Colonization pattern of Pasteurella pneumotropica in mice with latent pasteurellosis.
Colonization pattern of Pasteurella pneumotropica (P. pneumotropica) in mice with latent pasteurellosis was examined with the original selective media, NKBT medium and TGN broth. In the mice of 0 to 15 weeks old, the organism was mainly isolated from the upper respiratory tract, lower intestinal tract, feces and vagina, with the highest isolation rate in the pharyngolarynx. In the pregnant and lactating mice, the organism was isolated from the same sites, but not from the uterus, fetus or mammary gland. In the neonates, the organism was isolated from the respiratory and intestinal tracts within 24hr after birth. The organism was constantly detected in the feces of the 0- to 20-week-old mice, with the highest viable count one week after birth. Through the monitoring of mouse colonies, the pharyngolarynx always showed higher isolation rate than the feces in several mouse strains. These results reveal that the pharyngolarynx is the primary colonization site of P. pneumotropica in mice, and the lower intestinal tract and vagina are also the main sites. Further, frequent isolation of the organism from the feces and vagina, and the results in neonates suggest the mode of the transmission to newborn mice in the colony, i.e., intravaginal infection at the partition, and oro-nasal infection through the maternal feces and saliva.


Progesterone, follicular, and estrual responses to progesterone-based estrus and ovulation synchronization protocols at five stages of the estrous cycle.
The objective was to monitor changes in ovarian status in heifers exposed to a progesterone insert with or without concurrent GnRH injection. Estrus was manipulated in 283 heifers (31 breeding clusters) by administering GnRH, progesterone, and PGF(2alpha) at 5 stages of the estrous cycle. Estrus was presynchronized with a progesterone insert (CIDR) for 7 d before PGF(2alpha) was administered 24 h before insert removal. Successive clusters of heifers were assigned to treatments (2 heifers per treatment) on cycle d 2, 5, 10, 15, and 18. Treatments consisted of a progesterone insert (d 0) for 7 d plus: 1) PGF(2alpha) on d 6, 24 h before insert removal (early PGF); 2) GnRH on d 0 + early PGF(2alpha) (GnRH + early PGF); 3) PGF(2alpha) at insert removal (late PGF); and 4) GnRH on d 0 + late PGF (GnRH + late PGF). Controls received GnRH on d 0 and PGF(2alpha) on d 7. Ovaries were scanned by transrectal ultrasonography on d 0, 2, 7, 9, and 11 to assess follicle diameters and ovulation. Blood was collected on d 0, 2, 6, 7, 8, and 9 to quantify serum concentrations of progesterone. Insemination occurred after detected estrus or by timed artificial insemination (TAI) at 64 h after insert removal. Only 25% of 141 GnRH-treated heifers ovulated by d 2; twice as many ovulated when treatment was initiated on d 5 (46.4%) than on other cycle days (20.3%). Diameters of the largest follicle exposed to GnRH on d 0, 2, 7, or 9 did not differ regardless of whether ovulation occurred. Small treatment and stage of cycle differences in diameter of the largest follicle were detected on d 2, 7, and 9. Compared with controls, progesterone concentration was greater in all progesterone-treated heifers on d 2 and 6. Early- vs. late-PGF treatment resulted in less progesterone on d 7 and 8. Pregnancies per AI were less after TAI (44%) than after detected estrus (56%) and were less in controls than in all progesterone treatments. Heifers in which treatments were initiated on d 10 of the cycle had the most consistent (estrus vs. TAI) pregnancies per AI (65.4%) compared with other cycle days. Compared with controls, more progesterone-treated heifers ovulated by 96 h after insert removal. Application of the progesterone insert reduced variance of the interval to estrus after insert removal (or PGF(2alpha) injection in controls) by 1.6-fold compared with controls. These results do not support the use of GnRH in a progesterone-based synchronization protocol.


Respiratory function in animal food processing workers.
A group of 71 men employed in animal food processing was studied to assess the prevalence of acute and chronic respiratory symptoms and the presence of lung function abnormalities. In addition, a control group of 55 unexposed men was studied for the prevalence of chronic respiratory symptoms. A significantly higher prevalence for most of the chronic respiratory symptoms was found among the exposed workers compared to the control workers. Those workers who smoked had a significantly higher prevalence of chronic cough, chronic phlegm, chronic bronchitis, and chest tightness than the smokers in the control group. For nonsmokers, the differences between exposed and control workers were significant for chronic phlegm and chest tightness. The frequency of acute symptoms associated with the work shift was high among the animal food workers. There were significantly lower measured values for FVC, FEV1, and FEF50 in the exposed group (smokers and nonsmokers) compared to predicted lung function values. In smokers, all measured parameters of ventilatory capacity were significantly less than predicted; for nonsmokers, the FVC and FEV1 were less than normal. Our data indicate that exposure to dust in the animal food industry may be associated with the development of acute and chronic respiratory symptoms and the impairment of lung function. Smoking, in this setting, appears to aggravate these changes.


Prevalence of Taxa of Pasteurellaceae Among Populations of Healthy Captive Psittacine Birds.
Sixty-two strains of Pasteurellaceae-like bacteria were isolated from the tracheas of 87 clinically healthy psittacine birds in two Danish zoos. The isolates were identified by a combination of rpoB and 16S rRNA gene sequencing and by matrix-assisted laser desorption-ionization time of flight. Twenty-eight strains belonged to the genus Volucribacter or were related to this genus and to the unnamed taxon 34 of Bisgaard, and 28 strains were related to the unnamed taxon 44 of Bisgaard. Four strains were identified as Pasteurella multocida , two isolates were classified with the related taxon 45 of Bisgaard, and a single isolate was classified as Pasteurella sp. The investigation documented an unrecognized reservoir of rarely reported and unclassified or unnamed species of Pasteurellaceae-like bacteria in psittacine birds. The results were in accordance with a recent report on isolation of Pasteurellaceae from diseased psittacine birds, and the investigation documented that the same taxa of Pasteurellaceae-like bacteria can be isolated from apparently healthy birds as well as from diseased birds.


Introduction and expression of the interleukin 2 receptor (Tac) gene in hematopoietic stem cells with retrovirus vectors.
Retrovirus vectors provide an efficient carrier for introducing a gene into hematopoietic stem cells although expression of the inserted gene is not always successful. We constructed and compared three retrovirus vectors which carried cDNA encoding the light chain (Tac) of the interleukin 2 receptor under the control of different promoters; long terminal repeat (LTR) of murine retroviruses, the early promoter of simian virus 40 (SV40) and the promoter of the class I antigen gene of the major histocompatibility complex. We made three constructs containing these promoters. A first construct did not contain any additional promoter but LTR. A second and a third constructs contained the SV40 and the class I antigen gene promoters, respectively, in addition to LTR. The LTR of retrovirus vectors is derived from MoMuLV except that the U3 region of the 3'LTR of the third construct is derived from myeloproliferative sarcoma virus (MPSV). The second and third constructs were used for infection of bone marrow stem cells as the first construct was less efficient in expression of the interleukin 2 receptor in fibroblasts. Hematopoietic stem cells infected with the recombinant viruses were transplanted into lethally irradiated mice, and the expression of the transduced gene in hematopoietic progenitor cells was analyzed. Analysis of RNA isolated from spleen colonies showed that substantial amounts of interleukin 2 receptor mRNA were made by the construct containing the class I gene promoter and MPSV LTR. However, we could not detect any transcripts from the constructs containing MoMuLV LTR and SV40 early region promoter.


The influence of odd-even car trial on fine and coarse particles in Delhi.
The odd-even car trial scheme, which reduced car traffic between 08.00 and 20.00 h daily, was applied from 1 to 15 January 2016 (winter scheme, WS) and 15-30 April 2016 (summer scheme, SS). The daily average PM2.5 and PM10 exceeded national standards, with highest concentrations (313 μg m-3 and 639 μg m-3, respectively) during winter and lowest (53 μg m-3 and 130 μg m-3) during the monsoon (June-August). PM concentrations during the trials can be interpreted either as reduced or increased, depending on the periods used for comparison purposes. For example, hourly average net PM2.5 and PM10 (after subtracting the baseline concentrations) reduced by up to 74% during the majority (after 1100 h) of trial hours compared with the corresponding hours during the previous year. Conversely, daily average PM2.5 and PM10 were higher by up to 3-times during the trial periods when compared with the pre-trial days. A careful analysis of the data shows that the trials generated cleaner air for certain hours of the day but the persistence of overnight emissions from heavy goods vehicles into the morning odd-even hours (0800-1100 h) made them probably ineffective at this time. Any further trial will need to be planned very carefully if an effect due to traffic alone is to be differentiated from the larger effect caused by changes in meteorology and especially wind direction.


Copper-Nitrene-Catalyzed Desymmetric Oxaziridination/1,2-Alkyl Rearrangement of 1,3-Diketones toward Bicyclic Lactams.
Although copper-nitrene has been extensively studied as a versatile active species in various transformations, asymmetric reactions involving copper-nitrene have been limited to the aziridination of olefins. Herein, we report the novel copper-nitrene-catalyzed desymmetric oxaziridination reaction of cyclic diketones with alkyl azides and the subsequent rearrangement of the resulting highly active intermediate, which produces a synthetically challenging chiral bicyclic lactam containing a quaternary carbon center. This procedure not only enriches the copper-nitrene-catalyzed asymmetric reactions, but also provides an alternative strategy to address the inherent challenges of catalytic asymmetric Schmidt reactions. This unique reaction could inspire the investigation of novel copper-nitrene-catalyzed asymmetric transformations and their reaction mechanisms.


A Case of Severe Unicuspid Aortic Valve Stenosis: Valve Repair With Tricuspidization in an Adult.
A 33-year-old male was referred to our institute with acute heart failure. The patient was found to have a unicuspid aortic valve (UAV) and severe aortic stenosis. He had been followed at a local university hospital during childhood. However, he stopped visiting the outpatient clinic after becoming an adult. His condition subsequently worsened, and he ultimately presented to our hospital with cardiogenic shock. In Japan, some adult congenital heart disease (ACHD) patients continue to be followed by pediatric cardiologists, though the patterns of practice are variable. This report describes the case of a patient who became lost to follow-up in early adulthood. We thus focus on this ACHD case as an example of the effects of inadequate communication among doctors and the need to establish better ACHD management protocols for treating this patient population.


