Normal induction but attenuated progression of germinal center responses in BAFF and BAFF-R signaling-deficient mice.
The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell-activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF-/-) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF-/- mice, these responses are not sustained. In BAFF-/- mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.


[Predictive genetic testing for hereditary breast cancer and hereditary nonpolyposis colorectal cancer].
Genetic tests are no longer used exclusively for diagnostic purposes, but they serve in increasing numbers to assess the predisposition for illnesses. Predictive genetic testing of this kind includes screening for genetic predispositions towards tumours. Of special significance are familial breast and ovarian cancer caused by BRCA1 - and BRCA2- mutations and hereditary nonpolyposis colorectal cancer (HNPCC). The observation of such conditions constitutes a considerable burden for the individuals concerned as well as their families. So far it has not been sufficiently established to what extent methods of prevention and early diagnosis can offer effective protection against the risk of tumours. While prophylactic organ resections lower the morbidity and mortality associated with cancer, they are also responsible for a loss of physical and emotional well-being. Therefore, an awareness of hereditary predispositions towards tumours causes considerable need for competent medical advice and clinical research. Interdisciplinary projects can offer the suitable organisational base for these tasks. Doctors, universities and health insurances are faced with the challenge of developing and financing corresponding structures of medical care and research.


cis-acting translational effects of the 5' noncoding region of c-myc mRNA.
We have previously shown that the 5' noncoding region of mouse c-myc mRNA has a negative effect on translational efficiency in a rabbit reticulocyte lysate (A. Darveau, J. Pelletier, and N. Sonenberg, Proc. Natl. Acad. Sci. USA 82:2315-2319, 1985). We wanted to localize and characterize the inhibitory translational element(s) in the mRNA and to study its effect in other in vitro and in vivo systems. Here we report that the restrictive element is confined to a 240-nucleotide sequence of the 5' noncoding region of mouse c-myc mRNA and that this sequence acts in cis to inhibit the translation of a heterologous mRNA. In addition, we report that the cis-inhibitory effect is also exhibited in microinjected Xenopus oocytes and wheat-germ extracts but not in HeLa cell extracts. Transfection of corresponding plasmid DNA constructs into several established cell lines did not produce the cis-inhibitory effect. A model to explain these results is presented.


Infection and expression of Toll-like receptors in lymphoid malignancy patients after autologous stem cell transplantation.
High-dose chemotherapy with autologous stem cell transplantation (ASCT) is one of the main strategies for the treatment of haematological neoplasms. Infections are the most common cause of morbidity and mortality from the ASCT procedure. However, it is challenging to predict when these complications are likely to arise. Toll-like receptors (TLRs) are present on various immune cells and play a broad role in immune surveillance. The aim of the study was to investigate the association between the expression of TLR genes and the occurrence of infections in patients treated with ASCT. TLR expression was analysed in 60 patients who underwent ASCT. The median age was 54 years. Blood samples were taken before high-dose chemotherapy and at the time of haematopoietic recovery after ASCT. The expression of Toll-like receptor 4 (TLR4) was significantly higher in patients before ASCT than after transplantation. The expression of Toll-like receptor 9 (TLR9) was significantly higher in patients after ASCT than before transplantation. The expression of TLR9 and TLR4 at the start of the procedure was significantly lower in patients who went on to develop a bacterial infection after ASCT. Moreover, we also observed a significant positive correlation between the expression of TLR9 and neutrophil recovery time after ASCT. Our findings suggest that TLRs could be useful biomarkers to predict and monitor infections in patients treated with ASCT.


TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2-Mediated Immunopathology.
Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis.


[Leukocyte indices of patients with bronchial asthma: informative significance of use].
Determination of informativeness of leukocyte indices in patients with bronchial asthma, who have comorbid diseases in clinical remission of asthma. The work based on a single examination of 225 patients with bronchial asthma. Criteria for inclusion in the study are following: the presence of a verified diagnosis of bronchial asthma, the phase of clinical remission. The patients have been divided into 4 groups, taking into account the type of comorbid diseases: the 1 group (53 patients) bronchial asthma was combined with lesions of the upper gastrointestinal tract; the 2 group (73 patients) with allergic rhinitis; the 3 group (76 patients) with hypertension; the 4 group (23 patients) comparison group: the patients without comorbid pathology. According to the clinical blood analysis, 10 leukocyte indices were calculated for each group of patients and their values were analyzed taking into account the frequency and severity of deviations from the reference values. Mathematical processing of the material was carried out using the statistical software package SPSS13.0 for Windows. Using leukocyte indices, it has been revealed that even during the period of clinical remission, almost all examined patients with BA have endogenous intoxication, the severity of which increases in comorbid diseases. Intoxication was inflammatory in nature and, according to the data of leukocyte indices, was due to the presence of persistent inflammation (local and systemic) and during clinical remission. Violation of immunological reactivity has been revealed in most of the examined patients. The presence of correlation relationships of leukocyte indices with a number of biochemical and immunological indicators allows one to exclude the latter from the plan of examination of patients without reducing the quality of their examination: for example, in the conditions of polyclinics, small hospitals, and resorts. Eight leukocyte indices that are the most informative at BA have been selected. Additional information about the condition of BA patients who have comorbid diseases during clinical remission can be used to develop programs for their comprehensive treatment and rehabilitation.


Interactions between local anesthetics and spasmogens on the guinea-pig ileum.
The effect of various local anesthetics and other substances known to modify calcium fluxes in cells, on submaximal responses of guinea-pig ileum to substance P, acetylcholine, histamine and barium chloride was determined. Procaine caused a dose-related depression of the response to all the agonists but the response to substance P was far less susceptible to this depression. Lidocaine, bupivacaine, pramoxine and W 6211 also caused a lower degree of attenuation of the response to substance P than the responses to acetylcholine, histamine and barium chloride. Verapamil caused a dose-related depression of responses to all the agonists equally. The use of calcium-free solutions abolished responses to substance P, acetylcholine and histamine. The response to barium chloride was less affected by calcium withdrawal but was reduced markedly. In the presence of 10 mM lanthanum chloride, the response to all the agonists was abolished. The relative resistance of the substance P responses to antagonism by local anesthetics suggests that different and more efficient channels for calcium entry into the smooth muscle cell are involved.


A cell type annotation Jamboree-Revival of а communal science forum.
Cell Atlases are currently being constructed for human tissues as well as several model organisms. New technologies make creation of vast datasets in many species possible, but the value of such data crucially depends on the quality of annotation. The tools of annotating single cell data and creating knowledge representations comparable across organisms have been lagging. We argue that successfully creating Cell Atlases will require a revival of a boot-camp style forum for communal annotation combined with an intensive learning workshop, dubbed a "Jamboree". We report on our experience of successfully developing a structure and curriculum and running such a Jamboree for Xenopus Embryonic Cell Types at the Janelia Farms campus of the Howard Hughes Medical Institute.


Anaphylactic reaction to cytarabine: in vitro evidence that the response is immunoglobulin E mediated.
A 48-year-old female developed significant bronchospasm on two occasions after being treated with cytarabine (Ara-C) by the intraperitoneal route. In this report we present the first in vitro evidence that such a reaction to cytarabine can be associated with the release of histamine and therefore might be immunoglobulin E (IgE) mediated. In addition, this report emphasizes the fact that, while uncommon, severe allergic reactions to this useful chemotherapeutic agent do occur and must be considered in the differential diagnosis of anaphylaxis and related symptoms in patients receiving this drug.


A Cross-Sectional Study of the Relationship of Physical Activity with Depression and Cognitive Deficit in Older Adults.
The aim of this study was to examine the association of physical activity with depression and cognition deficit, separately and combined, in Brazilian older adults. We analyzed data from 622 older adults. Physical activity was assessed using the International Physical Activity Questionnaire. Depressive symptoms were assessed using the Geriatric Depression Scale, while cognitive deficit was assessed using the Mini-Mental State Examination. Multinomial logistic regressions were used to assess associations of depression and cognitive deficit with sociodemographic, health, and behavioral variables. Prevalence of physical inactivity (< 150 min of moderate-to-vigorous physical activity/ week), depression, and cognitive deficit were 35.7%, 37.4%, and 16.7%. Physical inactivity was associated with depression (OR: 1.83, 95% CI: 1.14-2.94) and with depression and cognitive deficit combined (OR: 4.23, 95% CI: 2.01-8.91). Physically inactive participants were also more likely to present limitations in orientation and language functions. Physical inactivity was associated with depression and also with depression and cognitive deficit combined in older adults.


The Insect Pathogens.
Fungi are the most common disease-causing agents of insects; aside from playing a crucial role in natural ecosystems, insect-killing fungi are being used as alternatives to chemical insecticides and as resources for biotechnology and pharmaceuticals. Some common experimentally tractable genera, such as Metarhizium spp., exemplify genetic diversity and dispersal because they contain numerous intraspecific variants with distinct environmental and insect host ranges. The availability of tools for molecular genetics and multiple sequenced genomes has made these fungi ideal experimental models for answering basic questions on the genetic and genomic processes behind adaptive phenotypes. For example, comparative genomics of entomopathogenic fungi has shown they exhibit diverse reproductive modes that often determine rates and patterns of genome evolution and are linked as cause or effect with pathogenic strategies. Fungal-insect pathogens represent lifestyle adaptations that evolved numerous times, and there are significant differences in host range and pathogenic strategies between the major groups. However, typically, spores landing on the cuticle produce appressoria and infection pegs that breach the cuticle using mechanical pressure and cuticle-degrading enzymes. Once inside the insect body cavity, fungal pathogens face a potent and comprehensively studied immune defense by which the host attempts to eliminate or reduce an infection. The Fungal Kingdom stands alone in the range, extent, and complexity of their manipulation of arthropod behavior. In part, this is because most only sporulate on cadavers, so they must ensure the dying host positions itself to allow efficient transmission.


