex. Structure-based virtual screening against HIV-1 IN using the ChemBridge database was performed through three different protocols of docking simulations with varying precisions and computational intensities. Six compounds based on the docking score, binding affinity and pharmacokinetic parameters were selected and an analysis of the interactions with key amino acid residues of IN was carried out. Subsequently, molecular dynamics simulations of these compounds in the LEDGF/p75 binding site of IN were carried out in order to study the stability of complexes and their hydrogen bonding interactions. IN residues Glu170, His171, and Thr174 in chain A as well as Gln95 and Thr125 in chain B were discovered to play important roles in the binding of compounds. These findings could be helpful for blocking IN-LEDGF/p75 interaction, and provide a method for avoiding viral resistance and cross-resistance.