Emerging role of METTL3 in inflammatory diseases: mechanisms and therapeutic applications.
Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of Abelmoschus manihot, and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes.


Awareness and action for eliminating health care disparities in pain care: Web-based resources.
Evidence shows that disparities in pain care exist, and this problem spans across all health care settings. Health care disparities are complex, and stem from the health system climate, limitations imposed by laws and regulations, and discriminatory practices that are deep seated in biases, stereotypes, and uncertainties surrounding communication and decision-making processes. A search of the Internet identified thousands of Web sites, documents, reports, and educational materials pertaining to health and pain disparities. Web sites for federal agencies, private foundations, and professional and consumer-oriented organizations provide useful information on disparities related to age, race, ethnicity, geography, socioeconomic status, and specific populations. The contents of 10 Web sites are examined for resources to assist health professionals and consumers in better understanding health and pain disparities and ways to overcome them in practice.


Reproductive decisions of parents of children with metabolic disorders.
The Interaction Model of Client Health Behavior (IMCHB) served as a guide for variable selection and instrument development for telephone interviews with 230 parents of children with metabolic disorders. Sociodemographic, psycho-affective and client-professional interaction variables were examined in relation to three outcomes: (1) receptivity to future prenatal diagnosis (56% were receptive); (2) likelihood of terminating an affected pregnancy (10% would); and (3) whether or not the parent had taken measures to prevent another affected pregnancy (41% had). All three outcomes were significantly correlated with higher scores on the Parent Stress Index, lower scores on the Vineland Adaptive Behavior Scales, fewer persons in the parent's social support network, greater worry about the living child's future and greater perceived difficulty meeting the child's extra care needs. A regression model constructed to explain taking measures to prevent a future affected pregnancy illustrated the usefulness of the IMCHB in research that involves multiple interacting variables on health outcomes. Few of the parents (7.4%) reported an interaction with a genetic counsellor, highlighting the need for practitioners from multiple disciplines to be adequately educated in principles of genetics, especially the psychological and affective aspects of counselling.


VentSim: a simulation model of cardiopulmonary physiology.
VentSim is a quantitative model that predicts the effects of alternative ventilator settings on the cardiopulmonary physiology of critically ill patients. VentSim is an expanded version of the physiologic model in VentPlan, an application that provides ventilator-setting recommendations for patients in the intensive care unit. VentSim includes a ventilator component, an airway component, and a circulation component. The ventilator component predicts the pressures and airflows that are generated by a volume-cycled, constant-flow ventilator. The airway component has anatomic and physiologic deadspace compartments, and two alveolar compartments that participate in gas exchange with two pulmonary blood-flow compartments in the circulatory component. The circulatory component also has a shunt compartment that allows a fraction of blood flow to bypass gas exchange in the lungs, and a tissue compartment that consumes oxygen and generates carbon dioxide. The VentSim model is a set of linked first-order difference equations, with control variables that correspond to the ventilator settings, dependent variables that correspond to the physiologic state, and one independent variable, time. Because the model has no steady state solution, VentSim solves the equations by numeric integration, which is computation intensive. Simulation results demonstrate that VentSim predicts the effects of a variety of physiologic abnormalities that cannot be represented in less complex models such as the VentPlan model. For a ventilator-management application, the time-critical nature of ventilator-setting decisions limits the use of complex models. Advanced ventilator-management applications may include a mechanism to select patient-specific models that balance the trade-off of benefit of model detail and cost of computation delay.


Alterations of Vaginal Microbiota in Women With Infertility and Chlamydia trachomatis Infection.
Chlamydia trachomatis (C. trachomatis) is the most common etiological agent of bacterial sexually transmitted infections (STIs) worldwide and causes serious health sequelae such as cervicitis, pelvic inflammatory disease, and even infertility if ascending from the lower to the upper female genital tract. Previous studies have revealed the pivotal role of vaginal microbiota in susceptibility to STIs. However, alterations in the vaginal microbiota in women who are infertile and infected with C. trachomatis remain unknown. This study used metagenomic analysis of sequenced 16S rRNA gene amplicons to examine the vaginal microbial profiles of women with tubal infertility who were C. trachomatis-negative and those who were C. trachomatis-positive pre- and post-antibiotic treatment. Women who were C. trachomatis-negative and deemed healthy were recruited as references of eubiosis and dysbiosis. Women with tubal infertility and C. trachomatis infection presented a unique Lactobacillus iners-dominated vaginal microbiota rather than one dominated by Lactobacillus crispatus and displayed a decrease in Lactobacillus, Bifidobacterium, Enterobacter, Atopobium, and Streptococcus, accompanied by decreased levels of cytokines such as interferon (IFN)-γ and interleukin (IL)-10. This altered vaginal microbiota could be restored with varying degrees after standard treatment for C. trachomatis. This shift could be a predictive vaginal microbiota signature for C. trachomatis infection among females with tubal infertility, while no significant differences in phylum, class, and operational taxonomic unit (OTU) levels were observed between women with tubal infertility who were C. trachomatis-negative and healthy controls. This is the first study to provide data on the association of vaginal microbiota with C. trachomatis infection among women with tubal infertility and highlights unprecedented potential opportunities to predict C. trachomatis infection.


Elastic deformations of grafted layers with surface stress.
We calculate the elastic response of thin films grafted to a solid substrate whose upper surface is subject to a stress. This issue is addressed in the context of biological cell adhesion where adhesive junctions consist of a thin layer of proteins grafted to the extracellular matrix and sheared by the cell contractility apparatus. We show that the finite thickness of the layer limits stress-induced deformations to short ranges proportional to the thickness of the film. In addition, we show that the attachment boundary condition creates an effective shear response to surface stresses that couples all the directions, even for fluidlike layers. We predict that perturbations with wavelengths of order of the film thickness induce resonancelike responses for isotropic rubberlike materials or anisotropic media with high shear moduli. We use these results to predict the elastic deformations of a layer of proteins under shear stress and propose that the resulting, polarized elastic response to local surface forces can explain the observed, anisotropic growth of cell-substrate junctions when subject to external stresses.


A polysaccharide purified from Radix Adenophorae promotes cell activation and pro-inflammatory cytokine production in murine RAW264.7 macrophages.
Radix Adenophorae, a traditional Chinese medicine, has been reported to have a variety of biological functions. In the present study, a polysaccharide component, Radix Adenophorae Polysaccharide (RAPS), was purified from Radix Adenophorae by decoloring with ADS-7 macroporous adsorption resin, DEAE-52 cellulose ion-exchange chromatography, and Sephacryl S-300HR gel chromatography, with the purity of 98.3% and a molecular weight of 1.8 × 10(4) Da. The cell viability assay and microscopic examination revealed that RAPS promoted the proliferation and activation of macrophages. At 400 μg·mL(-1), RAPS stimulated RAW264.7 cell proliferation by 1.91-fold compared with the control. Meanwhile, RAPS significantly increased the secretion of pro-inflammatory cytokines (TNF-α and IL-6) in a dose-dependent manner in the supernatant of RAW264.7 cell culture as determined by ELISA. At 400 μg·mL(-1), the production of TNF-iα was 20.8-fold higher than that of the control. Simultaneously, the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS) were increased in RAW264.7 cells incubated with RAPS, as measured by Griess assay and Western blot analysis. The NO production of cells treated with RAPS (400 μg·mL(-1)) reached 15.8 μmol·L(-1), which was 30.4-fold higher than that of the control (0.53 μmol·L(-1)). These data suggested that RAPS may enhance the immune function and protect against exogenous pathogens by activating macrophages.


Neural Networks for Clinical Order Decision Support.
Consistent and high quality medical decisions are difficult as the amount of literature, data, and treatment options grow. We developed a model to provide automated physician order decision support suggestions for inpatient care through a feed-forward neural network. Given a patient's current status based on information data-mined and extracted from the Electronic Health Record (EHR), our model predicts clinical orders a physician enters for a patient within 24 hours. As a reference benchmark of real-world standard-of-care clinical decision support, existing manually-curated order sets implemented in the hospital demonstrate precision: 0.21, recall: 0.48, AUROC: 0.75 relative to what clinicians actually order within 24 hours. Our feed-forward model provides an automated, scalable, and robust system that achieves precision: 0.41, recall: 0.61, AUROC: 0.80.


In vitro activity of aminoglycosides, clofazimine, d-cycloserine and dapsone against 83 Mycobacterium avium complex clinical isolates.
Treatment success rates for Mycobacterium avium complex (MAC) diseases range from 50% to 55% only. To explore effective antimicrobials against either Mycobacterium intracellulare or M. avium, we determined in vitro activities of five aminoglycosides, clofazimine, dapsone and d-cycloserine compared with primary (clarithromycin) and secondary (moxifloxacin and linezolid) antimycobacterial agents. 83 non-duplicate clinical MAC isolates were collected from sputum and identified at the species level by PCR and restriction enzyme analysis of the 65 kDa hsp and rpoB genes. Drug susceptibility testing was performed using broth microdilution method. The fractional inhibitory concentration was calculated to determine synergy between isepamicin and clofazimine. High susceptibility rates of five aminoglycosides (isepamicin, amikacin, kanamycin, streptomycin, capreomycin, 82.7-88%), d-cycloserine (82.7%), clofazimine (97.3%) and clarithromycin (92%) against M. intracellulare, and 2 aminoglycosides (isepamicin, streptomycin, 87.5%), d-cycloserine (100%) and clarithromycin (100%) against M. avium were found. Dapsone had no inhibitory activity and moxifloxacin had little effect against both M. intracellulare and M. avium. Linezolid had modest activity whereas clofazimine had little effect against M. avium. Most MAC isolates with non-susceptibility to isepamicin were also non-susceptible to the other four aminoglycosides. Most streptomycin-susceptible MAC isolates were also susceptible to amikacin. Synergistic effect of combination of isepamicin and clofazimine was demonstrated in all (100%) M. intracellulare isolates whereas in only 50% M. avium isolates. When treating MAC diseases, species identification plays an important role in choosing treatment regimens. Combination of isepamicin and clofazimine may be a promising regimen in M. intracellulare-associated disease.


Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis(®) noncontact ultra-widefield module versus the Optos(®) Optomap(®).
To compare ultra-widefield fluorescein angiography imaging using the Optos(®) Optomap(®) and the Heidelberg Spectralis(®) noncontact ultra-widefield module. Five patients (ten eyes) underwent ultra-widefield fluorescein angiography using the Optos(®) panoramic P200Tx imaging system and the noncontact ultra-widefield module in the Heidelberg Spectralis(®) HRA+OCT system. The images were obtained as a single, nonsteered shot centered on the macula. The area of imaged retina was outlined and quantified using Adobe(®) Photoshop(®) C5 software. The total area and area within each of four visualized quadrants was calculated and compared between the two imaging modalities. Three masked reviewers also evaluated each quadrant per eye (40 total quadrants) to determine which modality imaged the retinal vasculature most peripherally. Optos(®) imaging captured a total retinal area averaging 151,362 pixels, ranging from 116,998 to 205,833 pixels, while the area captured using the Heidelberg Spectralis(®) was 101,786 pixels, ranging from 73,424 to 116,319 (P = 0.0002). The average area per individual quadrant imaged by Optos(®) versus the Heidelberg Spectralis(®) superiorly was 32,373 vs 32,789 pixels, respectively (P = 0.91), inferiorly was 24,665 vs 26,117 pixels, respectively (P = 0.71), temporally was 47,948 vs 20,645 pixels, respectively (P = 0.0001), and nasally was 46,374 vs 22,234 pixels, respectively (P = 0.0001). The Heidelberg Spectralis(®) was able to image the superior and inferior retinal vasculature to a more distal point than was the Optos(®), in nine of ten eyes (18 of 20 quadrants). The Optos(®) was able to image the nasal and temporal retinal vasculature to a more distal point than was the Heidelberg Spectralis(®), in ten of ten eyes (20 of 20 quadrants). The ultra-widefield fluorescein angiography obtained with the Optos(®) and Heidelberg Spectralis(®) ultra-widefield imaging systems are both excellent modalities that provide views of the peripheral retina. On a single nonsteered image, the Optos(®) Optomap(®) covered a significantly larger total retinal surface area, with greater image variability, than did the Heidelberg Spectralis(®) ultra-widefield module. The Optos(®) captured an appreciably wider view of the retina temporally and nasally, albeit with peripheral distortion, while the ultra-widefield Heidelberg Spectralis(®) module was able to image the superior and inferior retinal vasculature more peripherally. The clinical significance of these findings as well as the area imaged on steered montaged images remains to be determined.


Characterization of Argentinian Endemic Aspergillus flavus Isolates and Their Potential Use as Biocontrol Agents for Mycotoxins in Maize.
Maize (Zea mays L.) is a highly valuable crop in Argentina, frequently contaminated with the mycotoxins produced by Aspergillus flavus. Biocontrol products formulated with atoxigenic (nontoxic) strains of this fungal species are well known as an effective method to reduce this contamination. In the present study, 83 A. flavus isolates from two maize regions of Argentina were characterized and evaluated for their ability to produce or lack of producing mycotoxins in order to select atoxigenic strains to be used as potential biocontrol agents (BCA). All of the isolates were tested for aflatoxin and cyclopiazonic acid (CPA) production in maize kernels and a liquid culture medium. Genetic diversity of the nonaflatoxigenic isolates was evaluated by analysis of vegetative compatibility groups (VCG) and confirmation of deletions in the aflatoxin biosynthesis cluster. Eight atoxigenic isolates were compared for their ability to reduce aflatoxin and CPA contamination in maize kernels in coinoculation tests. The A. flavus population was composed of 32% aflatoxin and CPA producers and 52% CPA producers, and 16% was determined as atoxigenic. All of the aflatoxin producer isolates also produced CPA. Aflatoxin and CPA production was significantly higher in maize kernels than in liquid medium. The 57 nonaflatoxigenic strains formed six VCG, with AM1 and AM5 being the dominant groups, with a frequency of 58 and 35%, respectively. In coinoculation experiments, all of the atoxigenic strains reduced aflatoxin from 54 to 83% and CPA from 60 to 97%. Members of group AM1 showed a greater aflatoxin reduction than members of AM5 (72 versus 66%) but no differences were detected in CPA production. Here, we described for the first time atoxigenic isolates of A. flavus that show promise to be used as BCA in maize crops in Argentina. This innovating biological control approach should be considered, developed further, and used by the maize industry to preserve the quality properties and food safety of maize kernels in Argentina.


Incidental gastrointestinal stromal tumor at a gastroscopic polypectomy specimen: A case report and review of literature.
Although gastrointestinal stromal tumors (GISTs) comprise less than 1% of all gastrointestinal (GI) tract tumors, they are the most common mesenchymal tumors of the GI tract. Gastrointestinal stromal tumors can occur anywhere along the GI tract, but the stomach and small intestine are the most frequently involved sites. Gastrointestinal stromal tumors are frequently asymptomatic, and one-third of all cases are found incidentally. Endoscopy, endoscopic ultrasonography, and computed tomography are useful tools in the diagnosis. Endoscopic mucosal resection, endoscopic submucosal dissection, laparoscopic endoscopic cooperative surgery, and surgery with either laparoscopic or open approaches are treatment modalities for GISTs. An R0 resection is the principle surgery. Imatinib is the main medical agent used in the adjuvant or neoadjuvant treatment of GIST. We present a 65-year-old woman with an asymptomatic GIST that arose from a gastric polyp treated via endoscopic polypectomy.


CuI-Catalyzed Fluorodesulfurization for the Synthesis of Monofluoromethyl Aryl Ethers.
An efficient CuI-catalyzed fluorodesulfurization for the synthesis of monofluoromethyl aryl ethers using DAST at room temperature has been developed. This approach exhibits a good functional group tolerance, a broad substrate scope, and a high synthesis efficiency.


The impact of proton pump inhibitors in liver diseases and the effects on the liver.
In this systematic and comprehensive overview, we aimed to evaluate the impact of proton pump inhibitors (PPIs) on chronic liver diseases, especially on cirrhosis. A manual and comprehensive search of the PubMed database was conducted to obtain relevant literatures. PPIs altered the composition and function of the intestinal microflora and might lead to small intestinal bacterial overgrowth and bacterial translocation, which were associated with adverse effects in liver diseases. They might increase the risk of hepatic encephalopathy, spontaneous bacterial peritonitis, infections, and are related to an increased mortality in cirrhosis. PPIs might lead to an increased risk of hepatocellular carcinoma, although the mechanism is unknown, and the results are controversial. PPIs also had an impact on the direct-acting antiviral regimen in patients with chronic hepatitis C. They were associated with an increased risk of liver abscess and increased mortality. Additionally, PPIs might lead to metabolic risk events, such as liver steatosis and weight gain. PPIs are associated with several adverse outcomes in liver diseases. Cautious use of PPIs is recommended and clinicians should be aware of the indications for their use in patients with liver diseases.


[Increased lung uptake and transient left ventricular dilatation at stress myocardial scintigraphy with 99mTc-MIBI].
On exercise 201Tl scintigraphy in coronary artery disease, left ventricular transient dilatation (LVTD) and increased lung uptake were noted as a marker of multivessel critical stenosis. To compare the two markers of 99mTc-methoxyisobutyl isonitrile (MIBI) and 201Tl, planar and SPECT myocardial scintigraphy were performed with both radiopharmaceuticals in 27 patients with ischemic heart disease. Lung uptake (lung/max myocardial ratio) of MIBI was significantly lower than that of 201Tl, but the relationship of the lung uptake was linearly correlated (r = 0.77). The LVTD ratio (mean radial ratio = m-RR) was determined by the mean radius of the immediate postexercise short axial image by that of rest (redistribution) image. There was no significant correlation between the m-RR of 201Tl and that of MIBI (r = 0.27). We suggest that the mechanism of LVTD is due to not only subendmyocardial ischemia but also another factors.


Total retinal detachment caused by a KIF11 mutation.
This is a case report of bilateral retinal detachment associated with KIF11 mutation. In our university hospital, an 8-week-old patient presented with a potential bilateral congenital cataract, iris atrophy, and iridocorneal contact in the left eye. An examination revealed microcephaly and edema of the dorsa of the feet. The eye examination showed a clear lens in both eyes with a dislodged anterior chamber in the left eye with vessels drawn from the iris to the lens. A retrolental white bilateral mass with vessels was also observed. The MRI and the ultrasound revealed a potential peritoneal hyperplastic glass body. Bilateral retinal detachment was diagnosed during surgery. Due to the external appearance of the eyes (microcephaly and edema) and the bilateral retinal detachments, a test for KIF11 mutations was requested, and the results were positive. There is a known association between KIF11 mutation and chorioretinopathy. The bilateral retinal detachment in the present case study has not been previously reported in the literature.


Crystal structure of tryptophanase.
The X-ray structure of tryptophanase (Tnase) reveals the interactions responsible for binding of the pyridoxal 5'-phosphate (PLP) and atomic details of the K+ binding site essential for catalysis. The structure of holo Tnase from Proteus vulgaris (space group P2(1)2(1)2(1) with a = 115.0 A, b = 118.2 A, c = 153.7 A) has been determined at 2.1 A resolution by molecular replacement using tyrosine phenol-lyase (TPL) coordinates. The final model of Tnase, refined to an R-factor of 18.7%, (Rfree = 22.8%) suggests that the PLP-enzyme from observed in the structure is a ketoenamine. PLP is bound in a cleft formed by both the small and large domains of one subunit and the large domain of the adjacent subunit in the so-called "catalytic" dimer. The K+ cations are located on the interface of the subunits in the dimer. The structure of the catalytic dimer and mode of PLP binding in Tnase resemble those found in aspartate amino-transferase, TPL, omega-amino acid pyruvate aminotransferase, dialkylglycine decarboxylase (DGD), cystathionine beta-lyase and ornithine decarboxylase. No structural similarity has been detected between Tnase and the beta 2 dimer of tryptophan synthase which catalyses the same beta-replacement reaction. The single monovalent cation binding site of Tnase is similar to that of TPL, but differs from either of those in DGD.