Ocular immunology in equine recurrent uveitis.
Equine recurrent uveitis (ERU) is a disease with high prevalence and relevance for the equine population, since it results in blindness. Over the last decade, important advancements have been made in our understanding of the underlying immune responses in this disease. ERU is mediated by an autoaggressive Th1 response directed against several retinal proteins. Interphotoreceptor-retinoid binding protein (IRBP) and cellular retinaldehyde-binding protein (CRALBP) are capable to induce ERU-like disease in experimental horses, with the unique possibility to activate relapses in a well-defined manner. Further, proteomic evidence now suggests that retinal Mueller glial cells (RMG) may play a fatal role in uveitic disease progression by directly triggering inflammation processes through the expression and secretion of interferon-gamma. Ongoing relapses in blind eyes can be associated with stable expression of the major autoantigens in ERU retinas. This review briefly summarizes the most significant developments in uveitis immune response research.


An Updated Systematic Review and Meta-Analysis on the Helicobacter pylori Antibiotic Resistance in Iran (2010-2020).
This updated systematic review and meta-analysis followed two objectives: (1) to determine Helicobacter pylori antibiotic resistance in Iran during 2010-2020 and (2) to assess the trend of resistance from 1997 to 2020. A systematic search in multiple databases, including ISI Web of Knowledge, PubMed, Scopus, Google Scholar, and the Scientific Information Database (SID), was performed using MeSH-extracted keywords. Meta-analysis was done on extracted data from a total of 27 included citations published between 2010 and January 20, 2020. The overall mean prevalence of H. pylori resistance was 64.9% for metronidazole, 25.3% for clarithromycin, 20.7% for amoxicillin, 16.1% for tetracycline, 21.9% for levofloxacin, 22.8% for rifampicin, 27.2% for furazolidone, 32.3% for ciprofloxacin, and 38.7% for erythromycin. In addition, the prevalence of multidrug-resistant strains of H. pylori was 26.5% in Iran. The pooled prevalence of point mutations A2143G, A2142G, and A2142C associated with clarithromycin resistance were 46.6%, 37.2%, and 5.5%, respectively; mutations in frxA and rdxA genes associated with metronidazole resistance were 46.4% and 19.7%, respectively; gyrA and gyrB genes mutations among fluoroquinolone-resistant strains were 55.3% and 48.2%, respectively; and resistance associated with integrons was 47%. According to the present findings, resistance of H. pylori to antibiotics used for eradication therapy has reached an alarming level in Iran. Furthermore, the trend of H. pylori resistance has increased between 1997 and 2020. Hence, continuous surveillance on resistance patterns, logical prescription and appropriate consumption of antibiotics, and selecting effective therapeutic regimens in accordance with local resistance patterns are required to prevent further spread of resistance and ensuing treatment failures.


An Enzymatic 2-Step Cofactor and Co-Product Recycling Cascade towards a Chiral 1,2-Diol. Part I: Cascade Design.
Alcohol dehydrogenases are of high interest for stereoselective syntheses of chiral building blocks such as 1,2-diols. As this class of enzymes requires nicotinamide cofactors, their application in biotechnological synthesis reactions is economically only feasible with appropriate cofactor regeneration. Therefore, a co-substrate is oxidized to the respective co-product that accumulates in equal concentration to the desired target product. Co-product removal during the course of the reaction shifts the reaction towards formation of the target product and minimizes undesired side effects. Here we describe an atom efficient enzymatic cofactor regeneration system where the co-product of the ADH is recycled as a substrate in another reaction set. A 2-step enzymatic cascade consisting of a thiamine diphosphate (ThDP)-dependent carboligase and an alcohol dehydrogenase is presented here as a model reaction. In the first step benzaldehyde and acetaldehyde react to a chiral 2-hydroxy ketone, which is subsequently reduced by to a 1,2-diol. By choice of an appropriate co-substrate (here: benzyl alcohol) for the cofactor regeneration in the alcohol dehydrogenases (ADH)-catalyzed step, the co-product (here: benzaldehyde) can be used as a substrate for the carboligation step. Even without any addition of benzaldehyde in the first reaction step, this cascade design yielded 1,2-diol concentrations of >100 mM with optical purities (ee, de) of up to 99%. Moreover, this approach overcomes the low benzaldehyde solubility in aqueous systems and optimizes the atom economy of the reaction by reduced waste production. The example presented here for the 2-step recycling cascade of (1R,2R)-1-phenylpropane-1,2-diol can be applied for any set of enzymes, where the co-products of one process step serve as substrates for a coupled reaction.


Nifedipine attenuates systemic and renal vasoconstriction during nitric oxide inhibition in humans.
Clinical states associated with nitric oxide deficiency are often accompanied by vasoconstriction. We studied the effects of prolonged infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on systemic and renal hemodynamics in humans and the reversibility of the established vasoconstriction by calcium channel blockade with nifedipine. Seven healthy men underwent three 7-hour clearance studies. During one study, L-NMMA (3 mg/kg priming dose plus 3 mg.kg-1.h-1) was infused during hours 2 through 5, and during another study, nifedipine (0.015 mg/kg priming dose plus 0.015 mg.kg-1.h-1) was coinfused during hours 4 and 5. A third study served as time control. L-NMMA elicited reproducible systemic and renal vasoconstriction that was stable during the 4 hours of infusion. Systemic vascular resistance index, calculated from bioimpedance-derived cardiac index, increased from 22 +/- 1 to 29 +/- 2 mm Hg.min.m2.L-1 (P < .05). Mean arterial pressure rose by 4 +/- 1 mm Hg (P < .05), and heart rate, stroke index, and cardiac index decreased. Renal blood flow, calculated from renal plasma flow, decreased from 1182 +/- 101 to 785 +/- 53 mL/min, and renal vascular resistance increased from 73 +/- 5 to 115 +/- 6 mm Hg.min.L-1 (P < .05). Glomerular filtration rate decreased from 114 +/- 6 to 104 +/- 6 mL/min (P < .05), and filtration fraction increased. Sodium excretion fell from 89 +/- 9 to 32 +/- 7 mumol/min (P < .05). Nifedipine completely reversed systemic vasoconstriction. Nifedipine caused partial restoration of renal vascular resistance and complete normalization of glomerular filtration rate and sodium excretion but left the elevated filtration fraction unaltered. We conclude that sustained nitric oxide deficiency in humans is accompanied by strong systemic and renal vasoconstriction, decreased glomerular filtration rate, and sodium retention. Nifedipine can reverse most of these effects, suggesting a role for calcium channel blockade in pathological states of impaired nitric oxide activity.


Effect of enzyme addition on the performance and gastrointestinal tract size of chicks fed lupin seed and their fractions.
Three experiments were conducted to study the effects of adding a crude enzyme preparation to diets containing whole, dehulled lupins and lupin hulls on performance, dry matter retention (DMR), AME, apparent protein digestibility (APD), and size of gastrointestinal tract of Leghorn and broiler chicks. In the first experiment, Leghorn chicks fed diets containing up to 70% whole lupins showed a depression in the performance. Progressive decreases in DMR (up to 30.2%), AME (up to 6.5%), and APD (up to 6.5%) and an increase in the relative gizzard weight (18.8%) were observed with increasing concentration of lupins (23.1, 46.9, and 70%) in the diet. Enzyme supplementation of diets containing lupins significantly improved the performance of the chicks. DMR and AME were improved by 4.2 and 3.1, respectively, and gizzard size was reduced (7.1%) by addition of the enzymes. In the second experiment, addition of 11.2 and 22.4% of lupin hulls to a dehulled lupin diet resulted in a dramatic depression in chick performance, with values ranging from 6.3% for feed consumption to 60.5% for fed to gain ratio, and an increase in the relative organ weight (up to 29.9%) and length (35.6%). These effects were partially counteracted by the action of enzymes. In the third experiment, increasing concentration of whole lupins (15, 35, and 45%) in broiler chicken diets caused a depression in the performance of birds fed 35 and 45% whole lupins as compared to those fed the wheat-soy diet. In contrast, 15% lupins improved weight gains compared to that obtained with the nonlupin diets. The lower content of lupins in the diet also had no or little effect on other performance values compared to the control group, whereas 35 and 45% dietary lupins tended to have negative effects. Likewise, increasing lupin content in the diet produced an enlargement in the relative size of several sections of the gastrointestinal tract. Enzyme supplementation of lupin diets improved weight gain (5.5%) and feed consumption (3.8%) with the values being similar to those obtained with the wheat-soy diet. Moreover, the enzymes also reduced the relative size of digestive organs from 5.3% for pancreas to 22.2% for crop. In summary, lupins appear to contain fibrous components that reduce the performance of the birds and increase the size of the gastrointestinal tract. The addition of enzymes counteracted these negative effects in birds fed whole, dehulled lupins and lupin hull diets.


High-resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow derived macrophages.
Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in-depth proteomics characterization of phagosomes from RAW 264.7 and bone marrow derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicate that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec-1. Moreover, bone marrow derived macrophages phagosomes mature considerably faster by fusion with endosomes and the lysosome which we validated using fluorogenic phagocytic assays. We provide a valuable resource for researcher in the field and recommend careful use of the RAW 264.7 cell line when studying phagosome functions. All MS data have been deposited in the ProteomeXchange with identifier PXD001293 (http://proteomecentral.proteomexchange.org/dataset/PXD001293).


Direct arylation reactions catalyzed by Pd(OH)2/C: evidence for a soluble palladium catalyst.
[reactions: see text] Palladium hydroxide on carbon (Pearlman's catalyst) effectively catalyzes direct arylation reactions of aryl iodides and bromides, providing excellent arylation-to-hydrodehalogenation ratios (>30:1) with broad scope for both intra- and intermolecular arylation processes. Studies aimed at determining the nature of the active catalyst indicate that an active homogeneous palladium species is produced under the reaction conditions.


The Effect of Pungent and Tingling Compounds from Piper nigrum L. on Background K+ Currents.
Black peppercorns (Piper nigrum L.) elicit a pungent and tingling oral impression. Their pungency is partially explained by the agonist activity of some of their active principles, especially piperine, on TRP channels. However, we recently showed that piperine, as well as other pungent compounds, also possess a marked effect on two-pore domain (KCNK, K2P) K+ channels. Members of this family play a key role in maintaining the resting membrane potential of excitable cells. Interestingly, tingling compounds have been shown to induce neuronal excitation by inhibiting KCNK channels. We addressed the question of whether it was plausible that KCNK channels could constitute a physiologically relevant target for the sensory active compounds present in black peppercorns. Because previous studies have demonstrated that mouse trigeminal neurons respond to several pungent compounds, to which humans are also sensitive, we used a primary culture of mouse trigeminal neurons to investigate whether the effect of piperine on these cell types could also be mediated by KCNK channels. We observed that even in the presence of classical TRP-antagonists, piperine was still able to activate a fraction of trigeminal neurons. Furthermore, our results showed that piperine is capable of inducing neuronal depolarization by a mechanism that does not require extracellular Na+ or Ca2+. This depolarization was mediated by the inhibition of a background K+ conductance, most likely corresponding to the KCNK channels of the TASK subfamily. We then performed a screening with 12 other pungent and/or tingling chemosensates isolated from black peppercorns. These compounds were evaluated on Xenopus laevis oocytes expressing the human orthologues of KCNK3, KNCK9 and KCNK18, which we previously showed to be inhibited by piperine. Remarkably, almost all of the isolated chemosensates inhibited the basal activity of hKCNK3, with 1-(octadeca-2E,4E,13/12Z-trienoyl)pyrrolidine acting as one of the most potent natural blockers for hKCNK3 found to date. Our results suggest that KCNK channels, especially KCNK3, are likely to play a complementary role to TRP channels in the complex orosensory impression elicited by black peppercorns, while they also help to expand the pharmacological knowledge of KCNK channels.


[Susceptibility and resistence of Pseudomonas aeruginosa to antimicrobial agents].
Pseudomonas aeruginosa is an opportunistic microorganism that is frequently the cause of nosocomial infections. Multiple mechanisms are involved in its natural and acquired resistance to many of the antimicrobial agents commonly used in clinical practice. The objective of this study was to assess the susceptibility and resistance patterns of P. aeruginosa strains isolated in Hospital Reina Sofia between 2000 and 2005, as well as to analyze the differences between intrahospital and extrahospital isolates in 2005 and to compare the results with those obtained in other studies. A total of 3,019 strains of P. aeruginosa from different hospitals and nonhospital settings were evaluated, taking into consideration their degree of sensitivity to different antibiotics. The MICs were determined by means of the Wider I automated system (Soria Melguizo), taking into consideration the criteria of susceptibility and resistance recommended by MENSURA. Results of the analysis showed that P. aeruginosa maintained similar levels of antimicrobial susceptibility during the period 2000-2005, with increased susceptibility to amikacin, gentamicin and tobramycin. There were also important differences in the degree of susceptibility between intrahospital and extrahospital strains, except for imipenem and fosfomycin. The intrahospital difference in susceptibility was also evaluated, emphasizing the importance of periodically studying susceptibility and resistance patterns of P. aeruginosa in each setting in order to evaluate different therapeutic guidelines, as it is not always advisable to extrapolate data from different regions. These differences can be explained by the different use of antibiotics in each center and the geographic variations of the resistance mechanisms of P. aeruginosa.


Emergence of Chinese drug discovery research: impact of hit and lead identification.
The identification of hits and the generation of viable leads is an early and yet crucial step in drug discovery. In the West, the main players of drug discovery are pharmaceutical and biotechnology companies, while in China, academic institutions remain central in the field of drug discovery. There has been a tremendous amount of investment from the public as well as private sectors to support infrastructure buildup and expertise consolidation relative to drug discovery and development in the past two decades. A large-scale compound library has been established in China, and a series of high-impact discoveries of lead compounds have been made by integrating information obtained from different technology-based strategies. Natural products are a major source in China's drug discovery efforts. Knowledge has been enhanced via disruptive breakthroughs such as the discovery of Boc5 as a nonpeptidic agonist of glucagon-like peptide 1 receptor (GLP-1R), one of the class B G protein-coupled receptors (GPCRs). Most of the original hit identification and lead generation were carried out by academic institutions, including universities and specialized research institutes. The Chinese pharmaceutical industry is gradually transforming itself from manufacturing low-end generics and active pharmaceutical ingredients to inventing new drugs.


Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
Little is known about the role of chronic gastritis on weight loss after laparoscopic sleeve gastrectomy (LSG). This study aims to investigate the relationship between histopathologic findings of gastric specimens, excess weight loss (% EWL), and excess BMI loss (% EBL) at 6 and 12 months follow up after LSG. We retrospectively reviewed the clinical records of 95 patients who had undergone LSG between January 2017 and December 2019. Based on the histopathological findings of gastric resection specimens, patients were divided into those with chronic gastritis (CG) and those without chronic gastritis (NoCG) and compared for their % EWL and % EBL at 6 and 12 months. The mean BMI was 44.74 kg/m2 in the CG group and 44.14 kg/m2 in the NoCG group. At 6 months follow up, the CG group had a mean % EWL of 45.7 and % EBL of 40.5, while NoCG had a mean % EWL of 51.1 and % EBL of 46.7. After 1-year follow-up, the CG group had a mean % EWL of 53.1 and a % EBL of 44.8, while the NoCG group had a % EWL of 54.1 and % EBL of 44. This observational study does not support the hypothesis that the occurrence of chronic gastritis can affect postoperative % EWL and % EBL.


Chronic modulation of the autoimmune response following parvovirus B19 infection.
We describe 2 patients with prolonged autoimmune alterations following parvovirus B19 infection. B19 induced aplastic crises were the revealing manifestations of asymptomatic hemolytic conditions in the 2 patients: a Coombs' positive hemolytic anemia induced by D-penicillamine in the first and congenital spherocytosis in the second. Both patients had transient clinical and serological manifestations highly suggestive of systemic lupus erythematosus. In addition, prolonged clinical and serological remission of rheumatoid arthritis was observed in the first patient, while arthralgias, FANA, and anti-Ro antibodies persisted in the second, previously healthy patient. Our data suggest that parvovirus B19 infection may lead to chronic modulation of the autoimmune response in predisposed individuals.


[Physical fitness during pregnancy].
In a study of longitudinal section 25 primigravidae were examined during pregnancy on the bicycle ergometer. A group of 10 non-pregnant women in their postmenstrual phase was used as controls. Blood glucose, cholesterol, triglyceride and lactic acid were analysed parameters in addition to cardiorespiratory. The reaction of the cardiovascular system to submaximal load in healthy pregnant women is economic. The metabolic system reacts with an intensified availability of energy via fat-metabolism and a diminished utilisation of glucose. Pregnancy is a physical stimulus for the female organism.


Organ specificity of lymphocyte migration: mediation by highly selective lymphocyte interaction with organ-specific determinants on high endothelial venules.
Evidence is presented that the organ specificity of lymphocyte migration is determined by selective interaction of lymphocytes with specialized endothelial cells. Mouse Peyer's patch and lymph node lymphocytes bind preferentially to high endothelial venules (HEV) in frozen sections of Peyer's patches and peripheral nodes, respectively, and this in vitro binding preference accurately predicts their differential segregation in vivo 30 min after i.v. injection. Both in vivo and in vitro, about 1.4 times as many as many Peyer's patch as lymph node lymphocytes bind HEV in Peyer's patches, and, conversely, twice as many lymph node cells interact with HEV in nonmesenteric lymph nodes. Even greater specificity is shown by certain homogeneous lymphocyte populations, i.e. thymic lymphomas. Some lymphomas bind with remarkable selectivity to HEV in Peyer's patches, and others interact almost exclusively with those in lymph nodes indicating that the mechanisms mediating selective recognition of HEV are capable of nearly absolute discrimination. Mesenteric node HEV are unique in that they allow both Peyer's patch- and lymph node-specific cells to bind. It is proposed that lymphocyte surface receptors specific for organ-restricted endothelial cell determinants mediate the antigen-independent organ specificity of lymphocyte migration. According to this model, there are at least 2 sets of complementary lymphocyte and endothelial cell receptors, one mediating lymphocyte-HEV adherence in Peyer's patches, the other in lymph nodes.


[Ureteroscopic lithotripsy using the laser].
The Cagliari urology team is very satisfied with the use of the dye laser for ureteroscopic lithotripsy. This apparatus is recommended in units possessing a well equipped endourology room, otherwise it is simpler to use endoureteric ballistic lithotripsy, which also provides good results.


Descriptors for predicting the lattice constant of body centered cubic crystal.
The prediction of the lattice constant of binary body centered cubic crystals is performed in terms of first principle calculations and machine learning. In particular, 1541 binary body centered cubic crystals are calculated using density functional theory. Results from first principle calculations, corresponding information from periodic table, and mathematically tailored data are stored as a dataset. Data mining reveals seven descriptors which are key to determining the lattice constant where the contribution of descriptors is also discussed and visualized. Support vector regression (SVR) technique is implemented to train the data where the predicted lattice constants have the mean score of 83.6% accuracy via cross-validation and maximum error of 4% when compared to experimentally determined lattice constants. In addition, trained SVR is successful in predicting material combinations from a desired lattice constant. Thus, a set of descriptors for determining the lattice constant is identified and can be used as a base descriptor for lattice constants of further complex crystals. This would allow for the acceleration of the search for lattice constants of desired atomic compositions as well as the prediction of new materials based on a specified lattice constant.