'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation.
Cerebral edema is a major contributor to morbidity associated with traumatic brain injury (TBI). The methods involved in most rodent models of TBI, including head fixation, opening of the skull, and prolonged anesthesia, likely alter TBI development and reduce secondary injury. We report the development of a closed-skull model of murine TBI, which minimizes time of anesthesia, allows the monitoring of intracranial pressure (ICP), and can be modulated to produce mild and moderate grade TBI. In this model, we characterized changes in aquaporin-4 (AQP4) expression and localization after mild and moderate TBI. We found that global AQP4 expression after TBI was generally increased; however, analysis of AQP4 localization revealed that the most prominent effect of TBI on AQP4 was the loss of polarized localization at endfoot processes of reactive astrocytes. This AQP4 dysregulation peaked at 7 days after injury and was largely indistinguishable between mild and moderate grade TBI for the first 2 weeks after injury. Within the same model, blood-brain barrieranalysis of variance permeability, cerebral edema, and ICP largely normalized within 7 days after moderate TBI. These findings suggest that changes in AQP4 expression and localization may not contribute to cerebral edema formation, but rather may represent a compensatory mechanism to facilitate its resolution.


Lithium lengthens circadian period of cultured brain slices in area specific manner.
Lithium has been used for the treatment of bipolar disorder (BD). However, the mechanisms how lithium exerts its mood stabilizing effects remain to be studied. The disorder in circadian pacemaking has been suggested as an underlying mechanism of the characteristic mood instability of the BD. Lithium is also known to lengthen the circadian periods. We recently proposed that chronic methamphetamine treatment induced circadian oscillation as a complex oscillator including multiple dopaminergic brain areas, and the complex oscillator regulates behavior rhythm independent from the central circadian oscillator in the suprachiasmatic nucleus (SCN). Sleep-wake pattern of rapid cycling BD exhibits similar rhythm disorganization to methamphetamine treated animals. Therefore, we hypothesized that the dysregulated circadian rhythm in BD patients is caused by desynchronization of sleep-wake rhythms from the central clock in the SCN, and that mood stabilizing effect of lithium is achieved through their resynchronization. In the present experiment, we examined how lithium affects the circadian rhythms of brain areas involved in the complex oscillator as well as the SCN. Here we report that lithium lengthens the circadian periods in the SCN, olfactory bulb, median eminence and substantia nigra with dose and area specific manner. The effective lithium dose was much higher than the plasma levels that are required for lengthening the circadian behavior rhythms as well for therapeutic use. Low dose of lithium did not lengthen the period but enhanced the amplitude of circadian rhythms, which may exert therapeutic effects on BD.


Rosuvastatin-induced rhabdomyolysis: case report and call for proactive multifactorial risk assessment and preventive management of statin therapy in high-risk patients.
Cholesterol-lowering statins are frequently prescribed for primary and secondary prevention of ischaemic vascular events. Whereas most patients tolerate statins without problems, statin-associated myopathy is well documented, as are several risk factors. We present a case report of an 80-90-year-old man with coronary artery disease who rapidly developed severe rhabdomyolysis during treatment with rosuvastatin while in intensive care. He had several concomitant risk factors for statin-induced myopathy including high dosage, old age, renal and hepatic impairment, and a pharmacogenetic SLCO1B1*1 a/*5 variant. Single known risk factors have a low predictive value for statin-induced myopathy and may therefore be underestimated in clinical practice. However, adverse drug reactions frequently involve the joint action of a multitude of environmental and genetic component causes, and statin-induced myopathy should be regarded as a multicausal event. We therefore advocate a proactive multifactorial risk assessment to guide and individualise statin therapy in high-risk patients.


Intravitreal Ranibizumab for Stage IV Proliferative Sickle Cell Retinopathy: A First Case Report.
Purpose. To present the case of a 27-year-old male patient with stage IV proliferative sickle cell retinopathy, treated with one intravitreal injection of ranibizumab, showing regression of the neovascularization and no recurrence at the 9-month follow-up. Methods. A 27-year-old male patient presented with blurred vision and floaters in the right eye since three days. His best corrected visual acuity was 6/18. Ophthalmological examination and fluorescein angiography revealed proliferative sickle cell retinopathy stage IV with vitreous hemorrhage and sea fan neovascularization, as well as ischemic areas at the temporal periphery. Results. The patient was treated with one intravitreal injection of ranibizumab, presenting improvement in the visual acuity from 6/18 to 6/6, resolution of vitreous hemorrhage, and regression of the neovascularization. Additionally, he underwent scatter laser photocoagulation at the ischemic areas. At the 9-month follow-up there was no recurrence, while no adverse effects were noticed. Conclusions. Intravitreal ranibizumab may be a useful adjunct to laser photocoagulation in the management of proliferative sickle cell retinopathy and may permit some patients to avoid pars plana vitrectomy for vitreous hemorrhage.


[The POSSUM scoring system: an instrument for measuring quality in surgical patients].
The POSSUM scale (Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity) is a scoring system that is used to predict risk-adjusted mortality and morbidity rates in a wide variety of surgical procedures. In this prospective study, the validity of the POSSUM scale was evaluated in patients undergoing laparotomy in a general surgery department. The POSSUM scale was prospectively applied in all patients undergoing elective and emergency laparotomy in the general surgery department of a level II hospital over 8 months. A total of 105 patients were included, of which 24 underwent emergency laparotomy and 81 underwent elective surgery. Predicted mortality and morbidity rates were calculated by using the POSSUM scale. These results were compared with actual outcomes by using Fisher's test. The mean physiological score was 23.4 points (range: 12-40 points), while the mean surgical score was 11.3 points (range: 6-24 points). Three patients died during the postoperative period and 47 had morbidity. When the observed results for mortality were compared with those predicted by the POSSUM scoring system, no significant differences were observed in the analysis by risk groups, except in the risk group < 20 %, in which the POSSUM scale overestimated mortality. The risk of morbidity was underestimated by the POSSUM scale in the risk group < 20 %. The POSSUM scoring system is a useful predictor of morbidity and mortality in patients undergoing emergency and elective laparotomy.


Use of Wild Type or Recombinant Lactic Acid Bacteria as an Alternative Treatment for Gastrointestinal Inflammatory Diseases: A Focus on Inflammatory Bowel Diseases and Mucositis.
The human gastrointestinal tract (GIT) is highly colonized by bacterial communities, which live in a symbiotic relationship with the host in normal conditions. It has been shown that a dysfunctional interaction between the intestinal microbiota and the host immune system, known as dysbiosis, is a very important factor responsible for the development of different inflammatory conditions of the GIT, such as the idiopathic inflammatory bowel diseases (IBD), a complex and multifactorial disorder of the GIT. Dysbiosis has also been implicated in the pathogenesis of other GIT inflammatory diseases such as mucositis usually caused as an adverse effect of chemotherapy. As both diseases have become a great clinical problem, many research groups have been focusing on developing new strategies for the treatment of IBD and mucositis. In this review, we show that lactic acid bacteria (LAB) have been capable in preventing and treating both disorders in animal models, suggesting they may be ready for clinical trials. In addition, we present the most current studies on the use of wild type or genetically engineered LAB strains designed to express anti-inflammatory proteins as a promising strategy in the treatment of IBD and mucositis.


Virtual Expert Mass Spectrometrist v3.0: an integrated tool for proteome analysis.
The number of tools described in the literature for analysis of proteome data is growing fast. However, most tools are not able to communicate or exchange data with other tools. In Virtual Expert Mass Spectrometrist (VEMS) v3.0 an effort has been made to interface and export to already existing tools. In this chapter, an outline of how to use the VEMS program to search tandem mass spectrometry data against databases is described. Additionally, examples on how to extend the analysis with other external tools are given.


Evidence for a pure time perception deficit in children with ADHD.
Deficits have been found previously in children with ADHD on tasks of time reproduction, time production and motor timing, implicating a deficit in temporal processing abilities, which has been interpreted as either secondary or primary to core executive dysfunctions. The aim of this study was to explore further the abilities of hyperactive children in skills of time estimation, using a range of time perception tasks in different temporal domains. Time estimation was tested in a verbal estimation task of 10 seconds. Time reproduction was also acquired for two time intervals of 5 and 12 seconds. A temporal discrimination task aimed to determine the idiosyncratic threshold of minimum time interval (in milliseconds) necessary to distinguish two intervals differing by approximately 300 milliseconds. Twenty-two children diagnosed with ADHD were compared to 22 healthy children, matched for age, handedness and working memory skills. Children with ADHD were significantly impaired in their time discrimination threshold: on average, time intervals had to be 50 ms longer for the hyperactive children in order to be discriminated when compared with controls. Children with ADHD also responded earlier on a 12-second reproduction task, which however only approached significance after controlling for IQ and short-term memory. No group differences were found for the 5-second time reproduction or verbal time estimation tasks. The findings suggest that children with ADHD perform poorly on time reproduction tasks which load heavily on impulsiveness and attentional processes and they also suggest that these children may have a perceptual deficit of time discrimination, which may only be detectable in brief durations which differ by several hundred milliseconds. A temporal perception deficit in the range of milliseconds in ADHD may impact upon other functions such as perceptual language skills and motor timing.


Tumorigenic transformation of established murine fibroblasts by transfection with amplification promoting DNA elements.
Deregulated replication of the cellular genome is assumed to result in tumorigenic transformation of the cell. We tested this hypothesis by using mouse DNA elements that promote amplification of transfected DNA in mammalian cells when linked to a selectable marker gene that is driven by a truncated promoter (Holst et al., Cell 52, 355-365 (1988); Wegner et al., Nucl. Acids Res. 17, 9909-9932 (1989)). Here, the DNA elements muNTS-1, e-1, e-2, e-4, e-5, and e-12 were inserted into the plasmid p-hyg, which contains the gene for resistance to hygromycin B driven by a constitutive promoter. After transfer into established rat fibroblasts (208F), transfected DNA constructs persist in low copy numbers (1-10 copies per cell) integrated into high molecular weight DNA. We observed a neoplastically transformed phenotype in 40% to 70% of hygromycin-resistant colonies of 208F cells which is dependent on the DNA element transfected. 208F cells transfected with vector DNA exhibit a "normal" phenotype and are not tumorigenic. The transformed cells, on the other hand, induced malignant tumors after injection into immunodeficient NMRI nu/nu mice. In contrast to established cells, primary rat embryo fibroblasts (REF) with limited life span are neither neoplastically transformed nor immortalized after transfection of e-4 DNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Bilateral primary breast cancer.
Primary carcinoma of breast was treated in 967 patients from 1962 through 1972. Thirty-five of these patients had a second primary tumor of which 50% were discovered simultaneously. A family history for cancer was recorded in 26% of the patients with bilateral cancer. Patients found their tumor more often than the physician except in the simultaneous cases where the physician was more successful. Pathological examination showed 10% of the tumors were comedo, lobular carcinoma in situ, papillary, or tubular cancers. In the metachronous group, 50% of the axillae were involved on both sides. In the simultaneous cases the axilla was less frequently involved. Mammography, biopsies of the second breast, and prophylactic mastectomy in certain high-risk patients should improve survival rates.