NLRP1 promotes tumor growth by enhancing inflammasome activation and suppressing apoptosis in metastatic melanoma.
Inflammasomes are mediators of inflammation, and constitutively activated NLRP3 inflammasomes have been linked to interleukin-1β (IL-1β)-mediated tumorigenesis in human melanoma. Whereas NLRP3 regulation of caspase-1 activation requires the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), caspase-1 activation by another danger-signaling sensor NLRP1 does not require ASC because NLRP1 contains a C-terminal CARD domain that facilitates direct caspase-1 activation via CARD-CARD interaction. We hypothesized that NLRP1 has additional biological activities besides IL-1β maturation and investigated its role in melanoma tumorigenesis. NLRP1 expression in melanoma was confirmed by analysis of 216 melanoma tumors and 13 human melanoma cell lines. Unlike monocytic THP-1 cells with prominent nuclear localization of NLRP1, melanoma cells expressed NLRP1 mainly in the cytoplasm. Knocking down NLRP1 revealed a tumor-promoting property of NLRP1 both in vitro and in vivo. Mechanistic studies showed that caspase-1 activity, IL-1β production, IL-1β secretion and nuclear factor-kB activity were reduced by knocking down of NLRP1 in human metastatic melanoma cell lines 1205Lu and HS294T, indicating that NLRP1 inflammasomes are active in metastatic melanoma. However, unlike previous reports showing that NLRP1 enhances pyroptosis in macrophages, NLRP1 in melanoma behaved differently in the context of cell death. Knocking down NLRP1 increased caspase-2, -9 and -3/7 activities and promoted apoptosis in human melanoma cells. Immunoprecipitation revealed interaction of NLRP1 with CARD-containing caspase-2 and -9, whereas NLRP3 lacking a CARD motif did not interact with the caspases. Consistent with these findings, NLRP1 activation but not NLRP3 activation reduced caspase-2, -9 and -3/7 activities and provided protection against apoptosis in human melanoma cells, suggesting a suppressive role of NLRP1 in caspase-3/7 activation and apoptosis via interaction with caspase-2 and -9. In summary, we showed that NLRP1 promotes melanoma growth by enhancing inflammasome activation and suppressing apoptotic pathways. Our study demonstrates a tumor-promoting role of NLRP1 in cancer cells.


Tourette syndrome and the norepinephrine transporter gene: results of a systematic mutation screening.
Tourette syndrome (TS) is a complex inherited neuropsychiatric disorder characterized by multiple motor and phonic tics. Involvement of central norepinephrine mechanisms is suggested by central norepinephrinic hyperactivity in patients with TS and by the therapeutic effects of the presynaptic alpha2-adrenergic agonist clonidine. The norepinephrine transporter gene (NET) was systematically screened by single-strand conformation analysis for genetic variants, including the whole coding region and adjacent exon-intron boundaries in 43 patients with TS and 46 healthy controls. We detected 12 DNA sequence variants, among them four missense mutations (Val69Ile, Thr99Ile, Va1245Ile, and Gly478Ser). The observed missense mutations may alter conformational rearrangements during gating of the transporter, assembly of subunits, and norepinephrine-specific uptake affinity. Allele frequency and genotype distribution of the genetic variants showed no differences between TS patients and controls. No mutation of likely functional significance was found that distinguished TS patients from healthy controls, indicating that genetic variants of the NET gene are not causally related to Tourette syndrome.


Corticosteroid enhances TNF-alpha-mediated leukocyte adhesion to pulmonary microvascular endothelial cells.
Some severe asthma patients are characterized by elevated levels of tumor necrosis factor alpha (TNF-alpha) and neutrophilic inflammation in the airways. Although such phenotypic changes in asthma might contribute to corticosteroid refractoriness, the role of TNF-alpha in the process remains unclear. TNF-alpha exerts its biological effects mainly by acting on the vascular endothelium, and thereby upregulates leukocyte recruitment into inflamed tissues. The aim of this study was to investigate the effects of dexamethasone (DEX) on the TNF-alpha-mediated responses of human microvascular endothelial cells from lung blood vessels (HMVEC-LBl) in vitro. HMVEC-LBl were cultured with TNF-alpha in the presence and absence of DEX. The effects of DEX on various TNF-alpha-mediated responses, such as the expressions of chemokines and cellular adhesion molecules, leukocyte adhesion were determined. TNF-alpha significantly induced growth-related oncogene alpha (GRO-alpha), interleukin 8 (IL-8), regulated on activation, normal T-cell expressed and secreted (RANTES) and interferon-inducible protein 10 (IP-10) productions and cell surface expressions of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on HMVEC-LBl. TNF-alpha-induced GRO-alpha and IL-8 were slightly attenuated by DEX treatment (reaches to 89% and 79%, respectively), whereas expressions of IP-10, ICAM-1 and VCAM-1 were significantly enhanced by the same treatment (up to 172%, 152% and 139%, respectively). Correspondingly, in vitro adhesion of eosinophils and neutrophils to TNF-alpha-treated HMVEC-LBl were significantly enhanced by DEX. Some proinflammatory effects of DEX, a corticosteroid, were found in TNF-alpha-mediated in vitro reactions of pulmonary microvascular endothelial cells, i.e. chemokine productions and leukocyte adhesion. These in vitro results may explain, at least in part, the corticosteroid refractoriness accompanied by a marked increase in TNF-alpha production that is seen in severe asthmatic patients.


Correlation of tissue-plasma partition coefficients between normal tissues and subcutaneous xenografts of human tumor cell lines in mouse as a prediction tool of drug penetration in tumors.
Understanding drug distribution and accumulation in tumors would be informative in the assessment of efficacy in targeted therapy; however, existing methods for predicting tissue drug distribution focus on normal tissues and do not incorporate tumors. The main objective of this study was to describe the relationships between tissue-plasma concentration ratios (Kp ) of normal tissues and those of subcutaneous xenograft tumors under nonsteady-state conditions, and establish regression equations that could potentially be used for the prediction of drug levels in several human tumor xenografts in mouse, based solely on a Kp value determined in a normal tissue (e.g., muscle). A dataset of 17 compounds was collected from the literature and from Genentech. Tissue and plasma concentration data in mouse were obtained following oral gavage or intraperitoneal administration. Linear regression analyses were performed between Kp values in several normal tissues (muscle, lung, liver, or brain) and those in human tumor xenografts (CL6, EBC-1, HT-29, PC3, U-87, MCF-7-neo-Her2, or BT474M1.1). The tissue-plasma ratios in normal tissues reasonably correlated with the tumor-plasma ratios in CL6, EBC-1, HT-29, U-87, BT474M1.1, and MCF-7-neo-Her2 xenografts (r(2) in the range 0.62-1) but not with the PC3 xenograft. In general, muscle and lung exhibited the strongest correlation with tumor xenografts, followed by liver. Regression coefficients from brain were low, except between brain and the glioblastoma U-87 xenograft (r(2) in the range 0.62-0.94). Furthermore, reasonably strong correlations were observed between muscle and lung and between muscle and liver (r(2) in the range 0.67-0.96). The slopes of the regressions differed depending on the class of drug (strong vs. weak base) and type of tissue (brain vs. other tissues and tumors). Overall, this study will contribute to our understanding of tissue-plasma partition coefficients for tumors and facilitate the use of physiologically based pharmacokinetics (PBPK) modeling for chemotherapy in oncology studies. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1355-1369, 2013.


Adult human brain neural progenitor cells (NPCs) and fibroblast-like cells have similar properties in vitro but only NPCs differentiate into neurons.
The ability to culture neural progenitor cells from the adult human brain has provided an exciting opportunity to develop and test potential therapies on adult human brain cells. To achieve a reliable and reproducible adult human neural progenitor cell (AhNPC) culture system for this purpose, this study fully characterized the cellular composition of the AhNPC cultures, as well as the possible changes to this in vitro system over prolonged culture periods. We isolated cells from the neurogenic subventricular zone/hippocampus (SVZ/HP) of the adult human brain and found a heterogeneous culture population comprised of several types of post-mitotic brain cells (neurons, astrocytes, and microglia), and more importantly, two distinct mitotic cell populations; the AhNPCs, and the fibroblast-like cells (FbCs). These two populations can easily be mistaken for a single population of AhNPCs, as they both proliferate under AhNPC culture conditions, form spheres and express neural progenitor cell and early neuronal markers, all of which are characteristics of AhNPCs in vitro. However, despite these similarities under proliferating conditions, under neuronal differentiation conditions, only the AhNPCs differentiated into functional neurons and glia. Furthermore, AhNPCs showed limited proliferative capacity that resulted in their depletion from culture by 5-6 passages, while the FbCs, which appear to be from a neurovascular origin, displayed a greater proliferative capacity and dominated the long-term cultures. This gradual change in cellular composition resulted in a progressive decline in neurogenic potential without the apparent loss of self-renewal in our cultures. These results demonstrate that while AhNPCs and FbCs behave similarly under proliferative conditions, they are two different cell populations. This information is vital for the interpretation and reproducibility of AhNPC experiments and suggests an ideal time frame for conducting AhNPC-based experiments.


F-box protein interactions with the hallmark pathways in cancer.
F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.


Assessment of cardiac function, blood flow and myocardial tissue relaxation parameters at 0.35 T.
A low field strength (B0) system could increase cardiac MRI availability for patients otherwise contraindicated at higher field. Lower equipment costs could also broaden cardiac MR accessibility. The current study investigated the feasibility of cardiac function with steady-state free precession and flow assessment with phase contrast (PC) cine images at 0.35 T, and evaluated differences in myocardial relaxation times using quantitative T1, T2 and T2* maps by comparison with 1.5 and 3 T results in a small cohort of six healthy volunteers. Signal-to-noise ratio (SNR) differences across systems were characterized with proton density-weighted spin echo phantom data. SNR at 0.35 T was lower by factors of 5.5 and 15.0 compared with the 1.5 and 3 T systems used in this study. All cine images at 0.35 T scored 3 or greater on a five-point image quality scale. Normalized blood-myocardium contrast in cine images, left ventricular volumes (end diastolic volume, end systolic volume) and function (ejection fraction and stroke volume) measures at 0.35 T matched 1.5 and 3 T results. Phase-to-noise ratio in 0.35 T PC images (11.7 ± 1.9) was lower than 1.5 T (18.7 ± 5.2) and 3 T (44.9 ± 16.5). Peak velocity and stroke volume determined from PC images were similar across systems. Myocardial T1 increased (564 ± 13 ms at 0.35 T, 955 ± 19 ms at 1.5 T and 1200 ± 35 ms at 3 T) while T2 (59 ± 4 ms at 0.35 T, 49 ± 3 ms at 1.5 T and 40 ± 2 ms at 3 T) and T2* (42 ± 8 ms at 0.35 T, 33 ± 6 ms at 1.5 T and 24 ± 3 ms at 3 T) decreased with increasing B0. Despite SNR deficits, cardiovascular function, flow assessment and myocardial relaxation parameter mapping is feasible at 0.35 T using standard cardiovascular imaging sequences.


JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death.
Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson's disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity.


[Human arbovirus infections in Burundi: results of a seroepidemiologic survey, 1980-1982].
A serological survey on 623 human sera was conducted in Burundi in 1980-1982, in order to evaluate the frequency of arboviral antibodies in the inhabitants of the three main areas: lowlands, central plateau and mountainous ridge. The results show a rather high activity of arboviruses, mainly in the lowlands (34.2% of inhabitants with antibodies). Chikungunya virus seems to be the most active arbovirus; the activity of Flavivirus is moderate; no trace of activity of yellow fever or West Nile viruses was found; Bunyavirus antibodies (particularly against Ilesha virus) were also detected.


Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM).
This article describes the results of a study of stereotactic radiosurgery (SRS) in the treatment of patients with recurrent malignant glioma. Thirty-two patients with recurrent glioblastoma multiforme (GBM) were treated for 36 lesions with SRS from 1993 to 2001. Nineteen patients were male and 13 were female. The median age at primary diagnosis of the tumor was 56 years (range, 33-76 yrs). At the time of initial diagnosis a total neurosurgical resection was performed in 7, a subtotal resection in 21, and a biopsy in 4 patients. Histology evaluations revealed glioblastoma multiforme (WHO Grade IV) in all 32 patients. In all patients radiotherapy was performed as the first-line therapy, applied as fractionated external beam radiotherapy. The median interval between primary irradiation and reirradiation was 10 months. The median dose applied was 15 Gy (range, 10-20 Gy) prescribed to the 80% isodose line that encompassed the target volume. No concomitant chemotherapy was applied. Treatment was well tolerated by all patients. No acute toxicities > CTC Grade II occurred. No severe long-term toxicities including radionecrosis were observed. The median follow-up time was 13 months (range, 1-89 mo). All patients died of tumor progression during follow-up. The median overall survival from primary diagnosis of the tumor was 22 months (range, 9-133 mo). The survival rate at 1 year was 90%, and 49% and 26% at 2 and 3 years, respectively. Median overall survival after SRS was 10 months. At 6 and 12 months after SRS, survival rates were 72% and 28%, respectively. Median progression-free survival after SRS was 7 months. SRS offers effective treatment as a salvage therapy for a subgroup of patients with smaller lesions of recurrent GBM.


Genetic strategies to access activated neurons.
A major goal of modern neuroscience is to understand how ensembles of neurons participate in neural circuits underlying behavior. The recent explosion of genetically-encoded circuit analysis tools has allowed neuroscientists to characterize molecularly-defined neuronal types with unprecedented detail. However, since neurons defined by molecular expression can be functionally heterogeneous, targeting circuit analysis tools to neurons based on their activity is critical to elucidating the neural basis of behavior. Here we review genetic strategies to access activated neurons and characterize their functional properties, molecular profiles, connectivity, and causal roles in sensory-coding, memory, and valence-encoding. We also discuss future possibilities for improving these strategies and using them to screen brain-wide activity patterns underlying adaptive and maladaptive behaviors.


Age-related changes in structure of labial minor salivary glands.
Despite an increasing number of reports on the effect of various systemic diseases on human labial salivary glands, the influence of the patient's age on the morphology of these glands has not previously been considered. A total of 78 healthy individuals aged from 19 to 87 years were biopsied, and their labial salivary glands were histologically assessed in a blind manner using criteria previously outlined by the author. The parameters recorded were: acinar atrophy, ductal dilatation, fatty change, fibrosis, periacinar callus formation, and inflammatory infiltration. Acinar atrophy was not found in individuals aged under 50 years, but after this it increased progressively as a function of age. The degree of fibrosis rose with advancing age as did fatty infiltration--although less linearly than fibrosis. Ductal dilatation and callus formation were not infrequent from age 50 onwards. Foci of inflammatory cells first appeared in the age group 30-39 years and the focus score was higher in older age groups. The results clearly indicate that an age- and sex-matched control group is mandatory when salivary gland changes associated with systemic diseases are evaluated.


High-Performance Thermomagnetic Gd-Si-Ge Alloys.
Exploring low-grade waste heat energy harvesting is crucial to address increasing environmental concerns. Thermomagnetic materials are magnetic phase change materials that enable energy harvesting from low-temperature gradients. To achieve a high thermomagnetic conversion efficiency, there are three main material requirements: (i) magnetic phase transition near room temperature, (ii) substantial change in magnetization with temperature, and (iii) high thermal conductivity. Here, we demonstrate a high-performance Gd5Si2.4Ge1.6 thermomagnetic alloy that meets these three requirements. The magnetic phase transition temperature was successfully shifted to 306 K by introducing Ge doping in Gd5Si4, and a sharper and more symmetric magnetization behavior with saturation magnetization of Mmax = 70 emu/g at a 2 T magnetic field was achieved in the ferromagnetic state. The addition of SeS2, as a low-temperature sintering aid, to the Gd-Si-Ge alloy improved the material's density and thermal conductivity by ∼45 and ∼275%, respectively. Our results confirm that the (Gd5Si2.4Ge1.6)0.9(SeS2)0.1 alloy is a suitable composite material for low-grade waste heat recovery in thermomagnetic applications.


Incidence rates of comorbidities among patients with psoriasis in the United States.
Psoriasis is associated with a substantial burden of comorbidities; however, incidence rates (IRs) of these comorbidities following psoriasis diagnosis are not well characterized. Using administrative claims data from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Databases between January 1, 2002 and September 30, 2015, we compared the incidence of newly diagnosed comorbidities among patients with psoriasis versus demographically matched (birth year, gender, and geographic region) control patients without psoriasis in the United States. Comorbidities of interest were identified using ICD-9-CM codes. A total of 114,824 matched pairs of patients with psoriasis and control patients were included. IRs of all selected comorbidities were significantly higher among patients with psoriasis compared with controls (P<0.05). The most common newly diagnosed comorbidities in both groups were hyperlipidemia (psoriasis versus control, IR per 1,000 patient-years, 127.5 versus 102.8) and hypertension (94.3 versus 80.6). The greatest differences in IRs between patients with psoriasis and controls were observed for rheumatoid arthritis (9.7 versus 3.1; IR ratio [IRR], 3.15) and psoriatic arthritis (24.0 versus 0.2; IRR, 151.57). In this real-world study, patients with psoriasis were more likely to develop new selected comorbidities after diagnosis compared with demographically matched patients without psoriasis.


Fetal response to intramuscular epinephrine for anaphylaxis during maternal penicillin desensitization for secondary syphilis.
Penicillin desensitization is indicated in pregnant patients with severe allergies to penicillin with syphilis. The immediate effects of intramuscular epinephrine on the fetus during desensitization remain unreported. We describe a pregnant patient with secondary syphilis and penicillin allergy who developed anaphylaxis during penicillin desensitization. Anaphylaxis resolved after administration of intramuscular epinephrine. Throughout the procedure, continuous electronic fetal monitoring showed a stable fetus without a decrease in variability, tachycardia, decelerations, or signs of fetal distress. This case showed that intramuscular epinephrine is effective in treatment of anaphylaxis in a pregnant patient with little to no immediate effects on the fetus.


Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.
Patients with systemic lupus erythematosus show an overexpression of type I IFN-responsive genes that is referred to as "IFN signature." We found that B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an IFN signature compared with non-autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs) (GM-CSF bone marrow-derived dendritic cells; BMDCs) from Sle1,2,3 mice constitutively overexpressed IFN-responsive genes such as IFN-β, Oas-3, Mx-1, ISG-15, and CXCL10 and members of the IFN signaling pathway STAT1, STAT2, and IRF7. The IFN signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the IFN signature in mDCs precedes disease onset and is independent from the autoantibodies. Sle1,2,3 BMDCs hyperresponded to stimulation with IFN-α and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyperresponse is induced by the IFN signature and only partially contributes to the signature, as oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive IFN signature, and pre-exposure to IFN-α induced the same hyperresponse in wild-type BMDCs as in Sle1,2,3 BMDCs. In vivo, mDCs and to a lesser extent T and B cells from young prediseased Sle1,2,3 mice also expressed the IFN signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the IFN signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the IFN signature in lupus pathogenesis.