Venous invasion as a risk factor for recurrence after gastrectomy followed by chemotherapy for stage III gastric cancer.
Although adjuvant chemotherapy with S-1 after curative gastrectomy has been performed as a standard treatment for Stage II and III gastric cancer (GC) in Japan, patients with Stage III GC still have a high incidence of recurrence and a poor prognostic outcome. The aim of this study was to investigate risk factors for recurrence in patients with Stage III GC despite of curative gastrectomy followed by adjuvant chemotherapy, suggesting an indicator for more intensive management. A total of 97 patients with pathological Stage III GC underwent adjuvant chemotherapy after curative gastrectomy between 2001 and 2014, were enrolled in this study. We retrospectively analyzed their hospital records from our hospital. The 5-year relapse-free survival (RFS) rates of patients with pStage III GC were 42.0%. Univariate and multivariate analyses for RFS revealed that venous invasion (v+) was an independent factor predicting a shorter RFS (v + vs. v-, 36.5% vs. 47.4%, P = 0.034, HR 1.82, 95% CI: 1.01-3.37). Venous invasion also predicted a shorter overall survival (OS) (v + vs. v-, 33.7% vs. 50.4%, P = 0.027). Regarding the patterns of recurrence, hematogenous recurrence was significantly occurred in patients with v + GC than those without (P = 0.022). Stage III GC with venous invasion is a high-risk subgroup for hematogenous recurrence after curative surgery followed by adjuvant chemotherapy. More intensive and effective adjuvant chemo and/or molecular targeted therapy for Stage III GC patients with venous invasion should be considered to improve their outcomes.


Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac function, and arterial remodeling.
Currently, dual- or triple-drug combinations comprising different vasodilators are the mainstay for the treatment of pulmonary arterial hypertension (PAH). However, the patient outcome continues to be disappointing because the existing combination therapy cannot restrain progression of the disease. Previously, we have shown that when given as a monotherapy, long-acting inhaled formulations of sildenafil (a phosphodiesterase-5 inhibitor) and rosiglitazone (a peroxisome proliferator receptor-γ agonist) ameliorate PAH in rats. Thus, with a goal to develop a new combination therapy, we prepared and characterized poly(lactic-co-glycolic acid) (PLGA)-based long-acting inhalable particles of sildenafil and rosiglitazone. We then assessed the efficacy of the combinations of sildenafil and rosiglitazone, given in plain forms or as PLGA particles, in reducing mean pulmonary arterial pressure (mPAP) and improving pulmonary arterial remodeling and right ventricular hypertrophy (RVH) in Sugen 5416 plus hypoxia-induced PAH rats. After intratracheal administration of the formulations, we catheterized the rats and measured mPAP, cardiac output, total pulmonary resistance, and RVH. We also conducted morphometric studies using lung tissue samples and assessed the degree of muscularization, the arterial medial wall thickening, and the extent of collagen deposition. Compared with the plain drugs, given via the pulmonary or oral route as a single or dual combination, PLGA particles of the drugs, although given at a longer dosing interval compared with the plain drugs, caused more pronounced reduction in mPAP without affecting mean systemic pressure, improved cardiac function, slowed down right heart remodeling, and reduced arterial muscularization. Overall, PLGA particles of sildenafil and rosiglitazone, given as an inhaled combination, could be a viable alternative to currently available vasodilator-based combination therapy for PAH.


Work stressors and impaired sleep: rumination as a mediator.
An association between stress at work and impaired sleep is theoretically plausible and supported by empirical evidence. The current study's main aim was to investigate how the influence of stressors is carried over into the evening and the night. We assume that this relationship is mediated by perseverative cognitions. We tested this assumption in two cross-sectional samples with structural equation modeling, using bootstrapped standard errors to test for significance. Effort–reward imbalance and time pressure were used as stressors, and rumination as a measure for perseverative cognitions. Results show that the stressors are related to perseverative cognitions, and these are related to impaired sleep in both samples. Indirect effects are significant in both samples. With rumination controlled, direct effects of stressors on sleep are only significant in one out of four cases. Thus, there is full mediation in three out of four cases, and partial mediation in the fourth one. Our results underscore the notion that perseverative cognitions are crucial for transferring negative effects of work stressors into private life, including sleep, thus hindering individuals to successfully recover.


Blood vessel/epicardial substance (bves) expression, essential for embryonic development, is down regulated by Grk/EFGR signalling.
The Pop1/Bves (blood vessel/epicardial substance) gene is a member of the popeye gene family recently identified in various species. It encodes a potential transmembrane glycoprotein and is a cell adhesion molecule present in skeletal and cardiac muscle and epithelia. We isolated the Drosophila homologue of Bves (DmBves) and found, using in situ hybridisation to RNA in ovaries, that bves is expressed in all follicular epithelial cells surrounding the oocyte at stage 10, except those in very posterior and anterior-dorsal regions adjacent to the oocyte. We show that the repression of bves expression in anterior-dorsal follicle cells is regulated by the Grk/EGFR signalling pathway. Bves is also expressed in nurse cells during oogenesis and its transcripts are then translocated into the oocyte. Expression of bves antisense RNA during oogenesis causes reduced viability in the resulting embryos. There is a failure in the migration of pole cells from the posterior towards the antero-dorsal side of the embryo, probably resulting from abnormal germband extension and we suggest that bves is essential for normal embryonic development.


Effect of L-carnitine on ethanol and acetate plasma levels after oral administration of ethanol in humans.
In a randomized double-blind, cross-over experiment, 0.5 g/kg of ethanol in the form of white wine and 3 g of L-carnitine by intravenous infusion were administered to 15 healthy volunteers. Ethanol and acetate plasma levels and the urine concentrations of acetylcarnitine were determined. Administration of ethanol induced a significant increase of both plasma ethanol and acetate, lasting 6-8 hr. The concomitant administration of carnitine resulted in a significant decrease of plasma acetate, whereas plasma ethanol levels remained unmodified. Urinary acetylcarnitine content significantly increased following administration of ethanol plus carnitine, but not when L-carnitine alone was administered. The resulting conclusion is that administered L-carnitine might trap excess acetyls derived both from free acetate, formed by ethanol oxidation, and from acetyl coenzyme A, accumulated as a result of the ethanol-induced decrease in the Krebs cycle flux.


Long-term breast cancer survivors' symptoms and morbidity: differences by sexual orientation?
Because little is known about morbidity and symptoms among sexual minority women with breast cancer, that is, lesbian or bisexual-identified women, and women with a preference for a woman partner, we examined differences by sexual orientation in long-term survivors' symptoms and morbidity, considering arm morbidity, systemic therapy side effects, hypertension, and number of comorbidities. From a state cancer registry, we recruited 257 heterosexual and 69 sexual minority women (SMW) with a diagnosis of primary, nonmetastatic breast cancer. To increase the number of SMW, we used convenience recruitment methods and obtained an additional 112 SMW who fit the same eligibility criteria as the registry-derived sample. Using a telephone survey, we collected demographic and self-reported data on arm morbidity and systematic therapy side effects, using the European Organization for Research and Treatment of Cancer Quality of Life scale, QLQ-BR23 and a comorbidity measure developed for breast cancer survivors. Sexual orientation was more strongly associated with arm morbidity and systemic side effects than with high blood pressure and comorbidities. Sexual orientation related indirectly to systemic side effects and arm morbidity through cancer treatments and some demographic factors. Our finding that SMW respond more negatively to certain cancer treatments compared to heterosexual women suggests an opportunity to intervene with education and support for SMW breast cancer survivors for whom these life-saving treatments are necessary. Because breast cancer survivors are at risk for multiple severe and persistent symptoms, assessing such symptoms is an important aspect of survivorship care. Cultural differences in perception of symptoms, communication issues, cultural barriers to reporting of symptoms, and different cultural norms about expressing pain or impairments have been established by studies. Knowledge about differences in impairment and symptoms by sexual orientation will help providers' efforts to provide high quality care to breast cancer survivors and may enhance cancer survivorship.


Generating a fractal butterfly Floquet spectrum in a class of driven SU(2) systems.
A scheme for generating a fractal butterfly Floquet spectrum, first proposed by Wang and Gong [Phys. Rev. A 77, 031405(R) (2008)], is extended to driven SU(2) systems such as a driven two-mode Bose-Einstein condensate. A class of driven systems without a link with the Harper-model context is shown to have an intriguing butterfly Floquet spectrum. The found butterfly spectrum shows remarkable deviations from the known Hofstadter's butterfly. In addition, the level crossings between Floquet states of the same parity and between Floquet states of different parities are studied and highlighted. The results are relevant to studies of fractal statistics, quantum chaos, and coherent destruction of tunneling, as well as the validity of mean-field descriptions of Bose-Einstein condensates.


Thermal decomposition modes for four-coordinate ruthenium phosphonium alkylidene olefin metathesis catalysts.
The four-coordinate ruthenium phosphonium alkylidenes 1-Cy and 1-iPr, differing in the substituent on the phosphorus center, were observed to decompose thermally in the presence of 1,1-dichloroethylene to produce [H(3)CPR(3)][Cl]. The major ruthenium-containing product was a trichloro-bridged ruthenium dimer that incorporates the elements of the 1,1-dichloroethylene as a dichlorocarbene ligand and a styrenic vinyl group on the supporting NHC ligand. Spectroscopic, kinetic, and deuterium-labeling experiments probed the mechanism of this process, which involves a rate-limiting C-H activation of an NHC mesityl ortho methyl group. These studies provide insight into intrinsic decomposition processes of active Grubbs type olefin metathesis catalysts, pointing the way to new catalyst design directions.