Longitudinal estimates of pulmonary function in refractory ceramic fiber manufacturing workers.
Refractory ceramic fibers (RCF) are man-made vitreous fibers (MMVF) used in high-temperature industrial applications. Between 1987 and 1994, a prospective study evaluated pulmonary function of 361 male workers currently employed in RCF manufacturing and related operations for plausibility of a causal relationship between RCF exposure and pulmonary function changes. Workers included in the analysis provided at least five pulmonary function tests. The exposure-response relationship was modeled with two exposure variables: years in a production job, and cumulative fiber exposure (fiber-mo/cc). Comparison groups were nonproduction workers and workers with up to 15 fiber-mo/cc cumulative exposure. A statistically significant decrease in FVC was demonstrated among workers employed in production jobs more than 7 yr prior to initial test. A similar but nonstatistically significant result was demonstrated for FVC in workers with greater than 60 fiber-mo/cc cumulative exposure prior to initial pulmonary function test. Similar but nonstatistically significant results were obtained for FEV1. These findings, which primarily reflect workers employed before 1980, did not persist with analysis of follow-up production years and accumulated RCF exposure from initial pulmonary function test. Since longitudinal analyses are sensitive to influences that continue to affect annual decline during the study period, lower RCF exposure levels since the 1980s may be responsible for eliminating any further effect on pulmonary function.


Premenstrual Syndrome Is Associated With a Higher Frequency of Female Sexual Difficulty and Sexual Distress.
Few prospective studies have evaluated the impact of premenstrual symptoms (PMS) on female sexual function and sexuality-related distress. The purpose of the present study was therefore to find out risk factors of PMS for female sexual function and sexuality-related personal distress. This prospective cohort study was conducted at the Süleymaniye Women and Children's Health Training and Research Hospital in Istanbul, Turkey, between February 2014 and March 2016. The study group consisted of women admitted to the general gynecology outpatient clinic aged 18 to 40 years who met the inclusion criteria. The American College of Obstetricians and Gynecologists criteria were used for the initial diagnosis of PMS and the participants were allocated to PMS(+) and PMS(-) groups (healthy subjects). All participants completed the Beck Depression Inventory to exclude those at risk for depression. The patients with an initial diagnosis of PMS then completed the PMS Daily Record of Severity of Problems form prospectively for two consecutive menstrual cycles to confirm PMS diagnosis. Lastly, both sexual function and sexual distress of eligible PMS(+) (n = 143) and PMS(-) (n = 143) participants were assessed with both the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R). According to the FSFI cutoff value, 77.6% of patients in the PMS(+) group and 27.3% of patients in the PMS(-) group had sexual concerns (p < 0.05). The sexuality-related personal distress rate was 51.7% in the PMS(+) group and 24.5% in the PMS(-) group (p < 0.05). Overall, 51.7% of the PMS(+) and 24.5% of the PMS(-) group were recognized as having sexual difficulties based on the presence of sexual distress and the low FSFI scores (p < 0.05). We concluded that women with PMS are likely to have sexual difficulties and a higher level of sexual distress, emphasizing the importance of the sexual aspects of PMS in clinical practice.


Landscape metrics and estuarine sediment contamination in the mid-Atlantic and southern New England regions.
In a previously published study, quantitative relationships were developed between landscape metrics and sediment contamination for 25 small estuarine systems within Chesapeake Bay. These analyses have been extended to include 75 small estuarine systems across the mid-Atlantic and southern New England regions of the USA. Because of the different characteristics and dynamics of the estuaries across these regions, adjustment for differing hydrology, sediment characteristics, and sediment origins were included in the analysis. Multiple linear regression with stepwise selection was used to develop statistical models for sediment metals, organics, and total polycyclic aromatic hydrocarbons (PAHs). The landscape metrics important for explaining the variation in sediment metals levels (R2 = 0.72) were the percent area of nonforested wetlands (negative contribution), percent area of urban land, and point source effluent volume and metals input (positive contributions). The metrics important for sediment organics levels (R2 = 0.5) and total PAHs (R2 = 0.46) were percent area of urban land (positive contribution) and percent area of nonforested wetlands (negative contribution). These models included silt-clay content (metals) or total organic C (organics, total PAHs) of sediments and grouping by estuarine hydrology, suggesting the importance of sediment characteristics and hydrology in mitigating the influence of the landscape metrics on sediment contamination levels. The overall results from this study are indicative of how statistical models can be developed relating landscape metrics to estuarine sediment contamination for distributions of land cover and point source discharges.


Contribution of Trf4/5 and the nuclear exosome to genome stability through regulation of histone mRNA levels in Saccharomyces cerevisiae.
Balanced levels of histones are crucial for chromosome stability, and one major component of this control regulates histone mRNA amounts. The Saccharomyces cerevisiae poly(A) polymerases Trf4 and Trf5 are involved in a quality control mechanism that mediates polyadenylation and consequent degradation of various RNA species by the nuclear exosome. None of the known RNA targets, however, explains the fact that trf mutants have specific cell cycle defects consistent with a role in maintaining genome stability. Here, we investigate the role of Trf4/5 in regulation of histone mRNA levels. We show that loss of Trf4 and Trf5, or of Rrp6, a component of the nuclear exosome, results in elevated levels of transcripts encoding DNA replication-dependent histones. Suggesting that increased histone levels account for the phenotypes of trf mutants, we find that TRF4 shows synthetic genetic interactions with genes that negatively regulate histone levels, including RAD53. Moreover, synthetic lethality of trf4Delta rad53Delta is rescued by reducing histone levels whereas overproduction of histones is deleterious to trf's and rrp6Delta mutants. These results identify TRF4, TRF5, and RRP6 as new players in the regulation of histone mRNA levels in yeast. To our knowledge, the histone transcripts are the first mRNAs that are upregulated in Trf mutants.


Associating community prevalence of Schistosoma mansoni infection with prevalence of signs and symptoms.
Information on the prevalence of morbidity is needed for re-calculation of the Global Burden of Disease (WHO) due to Schistosoma mansoni. This study presents a statistical association which can be used to predict the prevalence of morbidity from the prevalence of S. mansoni in a community. We collected data from field studies reporting prevalence of infection and prevalence of morbidity. Data on infection prevalence were standardised to a default diagnostic sensitivity (i.e. Kato-Katz technique 41.7 mg). The data were described by an expression related to logistic regression. We determined associations between prevalence of infection and prevalence of early morbidity (diarrhoea, blood in stool and abdominal pain), hepatosplenic morbidity and late morbidity (haematemesis and ascitis). Diarrhoea and blood in stool due to S. mansoni infection mainly occurs in communities with a high prevalence of infection. An influence on hepatosplenic morbidity is already present at low community prevalence of infection. For the aspecific symptom abdominal pain we did not find an association.


Rosmarinic acid attenuates β-amyloid-induced oxidative stress via Akt/GSK-3β/Fyn-mediated Nrf2 activation in PC12 cells.
Oxidative stress is an important pathogenic factor in Alzheimer's disease (AD). Recently, nuclear factor E2-related factor 2 (Nrf2) has emerged as a master regulator for the endogenous antioxidant response, and thus represents an attractive therapeutic target against AD. The aim of this study is to test the hypothesis that rosmarinic acid (RosA) attenuates amyloid-β (Aβ)-evoked oxidative stress through activating Nrf2-inducible cellular antioxidant defense system. Here, we reported that RosA attenuated Aβ-induced cellular reactive oxygen species (ROS) generation and lipid hydroperoxides (LPO). Interestingly, knockdown of Nrf2 by plasmid-based short hairpin RNA (shRNA) abrogated, at least in part, RosA-mediated neuroprotection in Aβ-challenged PC12 cells. Mechanistically, RosA enhanced the nuclear translocation of Nrf2 and binding to antioxidant response element (ARE) core element but did not induced Nrf2 transcription. Simultaneously, RosA induced a set of Nrf2 downstream target genes encoding phase-II antioxidant enzymes. Furthermore, RosA enhanced protein kinase B (Akt) phosphorylation, glycogen synthase kinase-3β (GSK-3β) phosphorylation at Ser9, and Fyn phosphorylation. Noteworthy, pharmacological inhibition or gene knockdown studies demonstrated that Akt locate upstream of GSK-3β and regulate Nrf2 through Fyn in the context of PC12 cells pre-incubated with RosA following exposed to Aβ. Conversely, the antioxidant effects of RosA could be blocked by Akt inhibitors LY294002, GSK-3β inhibitor LiCl, Nrf2 shRNA, or Fyn shRNA in Aβ-challenged PC12 cells. Consequently, the antioxidant effects of RosA are mediated predominantly by Akt/GSK-3β/Fyn pathway through increased activity of Nrf2. These results suggest, although do not prove, that RosA can be a promising candidate for neuroprotective treatment of AD.


Toward an Individual Binaural Loudness Model for Hearing Aid Fitting and Development.
The individual loudness perception of a patient plays an important role in hearing aid satisfaction and use in daily life. Hearing aid fitting and development might benefit from individualized loudness models (ILMs), enabling better adaptation of the processing to individual needs. The central question is whether additional parameters are required for ILMs beyond non-linear cochlear gain loss and linear attenuation common to existing loudness models for the hearing impaired (HI). Here, loudness perception in eight normal hearing (NH) and eight HI listeners was measured in conditions ranging from monaural narrowband to binaural broadband, to systematically assess spectral and binaural loudness summation and their interdependence. A binaural summation stage was devised with empirical monaural loudness judgments serving as input. While NH showed binaural inhibition in line with the literature, binaural summation and its inter-subject variability were increased in HI, indicating the necessity for individualized binaural summation. Toward ILMs, a recent monaural loudness model was extended with the suggested binaural stage, and the number and type of additional parameters required to describe and to predict individual loudness were assessed. In addition to one parameter for the individual amount of binaural summation, a bandwidth-dependent monaural parameter was required to successfully account for individual spectral summation.


[Immunologic study in HIV-positive patients. Hypergammaglobulinemia in HIV infection].
In all groups of patients--HIV, ARC, AIDS carriers--elevated serum concentration of IgG, IgA, IgM were found. In the group of HIV carriers a significant increase of the serum concentration of IgG at the 5% level was observed and of IgM at the 1% level. In patients with ARC a significant increase of IgG and IgA was found at the 5% level and of IgM at the 1% level. In patients with AIDS significantly raised IgG values at the 5% level were recorded, and of IgA and IgM at the 1% level. In IgA a permanent increase of values occurs in AIDS carriers. In the AIDS stage 86% of the patients have values higher than mean +/- SD of controls. In all three stages of HIV infection a rise of concentrations of circulating immunocomplexes was observed (p < 0.01). The highest levels were recorded in patients with AIDS. In none of the patients the presence of antinuclear antibodies was detected. The authors discuss also possible causes of hypergammaglobulinaemia in HIV infection.


On the perceptual aesthetics of interactive objects.
This study examined the aesthetics of interactive objects (IOs), which are three-dimensional physical artefacts that exhibit autonomous behaviour when handled. The aim of the research was threefold: first, to investigate whether aesthetic preference for distinctive objects' structures emerges in compound stimulation; second, to explore whether there exists aesthetic preference for distinctive objects' behaviours; and, finally, to test whether there exists aesthetic preference for specific combinations of objects' structures and behaviours. The following variables were systematically manipulated: (a) IOs' contour (rounded vs angular), (b) IOs' size (small vs large), (c) IOs' surface texture (rough vs smooth), and (d) IOs' behaviour (lighting, sounding, vibrating, and quiescent). Results show that behaviour was the dominant factor: it influenced aesthetics more than any other characteristic; vibrating IOs were preferred over lighting and sounding IOs, supporting the importance of haptic processing in aesthetics. Results did not confirm the size and smoothness effects previously reported in vision and touch, respectively, which suggests that the aesthetic preference that emerges in isolated conditions may be different in compound stimulation. Results corroborate the smooth curvature effect. We suggest that behavior may be an aesthetic primitive.


Protease-activated receptor 2 protects against myocardial ischemia-reperfusion injury through the lipoxygenase pathway and TRPV1 channels.
This study tests the hypothesis that the lipoxygenase (LOX) pathway mediates protease-activated receptor (PAR) 2-induced activation of the transient receptor potential vanilloid receptor 1 (TRPV1) to protect the heart from ischemia/reperfusion (I/R) injury. SLIGRL, a PAR2 activating peptide, was administered prior to reperfusion following left anterior descending coronary artery ligation in wild type (WT) and TRPV1 knockout (TRPV1-/-) mice. In a Langendorffly perfused heart I/R model, hemodynamic parameters, including left ventricular end-diastolic pressure, left ventricular developed pressure, coronary blood flow and left ventricular peak +dP/dt were evaluated after I/R. SLIGRL reduced the cardiac infarct size in WT and TRPV1-/- mice with a greater effect in the former strain (P<0.05). SLIGRL increased plasma levels of calcitonin gene-related peptide (CGRP) and substance P in WT (both P<0.05) but not in TRPV1-/- mice. Pretreatment with CGRP8-37 (a CGRP receptor antagonist) or RP67580 (a neurokinin-1 receptor antagonist) alone had no effect on SLIGRL-induced cardiac protection in either strain. However, combined administration of CGRP8-37 and RP67580 abolished SLIGRL-induced cardiac protection in WT but not in TRPV1-/- mice. Nordihydroguaiaretic acid (a general LOX inhibitor) and baicalein (a 12-LOX inhibitor), but not indomethacin (a cyclooxygenase inhibitor) and hexanamide (a selective cytochrome P450 epoxygenase inhibitor), abolished the protective effects of SLIGRL in WT (all P<0.05) but not in TRPV1-/- hearts. These data suggested that PAR2, possibly via 12-LOX, activates TRPV1 and leads to CGRP and substance P release to prevent I/R injury in the heart, indicating that the 12-LOX-TRPV1 pathway conveys cardiac protection to alleviate myocardial infarction.


Species diversity and activity of insectivorous bats in three habitats in La Virgen de Sarapiquí, Costa Rica.
Pineapple farms make up 45,000 ha of Costa Rican landscape and are the second most exported crop. This is economically beneficial for the Costa Ricans, but greatly affects the natural flora and fauna because it is such a low growing crop. This study examined the differences in insectivorous bat species diversity and activity in the habitat gradient between the forest in Tirimbina Biological Reserve in La Virgen de Sarapiquí, Heredia, Costa Rica and the nearby pineapple farm called Finca Corsicana. Over a four week period in March and April 2013, ultrasonic recorders were placed at different sites to pick up the bats' calls. Then the recordings were analyzed to identify the species. There were four families present and 19 different species. There was a significant decrease in the number of bat passes (the number of times a bat passes the recorder) in the pineapple farm (x = 22.6), in comparison to the border (x = 39.9), and the forest (x = 44.2) (p = 0.0028). Agricultural environ- ments affected and lowered bat presence. Also, a greater mean number of bats recorded between 1900-1930 hrs compared to 1730-1800 hrs, coincided with the setting of the sun and beginning of bat activity. More research is need throughout the night and the year to establish clearer patterns of bat use and activity in different habitats.


Feeding sources and natural infection of Belminus herreri (Hemiptera, Reduviidae, Triatominae) from dwellings in Cesar, Colombia.
Belminus herreri, originally described from specimens collected in Panama, was considered entirely silvatic until to 2000 when it was found for the first time in a domestic habitat in Colombia. In 2001, during a new search of houses in the Department of Cesar, Colombia, 121 specimens were collected. Study of their feeding sources using an ELISA test revealed that 96% of these specimens had fed on cockroaches (Blattidae). However, a small proportion of these B. herreri specimens also showed the presence of Trypanosoma cruzi in their gut contents, suggesting a possible role for these insects in the epidemiology of Chagas disease.


Current status and future perspectives of post-operative adjuvant therapy for gastric carcinoma.
The clinical benefit of post-operative adjuvant immunochemotherapy for survival of patients with gastric carcinoma is unclear, although a number of prospective randomized controlled studies have been conducted. The current status and future perspectives of post-operative adjuvant chemotherapy in gastric carcinoma have been evaluated in terms of survival benefit. The results of randomized clinical studies vary in accordance with the regimen and sample size. A meta-analysis, however, indicated a survival benefit in patients treated with post-operative adjuvant chemotherapy including mitomycin, anthracyclines, cyclophosphamide, alkylating agents and 5-fluorouracil (odds ratio: 0.8 to approximately 0.82, 95% CI<1.0). The survival benefit was observed in patients with stage II and stage III gastric carcinoma, but not those with stage I. Further, the survival benefit in node-positive and high histological grade subgroups was superior to that in node-negative and low histological grade subgroups. Although combination therapy with mitomycin, 5-fluorouracil and non-specific immunomodulators, such as PSK and OK-432, appeared to improve overall survival without immunomodulators, the survival effect of immunomodulators is still not clear. There are several possible reasons why the survival benefit of adjuvant chemotherapy or immunochemotherapy is small and marginal compared to surgery alone: (i) low efficacy of the chemotherapy regimen; (ii) small sample size; and (iii) differences in chemosensitivity of treated patients based on genetic background. The determination of subgroups responsive to chemotherapy and the development of a rationale-based and molecular-targeted chemotherapy are required to clearly demonstrate whether there is a survival benefit of post-operative adjuvant chemotherapy in gastric carcinoma.


Oral squamous cell cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma.
The aim of this study is to present the oral Squamous Cell Cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma. Oral squamous cell cancer (OSCC) is a common disease worldwide, with poor prognosis and limited treatment. Thus, introducing molecular markers through network analysis can be helpful. STRING database (DB) was applied for network construction through Cytoscape 3.4.0. Clue GO handled the gene annotation for the retrieved clusters. Eight proteins were indicated to be differential in the network constitution. The centrality and clustering analysis indicate that TP53 plays an over-significant role in network integrity among eight most central proteins including TP53, AKT1, EGFR, MYC, JUN, CDH1, CCND1, and CTNNB1. The suggested biomarker set is very similar to the related biomarker panel of esophageal adenocarcinoma. The ontology analysis implies that the prominent proteins are involved in regulation of smooth muscle cell proliferation, regulation of fibroblast proliferation, and response to UV-A processes. In conclusion, these proteins and their associated biological processes may be more critical compared to other reported biomarkers for OSCC. Nevertheless, validation studies are required for confirming the pivotal role of potential candidates. Similar biomarker panel of this disease and esophagus adenocarcinoma is corresponded to the origin of the two malignancies.


Tobit regression for modeling mean survival time using data subject to multiple sources of censoring.
Mean survival time is often of inherent interest in medical and epidemiologic studies. In the presence of censoring and when covariate effects are of interest, Cox regression is the strong default, but mostly due to convenience and familiarity. When survival times are uncensored, covariate effects can be estimated as differences in mean survival through linear regression. Tobit regression can validly be performed through maximum likelihood when the censoring times are fixed (ie, known for each subject, even in cases where the outcome is observed). However, Tobit regression is generally inapplicable when the response is subject to random right censoring. We propose Tobit regression methods based on weighted maximum likelihood which are applicable to survival times subject to both fixed and random censoring times. Under the proposed approach, known right censoring is handled naturally through the Tobit model, with inverse probability of censoring weighting used to overcome random censoring. Essentially, the re-weighting data are intended to represent those that would have been observed in the absence of random censoring. We develop methods for estimating the Tobit regression parameter, then the population mean survival time. A closed form large-sample variance estimator is proposed for the regression parameter estimator, with a semiparametric bootstrap standard error estimator derived for the population mean. The proposed methods are easily implementable using standard software. Finite-sample properties are assessed through simulation. The methods are applied to a large cohort of patients wait-listed for kidney transplantation.