Stability and Priority of Symptoms and Symptom Clusters Among Allogeneic HSCT Patients Within a 5-Year Longitudinal Study.
Due to toxicity and invasiveness, allogeneic hematopoietic stem cell transplantation causes severe and longstanding symptom burden. Longitudinal studies on symptoms and symptom clusters (SC) would be helpful to optimize symptom control but are rare to date. The objective of this study was to investigate stability of symptoms, extract time stable SC, and determine their priority in symptom management. In this multicenter study, patients diagnosed with hematologic cancer were assessed before conditioning (T0) and three months (T1), one year (T2), and five years (T3) after transplantation. Symptoms were assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Symptoms were stable when rated as present at three consecutive time points. Applying factor analysis, stable SC were composed of symptoms loading on the same factor across all time points. Priority in symptom management was derived from a combination of severity and predictive power for quality of life (QoL). Two hundred thirty-nine patients participated at T0, 150 (63%) at T1, 102 (43%) at T2, and 45 (19%) at T3. We identified three stable SC, composed of rest-tired-weak-dyspnea-loss of appetite (exhausted), tense-worried-irritable-depressed (affective), and nausea-vomiting (gastrointestinal). Fatigue was most persistent and also most severe and predictive for QoL, both as symptom and in cluster (exhausted). Given its high stability, severity, and impact on QoL, fatigue should have priority in symptom management. The treatment of this symptom could be enhanced by also incorporating interventions addressing dyspnea and loss of appetite.


Baud rate and shaping blocklength effects on the nonlinear performance of super-symbol transmission.
In this paper we study the nonlinear performance of super-symbol (SUP) transmission. We analyze the spectral dip, a unique feature of SUP, as a function of various system parameters and discuss how this dip and the associated nonlinear benefit would vary with different baud rates and shaping blocklengths. We then conduct simulations to verify our analysis, by which we confirm that the SUP performance can be optimized via a judicious choice on the baud rate and/or blocklength. Furthermore, a nonlinear noise study confirms that the nonlinear benefit of SUP mainly comes from its significant nonlinear phase noise (NLPN) reduction.


Situationally Selective Activation of Moral Disengagement Mechanisms in School Bullying: A Repeated Within-Subjects Experimental Study.
With reference to social-cognitive theory, the aim of the present study was to examine whether school students' tendency to display different moral disengagement mechanisms varies according to different social cues in hypothetical events in which they are engaged in bullying behavior. A repeated within-subjects experimental design was adopted. A total of 706 Swedish students (aged 10-20) from 75 classrooms responded to four verbal bullying vignettes by filling out a self-report survey. The results showed changes in moral disengagement mechanisms across the bullying situations. For instance, moral justification, victim blaming, and dehumanization scored higher in the mean victim condition and lower in the likable victim condition than in the other two conditions. Diffusion of responsibility was higher in the group conformity condition than in the other conditions. The findings also revealed differences in the levels of moral disengagement mechanisms within the bullying conditions. For example, euphemistic labeling and displacement of responsibility scored higher than the other mechanisms in the laughing audience condition. Victim blaming scored higher than the other mechanisms in the mean victim condition. Dehumanization, victim blaming, and moral justification scored lowest while euphemistic labeling was higher than most of the other mechanisms in the likable victim condition.


Surface investigation on biomimetic materials to control cell adhesion: the case of RGD conjugation on PCL.
The cell recognition of bioactive ligands immobilized on polymeric surfaces is strongly dependent on ligand presentation at the cell/material interface. While small peptide sequences such as Arg-Gly-Asp (RGD) are being widely used to obtain biomimetic interfaces, surface characteristics after immobilization as well as presentation of such ligands to cell receptors deserve more detailed investigation. Here, we immobilized an RGD-based sequence on poly(epsilon-caprolactone) (PCL), a largely widespread polymeric material used in biomedical applications, after polymer aminolysis. The surface characteristics along with the efficacy of the functionalization was monitored by surface analysis (FTIR-ATR, contact angle measurements, surface free energy determination) and spectrophotometric assays specially adapted for the analytical quantification of functional groups and/or peptides at the interface. Particular attention was paid to the evaluation of a number, morphology, and penetration depth of immobilized functional groups and/or peptides engrafted on polymeric substrates. In particular, a typical morphology in peptide distribution was evidenced on the surface raised from polymer crystallites, while a significant penetration depth of the engrafted molecules was revealed. NIH3T3 fibroblast adhesion studies verified the correct presentation of the ligand with enhanced cell attachment after peptide conjugation. Such work proposes a morphological and analytical approach in surface characterization to study the surface treatment and the distribution of ligands immobilized on polymeric substrates.


The clinical and economic potential of hyperbaric oxygen therapy in the treatment of diabetic ulceration and other conditions.
Selective use of systemic hyperbaric oxygen therapy (HBOT) is a treatment that deserves further study and analysis. The current situation in the United Kingdom (UK) is discussed in relation to available evidence and practices elsewhere. It would appear that there is increasing evidence that HBOT could benefit many patients and health care budgets through improved clinical efficacy and cost-efficiency in the treatment of specific conditions, notably nonhealing diabetic ulceration of the lower limbs. This is not only disabling, it may lead to amputation. It is also a financial burden to patients and health service providers. In the UK, it is estimated that chronic wound care costs more than pound1 billion a year, with diabetic ulceration accounting for a substantial part of that staggering sum. It has been said repeatedly, and quite correctly, that there is insufficient good-quality evidence upon which a properly informed decision may be made on the contribution HBOT might make to alleviate that situation. It is intriguing that no determined effort is apparent that would seek to settle the issue by encouraging and facilitating appropriately designed and conducted randomized controlled trials to assess the actual effects of this treatment. Indeed, a proposed government research initiative appears to have been cancelled. Is lack of research preventing provision of HBOT?


Dietary fenugreek and onion attenuate cholesterol gallstone formation in lithogenic diet-fed mice.
An animal study was conducted to evaluate the antilithogenic effect of a combination of dietary fenugreek seeds and onion. Lithogenic conditions were induced in mice by feeding them a high (0.5%) cholesterol diet (HCD) for 10 weeks. Fenugreek (12%) and onion (2%) were included individually and in combination in this HCD. Fenugreek, onion and their combination reduced the incidence of cholesterol gallstones by 75%, 27% and 76%, respectively, with attendant reduction in total cholesterol content by 38-42%, 50-72% and 61-80% in serum, liver and bile respectively. Consequently, the cholesterol/phospholipid ratio was reduced significantly in serum, liver and bile. The cholesterol saturation index of bile was reduced from 4.14 to 1.38 by the combination of fenugreek and onion and to 2.33 by onion alone. The phospholipid and bile acid contents of the bile were also increased. Changes in the hepatic enzyme activities (3-hydroxy-3-methylglutaryl Coenzyme A reductase, cholesterol-7α-hydroxylase and cholesterol-27-hydroxylase) induced by HCD were countered by fenugreek, onion and their combination. Hepatic lipid peroxides were reduced by 19-22% and 39-45% with fenugreek, onion and their combination included in the diet along with the HCD. Increased accumulation of fat in the liver and inflammation of the gallbladder membrane produced by HCD were reduced by fenugreek, onion and their combination. The antilithogenic influence was highest with fenugreek alone, and the presence of onion along with it did not further increase this effect. There was also no additive effect of the two spices in the recovery of antioxidant molecules or in the antioxidant enzyme activities.


Effect of exogenous fibrolytic enzymes and ammonia fiber expansion on the fermentation of wheat straw in an artificial rumen system (RUSITEC)1.
This study investigated the effect of treatment of wheat straw using ammonia fiber expansion (AFEX) and exogenous fibrolytic enzymes (Viscozyme) on fiber digestibility, rumen fermentation, microbial protein synthesis, and microbial populations in an artificial rumen system [Rumen Simulation Technique (RUSITEC)]. Four treatments were assigned to 16 vessels (4 per treatment) in 2 RUSITEC apparatuses in a randomized block design. Treatments were arranged as a 2 × 2 factorial using untreated or AFEX-treated wheat straw with or without exogenous fibrolytic enzymes [0 or 500 μg of protein/g straw dry matter (DM)]. Fibrolytic enzymes were applied to straw, prior to sealing in nylon bags. The concentrate mixture was provided in a separate bag within each fermentation vessel. The RUSITECs were adapted for 8 d and disappearance of DM, neutral detergent fiber (NDF), acid detergent fiber (ADF), and crude protein (CP) was measured after 48 h of incubation. Ammonia fiber expansion increased (P < 0.01) the disappearance of wheat straw DM (69.6 vs. 38.3%), NDF (65.6 vs. 36.8%), ADF (61.4 vs. 36.0%), and CP (68.3 vs. 24.0%). Total dietary DM, organic matter (OM), and NDF disappearance was also increased (P ≤ 0.05) by enzymes. Total microbial protein production was greater (P < 0.01) for AFEX-treated (72.9 mg/d) than untreated straw (63.1 mg/d). Total gas and methane (CH4) production (P < 0.01) were also greater for AFEX-treated wheat straw than untreated straw, with a tendency for total gas to increase (P = 0.06) with enzymes. Ammonia fiber expansion increased (P < 0.01) total volatile fatty acid (VFA) production and the molar proportion of propionate, while it decreased (P < 0.01) acetate and the acetate-to-propionate ratio. The AFEX-treated straw had lower relative quantities of fungi, methanogens, and Fibrobacter succinogenes (P < 0.01) and fewer protozoa (P < 0.01) compared to untreated straw. The pH of fermenters fed AFEX-treated straw was lower (P < 0.01) than those fed untreated straw. Both AFEX (P < 0.01) and enzymes (P = 0.02) decreased xylanase activity. There was an enzyme × straw interaction (P = 0.02) for endoglucanase activity. Enzymes increased endoglucanase activity of AFEX-treated wheat straw, but had no effect on untreated straw. The addition of enzymes lowered the relative abundance of Ruminococcus flavefaciens, but increased F. succinogenes. These results indicate that AFEX increased the ruminal disappearance of wheat straw and improved fermentation and microbial protein synthesis in the RUSITEC.