Transcripts of the NADH-dehydrogenase subunit 3 gene are differentially edited in Oenothera mitochondria.
A number of cytosines are altered to be recognized as uridines in transcripts of the nad3 locus in mitochondria of the higher plant Oenothera. Such nucleotide modifications can be found at 16 different sites within the nad3 coding region. Most of these alterations in the mRNA sequence change codon identities to specify amino acids better conserved in evolution. Individual cDNA clones differ in their degree of editing at five nucleotide positions, three of which are silent, while two lead to codon alterations specifying different amino acids. None of the cDNA clones analysed is maximally edited at all possible sites, suggesting slow processing or lowered stringency of editing at these nucleotides. Differentially edited transcripts could be editing intermediates or could code for differing polypeptides. Two edited nucleotides in an open reading frame located upstream of nad3 change two amino acids in the deduced polypeptide. Part of the well-conserved ribosomal protein gene rps12 also encoded downstream of nad3 in other plants, is lost in Oenothera mitochondria by recombination events. The functional rps12 protein must be imported from the cytoplasm since the deleted sequences of this gene are not found in the Oenothera mitochondrial genome. The pseudogene sequence is not edited at any nucleotide position.


AMPK activator AICAR promotes 5-FU-induced apoptosis in gastric cancer cells.
The aim of the present study was to determine the effect of AICAR, an AMPK activator, on apoptosis in gastric carcinoma cells (SGC-7901) with or without 5-fluorouracil (5-FU). SGC-7901 cells were treated with AICAR (0.2-5 mM, for 24-48 h) with or without 5-FU. Cell viability was determined using MTT assay, while apoptosis were measured through the evaluation of active caspase-3 activity and DNA fragmentation. Real-time PCR was employed to determine the expression of tumor suppressor and multi-drug resistant (mdr1) gene. Cleaved caspase-3 and phosphorylated AMPK (p-AMPK) were measured by Western blot. AICAR significant reduced cellular viability but increased apoptosis in a time- and dose-dependent manner, which is associated with an increase in p-AMPK levels. Importantly, AICAR enhanced the sensitivity to 5-FU-induced reduction of cellular viability and increased apoptosis in SGC-7901 cells. Furthermore, AICAR increased tumor suppressor genes [F-box and WD repeat domain containing 7 (FBXW7), semaphorin III/F (SEMA3F), and p21(Cip1) (p21)] but reduced mdr1 expression. Finally, p-AMPK levels were reduced in 5-FU-resistant gastric cancer cells compared to human immortalized gastric epithelial cell line and 5-FU-sensitive gastric cancer cells. AICAR not only induces apoptosis alone but also enhances pro-apoptotic effect of 5-FU in SGC-7901 cells, which lays an experimental foundation to develop AICAR as a chemotherapeutic sensitizer against gastric cancer.


The Role of Subretinal Injection in Ophthalmic Surgery: Therapeutic Agent Delivery and Other Indications.
Subretinal injection is performed in vitreoretinal surgery with two main aims, namely, the subretinal delivery of therapeutic agents and subretinal injection of fluid to induce a controlled and localized macular detachment. The growing interest in this technique is mainly related to its suitability to deliver gene therapy in direct contact with target tissues. However, subretinal injection has been also used for the surgical management of submacular hemorrhage through the subretinal delivery of tissue plasminogen activator, and for the repair of full-thickness macular holes, in particular refractory ones. In the light of the increasing importance of this maneuver in vitreoretinal surgery as well as of the lack of a standardized surgical approach, we conducted a comprehensive overview on the current indications for subretinal injection, surgical technique with the available variations, and the potential complications.


Identification of the long non‑coding RNA LET as a novel tumor suppressor in gastric cancer.
Long non-coding RNAs (lncRNAs) have emerged recently as important factors in regulating fundamental biological processes. Alterations in the expression and function of lncRNAs have been observed to promote tumor formation, progression and metastasis. Although downregulation of the expression levels of LET lncRNA in several tumors has been reported, its role in gastric cancer remains unknown. The aim of the present study was to investigate the expression and function of LET in gastric cancer development. The expression levels of LET in 37 pairs of gastric cancer and adjacent non‑tumor tissues were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). In addition, LET expression in gastric cancer cell lines was analyzed by RT‑qPCR assay analysis. Furthermore, the impact of LET on cell proliferation, migration and apoptosis were detected using the cell counting kit‑8, wound scratch and ELISA assays, respectively. The results demonstrated that the expression level of LET was downregulated in gastric cancer tissues and cell lines (SGC‑7901 and MGC‑803) compared with normal tissues and a normal human gastric epithelial cell line (GES‑1). Restoration of LET expression using a synthesized recombinant overexpression vector transfected into SGC‑7901 and MGC‑803 cells, significantly inhibited cell proliferation and migration, and promoted cell apoptosis in vitro. The present study is the first to demonstrate that LET may function as a tumor suppressor in gastric cancer. The results indicate that LET may be a promising biomarker and/or a therapeutic target for gastric cancer.


The Use of Bronchoscopy During the Coronavirus Disease 2019 Pandemic: CHEST/AABIP Guideline and Expert Panel Report.
The coronavirus disease 2019 (COVID-19) has swept the globe and is causing significant morbidity and mortality. Given that the virus is transmitted via droplets, open airway procedures such as bronchoscopy pose a significant risk to health-care workers (HCWs). The goal of this guideline was to examine the current evidence on the role of bronchoscopy during the COVID-19 pandemic and the optimal protection of patients and HCWs. A group of approved panelists developed key clinical questions by using the Population, Intervention, Comparator, and Outcome (PICO) format that addressed specific topics on bronchoscopy related to COVID-19 infection and transmission. MEDLINE (via PubMed) was systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to assess the quality of studies and to grade the level of evidence to support each recommendation. When evidence did not exist, suggestions were developed based on consensus using the modified Delphi process. The systematic review and critical analysis of the literature based on six PICO questions resulted in six statements: one evidence-based graded recommendation and 5 ungraded consensus-based statements. The evidence on the role of bronchoscopy during the COVID-19 pandemic is sparse. To maximize protection of patients and HCWs, bronchoscopy should be used sparingly in the evaluation and management of patients with suspected or confirmed COVID-19 infections. In an area where community transmission of COVID-19 infection is present, bronchoscopy should be deferred for nonurgent indications, and if necessary to perform, HCWs should wear personal protective equipment while performing the procedure even on asymptomatic patients.


Surgical resection of lumbar intradural metastatic renal cell carcinoma.
A 60-year-old male with renal cell carcinoma (RCC) presented with back pain, weakness, and bowel and bladder urgency. MRI demonstrated a cauda equina tumor at L2. Following L1-3 laminectomies, intraoperative ultrasound localized the tumor. After dural opening, a vascular tumor was adherent to the cauda equina. Intraoperative nerve stimulation helped to identify the nerve rootlets. Tumor was removed in a piecemeal fashion. Tumor dissection caused periodic spasms in L1-3 distributions. A neuromonitoring checklist was used to recover motor evoked potential signals with elevated mean arterial pressures. Hemostasis was challenging with the vascular tumor. Intraoperative ultrasound confirmed tumor debulking. Pathology confirmed metastatic RCC.


[Microbial decontamination of hospital linens using radiation].
The irradiation of hospital linen contaminated with radioresistant microorganisms or hospital microflora with gamma radiation in a dose of 10 kGy ensures the reliable microbial decontamination of such linen. Cotton linen has been found capable of withstanding 15 irradiation cycles in a dose of 10 kGy.


An interprofessional training program for intrahospital transport of critically ill patients: model build-up and assessment.
Intrahospital transport of critically ill patients for diagnostic or therapeutic procedures can be compromised by patient instability, equipment problems or inexperienced teamworking. This quasi-experimental study aimed to assess the effectiveness of an in-situ interprofessional simulation-based training (IIST) model for junior member transport teams. Newly registered postgraduate physicians, nurses and respiratory therapists underwent the IIST. The technical skills (TS) of each participant and non-technical skills (NTS) of each interprofessional team were assessed using well-validated checklists. Thirty-six participants enrolled and were randomly assigned to six experimental and six control teams. Most participants achieved a significantly higher level of both TS and NTS. Both the control and experimental teams overvalued their NTS in the pretest, while the posttest self-assessment scores among the experimental groups more closely matched the expert assessments. Despite challenges in scheduling and the setting, the IIST was successfully conducted in a crowded hospital, which enabled trainees to optimize their learning in a real-life environment. In conclusion, the IIST model can facilitate the development of both TS and NTS for transport team members. Transport teams made up of newly registered staff from different disciplines may lack insight into their NTS in critical patient transfer management, but simulation training may cause improvements.


Thermorefractive noise reduction of photonic molecule frequency combs using an all-optical servo loop.
Phase and frequency noise originating from thermal fluctuations is commonly a limiting factor in integrated photonic cavities. To reduce this noise, one may drive a secondary "servo/cooling" laser into the blue side of a cavity resonance. Temperature fluctuations which shift the resonance will then change the amount of servo/cooling laser power absorbed by the device as the laser moves relatively out of or into the resonance, and thereby effectively compensate for the fluctuation. In this paper, we use a low noise laser to demonstrate this principle for the first time in a frequency comb generated from a normal dispersion photonic molecule micro-resonator. Significantly, this configuration can be used with the servo/cooling laser power above the usual nonlinearity threshold since resonances with normal dispersion are available. We report a 50 % reduction in frequency noise of the comb lines in the frequency range of 10 kHz to 1 MHz and investigate the effect of the secondary servo/cooling noise on the comb.