Prenatal sonographic diagnosis of congenital ductus arteriosus aneurysm: a case report.
The objective of this report was to demonstrate prenatal sonographic features of congenital ductus arteriosus aneurysm (DAA), a rare, but possibly fatal abnormality. It is characterized by a saccular or fusiform dilatation of the ductus arteriosus. The majority of affected neonates are clinically asymptomatic and tend to progressively diminish in size of DAA and spontaneous closure. However, serious complications can occur during waiting periods, including spontaneous rupture or thromboembolism. A 35 year-old Thai woman, G2P1, underwent ultrasound examination at 34 weeks' gestation. Fetal echocardiography revealed markedly enlarged and tortuous ductus arteriosus with saccular dilation at the distal end, just before joining the descending aorta. The cross-sectional diameter of the saccular portion of the ductus arteriosus was 10 mm. The active female baby was vaginally delivered at 34 weeks' gestation, weighing 1050 grams. Postnatal echocardiography confirmed the prenatal findings. The DAA was gradually decreased in size and finally spontaneously closed without medical or surgical intervention.


Spousal role and caregiver burden in HIV affected families in Anhui Province, China.
This study examined the burden experienced by various roles of family caregivers of people living with HIV (PLH), in particular spouses vs. non-spouses. A total of 475 family members of PLH were recruited from Anhui Province, China. Participants responded to a survey using the Computer Assisted Personal Interview method. The assessment collected data on demographic characteristics and their perceived caregiver burden, which was compared between spouses and non-spouses. Multiple regression models were built to identify factors associated with caregiver burden. About 64.4% of our study participants were female and the mean age was 42.1 years. Among various relationships to PLH, almost half reported being a spouse. Spouses reported significantly higher caregiver burden than non-spouses. In addition, older age and lower family income were significantly associated with higher level of caregiver burden. Among the subsample of spouses, significantly higher level of caregiver burden was identified among wives. Future studies should give special consideration to address the needs of female spouses in order to reduce their caregiver burden.


Cell-Free Total Biosynthesis of Plant Terpene Natural Products using an Orthogonal Cofactor Regeneration System.
Here we report the one-pot, cell-free enzymatic synthesis of the plant monoterpene nepetalactol starting from the readily available geraniol. A pair of orthogonal cofactor regeneration systems permitted NAD+-dependent geraniol oxidation followed by NADPH-dependent reductive cyclization without isolation of intermediates. The orthogonal cofactor regeneration system maintained a high ratio of NAD+ to NADH and a low ratio of NADP+ to NADPH. The overall reaction contains four biosynthetic enzymes, including a soluble P450; and five accessory and cofactor regeneration enzymes. Furthermore, addition of a NAD+-dependent dehydrogenase to the one-pot mixture led to ~1 g/L of nepetalactone, the active cat- attractant in catnip.


Improving the timeliness and completeness of childhood vaccination through color-coded bracelets: a pilot study among Fulani tribe populations in Nigeria.
Childhood immunization remains one of the most cost-effective public health interventions. Globally, millions of children are not being reached with safe and effective vaccines and Nigeria has the highest number of unprotected children. The effects of locally adapted interventions on vaccination timeliness and completeness were studied amongst Fulani populations across 6 health facilities in 2 districts of Bauchi State, Nigeria. The intervention group consisted of newborns who received 5-color-coded bracelets representing different immunization contacts, while the control group had no bracelets. Vaccination rates across contacts were followed for 11 months. In addition, mothers of children in the intervention group were voluntarily recruited as peer-to-peer mobilizers (PPM). In this study, 435 children were studied. Vaccination completeness was higher in the intervention group compared to the control group at all contacts during follow-up. The difference was most noticeable at the fifth contact, with 158/256 (62%) children in the intervention group completing, compared to 73/179 (41%) in the control group (P<0.0001). Vaccination timeliness was better in the intervention group compared to the control one, which reached statistical significance at the second and third vaccination contacts (P<0.05). 68% of women volunteered as PPM and recruited 82 additional children for vaccination. This study demonstrated the feasibility of a composite intervention (bracelets and PPM) to increase the completeness and timeliness of childhood immunization and provided preliminary evidence for its efficacy among Fulani populations in Nigeria. Findings from this pilot study should be confirmed through a larger cluster randomized controlled trial.


2'-Amino-3-methoxypyrimidino[5',4':16,17]estra-1,3,5(10),16-tetraene.
In the title compound, C21H25N3O, the six-membered ring that is fused to two other six-membered rings in the estrane moiety adopts an envelope conformation. The compound shows intermolecular hydrogen bonding of the amine group to an N atom of the pyrimidine moiety, as well as weak intermolecular interactions involving H atoms in the hydrophobic residue of the molecule.


Predictive and protective autoimmunity in cardiovascular diseases: is vaccination therapy a reality?
The role of the immune system in modulating atherosclerosis has recently been well documented. Studies have revealed that cellular and humoral immunity plays crucial roles in atherogenic plaque formation. This includes macrophages, CD4+ T cells and dendritic cells as well as autoantigens such as oxidized low density lipoprotein (oxLDL), heat shock proteins and beta2-glycoprotein I. Given these recent advances, various modifications of the immune system in experimental models have been proposed as therapeutic strategies, with the potential of inhibiting atherosclerosis progression. These modifications are switching the immune system (CD4+ T cells) from Th1 towards a Th2 anti-inflammatory cytokine secretion, and the induction of protective antibodies both of which may be induced by specific vaccination. Recent identification of specific immunoreactive antigenic epitopes on modified LDL, their successful implementation for immunization and the induction of atheroprotection, supports the idea that active vaccination may emerge as a novel immuno-modulating atheroprotective strategy.


Amyloid-β Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease.
The mechanisms leading to amyloid-β (Aβ) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Aβ plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Aβ precursor protein (APP) were transfected with Testican-1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Aβ40 and Aβ42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Aβ accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Aβ species.


Regulation of presynaptic cellular function. Biochemical studies using clonal neuronal cells.
Experiments from several different laboratories are reviewed in which clonal neuronal cell lines are being used to study neuronal cellular functions. Primary emphasis is placed on two cell lines, the neuroblastoma X glioma hybrid clone NG108-15 and the pheochromocytoma clone PC12. These particular cell lines are useful because they display many of the properties normally associated with differentiated neurons. The properties which have been studied include: the regulation of adenylate cyclase and the receptors which activate or inhibit its activity, regulation of the cholinergic properties of NG 108-15 and both adrenergic and cholinergic properties of PC12, the response of PC12 to nerve growth factor, and the regulation of synaptogenesis between NG 108-15 cells and cultured muscle. The goal of the review is to not only summarize the information obtained with these two cell lines but also to emphasize the types of research in which clonal cell lines may be most useful in the future.


Painful nail lesions.
A man, 58 years of age, presented with a 4 year history of painful lesions of his nails. His previous history included hypertension, diabetes mellitus and hyperlipidaemia. These were treated with enalapril, metformin and simvastatin respectively. He also had asymptomatic skin lesions for over 15 years that had worsened in the past 4 years. His father had similar nail lesions that had been diagnosed as onychomycosis.


In vivo characterization of 3D-printed polycaprolactone-hydroxyapatite scaffolds with Voronoi design to advance the concept of scaffold-guided bone regeneration.
Three-dimensional (3D)-printed medical-grade polycaprolactone (mPCL) composite scaffolds have been the first to enable the concept of scaffold-guided bone regeneration (SGBR) from bench to bedside. However, advances in 3D printing technologies now promise next-generation scaffolds such as those with Voronoi tessellation. We hypothesized that the combination of a Voronoi design, applied for the first time to 3D-printed mPCL and ceramic fillers (here hydroxyapatite, HA), would allow slow degradation and high osteogenicity needed to regenerate bone tissue and enhance regenerative properties when mixed with xenograft material. We tested this hypothesis in vitro and in vivo using 3D-printed composite mPCL-HA scaffolds (wt 96%:4%) with the Voronoi design using an ISO 13485 certified additive manufacturing platform. The resulting scaffold porosity was 73% and minimal in vitro degradation (mass loss <1%) was observed over the period of 6 months. After loading the scaffolds with different types of fresh sheep xenograft and ectopic implantation in rats for 8 weeks, highly vascularized tissue without extensive fibrous encapsulation was found in all mPCL-HA Voronoi scaffolds and endochondral bone formation was observed, with no adverse host-tissue reactions. This study supports the use of mPCL-HA Voronoi scaffolds for further testing in future large preclinical animal studies prior to clinical trials to ultimately successfully advance the SGBR concept.


Vitamin D3 metabolism in a pig strain with pseudo vitamin D-deficiency rickets, type I.
Vitamin D metabolism was studied in the 'Hannover Pig', a strain which suffers from pseudo vitamin D-deficiency rickets, type I. Animals of this strain are known to be devoid of renal 25-hydroxyvitamin D3-1 alpha-hydroxylase and -24-hydroxylase activities. Pigs with florid rickets and hypocalcaemia were treated with single im injections of 0.25 to 1.25 mg of vitamin D3, doses that have been shown in previous studies to be effective in producing transient healing of rachitic symptoms. The levels of vitamin D3 and its most relevant physiological metabolites in plasma were estimated at intervals before and after this vitamin D3 treatment. Vitamin D3 rose from 14.8 +/- 8.1 to 364 +/- 190 nmol/l (mean +/- SD) 2 to 3 days post injectionem, 25-hydroxyvitamin D3 from 131.0 +/- 46.2 to 1068 +/- 160 nmol/l within 7 days post injectionem. The 1 alpha, 25-dihydroxyvitamin D3 concentration in plasma was elevated from 73.9 +/- 25.0 to 281 +/- 168 pmol/l 2 to 3 days post injectionem and declined continually from that time. 24R,25-dihydroxyvitamin D3 and 25S,26-dihydroxyvitamin D3 levels after treatment showed different responses in different animals being either elevated or unchanged. Clinical healing of the pigs with these doses of vitamin D3 was attributed to the transient rise of 1 alpha,25-dihydroxyvitamin D3 in plasma. It was assumed that 1 alpha,25-dihydroxyvitamin D3 synthesis takes place under these circumstances in extrarenal tissues.


Photo-response of water intercalated Ti3C2O2 MXene.
Two-dimensional (2D) transition metal carbides, nitrides, and carbonitrides (MXenes) have drawn a lot of attention because of their unique physicochemical properties. Recent experimental and theoretical findings reveal that water intercalation in MXene results in surface reconstruction and hydrolysis. In the current study, we investigated the electronic and optical characteristics of the water-intercalated Ti3C2O2 MXene using first-principles quantum simulations via density functional theory (DFT) and time-dependent density functional theory (TD-DFT). We show that water intercalation impacts the electronic states close to the Fermi level, which has a considerable effect on the electronic and optical properties of Ti3C2O2 MXene. Importantly, we linked hydrolysis with the changes in the HOMO and LUMO states and with the optical properties. The findings in this study contribute to a better understanding of the photo-response of the water-intercalated MXene.


Cimetidine and placebo-cimetidine in the treatment of patients with chronic gastric ulcer (a multiclinical randomized double-blind comparative study).
The efficacy of a 4-week cimetidine treatment was examined by a double-blind randomized study in 37 outpatients with endoscopically verified chronic gastric ulcer. The patients received a daily dose of 3 times 1 tablet and, at night before going to bed 2 more tablet, thus a total amount of 1 g cimetidine, or cimetidine-placebo, but in case of complaints they could take in addition a mixed alkaline powder. Patients not recovering in response to a 4-week treatment, were then administered daily 5 tablets of cimetidine up to their complete recovery. Endoscopic, laboratory and clinical examinations were carried out every other week. As a result of a 4-week treatment, 56% of the cimetidine group recovered. The difference was not significant (P less than 0.2). The size of the ulcer and the intensity of the complaints were reduced significantly in both groups. The decrease in the size of the ulcer was significantly greater in the first two weeks of cimetidine treatment than in the cimetidine-placebo group (P less than 0.05). This favourable dynamics of ulcer healing was not felt in the second two weeks of treatment, and after four weeks there was no difference in the size of the residual ulcer to between the two groups. Cimetidine seemed to be a suitable drug for treating chronic gastric ulcer, since its healing rate proved to be better than that of placebo, the gain in weight also was favourable and there were no side-effects.


Sesquiterpenes and aliphatic diketones from cultures of the basidiomycete Conocybe siliginea.
Five new tremulane-type sesquiterpenes, 11,12-dihydroxy-1-tremulen-5-one (1), 11,12-epoxy-12beta-hydroxy-1-tremulen-5-one (2), 5alpha,12-dihydroxy-1-tremulen-11-yl 2(S)-pyroglutamate (3), 2alpha,11-dihydroxy-1(10)-tremulen-5,12-olide (4), and 10beta,11-dihydroxy-5,6- seco-1,6(13)-tremuladien-5,12-olide (5), as well as three new aliphatic diketones, 2,3-dihydroxydodecane-4,7-dione (9 and 10) and 1-hydroxydecane-2,5-dione (11), together with three known sesquiterpene analogues, tremulenediol A (6), conocenol B (7), and conocenolide A (8), were isolated from cultures of the basidiomycete Conocybe siliginea.


De novo transcriptome sequencing and analysis of the juvenile and adult stages of Fasciola gigantica.
Fasciola gigantica is regarded as the major liver fluke causing fasciolosis in livestock in tropical countries. Despite the significant economic and public health impacts of F. gigantica there are few studies on the pathogenesis of this parasite and our understanding is further limited by the lack of genome and transcriptome information. In this study, de novo Illumina RNA sequencing (RNA-seq) was performed to obtain a comprehensive transcriptome profile of the juvenile (42days post infection) and adult stages of F. gigantica. A total of 49,720 unigenes were produced from juvenile and adult stages of F. gigantica, with an average length of 1286 nucleotides (nt) and N50 of 2076nt. A total of 27,862 (56.03%) unigenes were annotated by BLAST similarity searches against the NCBI non-redundant protein database. Because F. gigantica needs to feed and/or digest host tissues, some proteases (including cysteine proteases and aspartic proteases), which play a role in the degradation of host tissues (protein), have been paid more attention in the present study. A total of 6511 distinct genes were found differentially expressed between juveniles and adults, of which 3993 genes were up-regulated and 2518 genes were down-regulated in adults versus juveniles, respectively. Moreover, stage-specific differentially expressed genes were identified in juvenile (17,009) and adult (6517) F. gigantica. The significantly divergent pathways of differentially expressed genes included cAMP signaling pathway (226; 4.12%), proteoglycans in cancer (256; 4.67%) and focal adhesion (199; 3.63%). The transcription pattern also revealed two egg-laying-associated pathways: cGMP-PKG signaling pathway and TGF-β signaling pathway. This study provides the first comparative transcriptomic data concerning juvenile and adult stages of F. gigantica that will be of great value for future research efforts into understanding parasite pathogenesis and developing vaccines against this important parasite.


Artificial allosteric receptors.
Cooperative effects in the binding of two or more substrates to different binding sites of a receptor that are a result of a conformational change caused by the binding of the first substrate--also referred to as the effector--are called allosteric effects. In biological systems, allosteric regulation is a widely used mechanism to control the function of proteins and enzymes in cellular metabolism. Inspired by this a lot of efforts have been made in supramolecular chemistry to implement this concept into artificial systems to control functions as molecular recognition, signal amplification, or even reactivity and catalysis. This review gives an up-to-date overview over the different approaches that have been reported ever since the first examples from the late 1970s/early 1980s. It covers both homo- and heterotropic examples and is divided according to the nature of the effector--cationic, anionic, or neutral--effectors and systems that use combinations of those.


Orbital metastasis from medullary thyroid carcinoma.
A 46-year-old woman with known multiple endocrine neoplasia type 2A was referred for evaluation of left-sided progressive diplopia and proptosis. She was given the presumptive diagnosis of progressive thyroid-associated orbitopathy. Clinical examination revealed significant proptosis and restricted motility of the left eye. Serial CT demonstrated a marked progression in size of the left inferior rectus muscle. This was postulated to be a rare case of metastasis of a medullary thyroid carcinoma to the left inferior rectus muscle, which was confirmed by lateral orbitotomy and excisional biopsy. The presence of unilateral proptosis raises the possibility of intraorbital or intracranial disease and warrants further investigation. Detection of metastases and subsequent surgical excision or debulking has palliative benefits, including prevention of compression or invasion of major structures and cooperative planning with oncology and participation in treatment regimens that may prove beneficial in patients with metastatic medullary thyroid carcinoma.


Redox Potentials for Tetraplatin, Satraplatin, Its Derivatives, and Ascorbic Acid: A Computational Study.
Redox potentials of the Pt(IV) complexes, such as satraplatin, tetraplatin, and several others, are determined at the density functional theory (DFT) level (with B3LYP, ω-B97XD, PBE1PBE, TPSSTPSS, M06-L, M11-L, and MN12-L functionals) and compared with post-Hartree-Fock methods MP2 and CCSD(T). Calculations are performed in water solution employing an implicit solvation model. The impact of replacement of a chloro ligand by a water molecule (hydration in the equatorial plane of the complexes) is also explored. Furthermore, an influence of solvent pH on the magnitude of the redox potentials is discussed for such hydrated complexes. The obtained results are compared with available experimental data leading to a root-mean-square deviation (RMSD) of ca. 0.23 V, using the CCSD(T)/6-31+G(d)/IEF-PCM/scaled-UAKS level. Distribution of the electron density is analyzed at the B3LYP/6-311++G(2df,2pd) level. Also, a correlation between binding energies of axial ligands and the redox potential is demonstrated. Since the Pt(IV) complexes are considered in the framework of anticancer treatment, possible reducing agents in bioenvironment are searched. From this reason, the reduction potential of different protonation states of ascorbic acid is also presented.


CD40 Ligand Is Increased in Mast Cells in Psoriasis and Actinic Keratosis but Less So in Epithelial Skin Carcinomas.
The expression of CD40 ligand (CD40L) in mast cells was investigated in biopsies from lesional and non-lesional skin samples of patients with psoriasis, actinic keratosis (AK), basal cell carcinoma, and squamous cell carcinoma using a sequential double-staining technique. The percentage of CD40L+ mast cells was higher in the lesional than in the non-lesional skin (p < .003). Interestingly, this percentage was lower in both carcinomas than in psoriasis and actinic keratosis (p < .025). Cells immunopositive for CD40 receptor were increased in all lesion types but especially so in carcinomas. The results suggest a dysregulated anti-tumoral immune response by mast cell CD40L in skin carcinomas.


Evaluating optimal therapy robustness by virtual expansion of a sample population, with a case study in cancer immunotherapy.
Cancer is a highly heterogeneous disease, exhibiting spatial and temporal variations that pose challenges for designing robust therapies. Here, we propose the VEPART (Virtual Expansion of Populations for Analyzing Robustness of Therapies) technique as a platform that integrates experimental data, mathematical modeling, and statistical analyses for identifying robust optimal treatment protocols. VEPART begins with time course experimental data for a sample population, and a mathematical model fit to aggregate data from that sample population. Using nonparametric statistics, the sample population is amplified and used to create a large number of virtual populations. At the final step of VEPART, robustness is assessed by identifying and analyzing the optimal therapy (perhaps restricted to a set of clinically realizable protocols) across each virtual population. As proof of concept, we have applied the VEPART method to study the robustness of treatment response in a mouse model of melanoma subject to treatment with immunostimulatory oncolytic viruses and dendritic cell vaccines. Our analysis (i) showed that every scheduling variant of the experimentally used treatment protocol is fragile (nonrobust) and (ii) discovered an alternative region of dosing space (lower oncolytic virus dose, higher dendritic cell dose) for which a robust optimal protocol exists.


Glucosamine inhibits lipopolysaccharide-stimulated inducible nitric oxide synthase induction by inhibiting expression of NF-kappaB/Rel proteins at the mRNA and protein levels.
Expression of inducible nitric oxide synthase (iNOS) protein by lipopolysaccharide (LPS) in BV2 microglia cells increased in a biphasic manner. Glucosamine (GlcN) selectively suppressed the late- but not early-stage iNOS response to LPS. Prolonged induction of iNOS expression by LPS was inhibited by cycloheximide, suggesting that de novo protein synthesis was required. Late-phase activation of nuclear factor-kappaB (NF-κB) activity required for sustained iNOS induction. Nuclear translocation and DNA binding of NF-κB, and Rel proteins expressions were inhibited by GlcN at later time points but not upon immediate early-stage activation by LPS. We show that GlcN selectively inhibits sustained iNOS induction by inhibiting Rel protein expression at both the mRNA and protein levels; such expression is required for prolonged iNOS induction by LPS. Our results provide mechanistic evidence that GlcN regulates inflammation, represented by iNOS. The implication of these results is that GlcN may be a potent transcriptional regulator of iNOS and other genes involved in the general inflammation process.