Metabolic tumor volume and total lesion glycolysis predict tumor progression and survival after salvage surgery for recurrent oral cavity squamous cell carcinoma.
This study evaluated the prognostic role of Fluorine 18-fluorodeoxyglucose positron emission tomography/CT (18 F-FDG PET/CT) parameters quantitatively measured in patients with recurrent oral cavity cancer. Cox proportional hazards regression analyses were used to assess the associations between quantitative 18 F-FDG PET/CT parameters and other clinicopathological factors and progression-free survival (PFS) and overall survival (OS). All of the 18 F-FDG PET parameters (SUVmax , SUVmean , SUVpeak , metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were significantly associated with poor PFS and OS outcomes after salvage treatment (P < .01). In multivariate analyses, Karnofsky performance score, recurrence site, MTV, and TLG were independent variables predictive of both PFS and OS (P < .05). High MTV (>8.8 mL) or TLG (>29.4 g) values at recurrent lesions were associated with >5-fold increased risk for tumor progression and mortality after salvage surgery. The PET parameters of MTV and TLG measured at recurrent lesions may predict tumor progression and survival after salvage treatment. This study examined the role of 18 F-FDG PET/CT at recurrent staging for predicting tumor progression and survival in 71 consecutive patients with recurrent oral cavity squamous cell carcinomas. Of 18 F-FDG parameters, metabolic tumor volume and total lesion glycolysis were independent factors predictive of tumor progression and survival after salvage treatment.


Positive Cumulative Fluid Balance Is Associated With Mortality in Pediatric Acute Respiratory Distress Syndrome in the Setting of Acute Kidney Injury.
As acute kidney injury and elevated cumulative fluid balance commonly co-occur in pediatric acute respiratory distress syndrome, we aimed to identify risk factors for their development and evaluate their independent relationships with mortality. We hypothesized that acute kidney injury and elevated cumulative fluid balance would be associated with markers of inflammation and that children with elevated cumulative fluid balance and concomitant acute kidney injury would have worse outcomes than other children. Prospective observational study using the pediatric Risk, Injury, Failure, Loss, End-Stage acute kidney injury classification. Five academic PICUs. Two-hundred sixty patients 1 month to 18 years old meeting the Berlin definition of acute respiratory distress syndrome between 2008 and 2014. None. PICU mortality was 13% (34/260). Relative to survivors, nonsurvivors had greater cumulative fluid balance on day 3 of acute respiratory distress syndrome (+90.1 mL/kg; interquartile range 26.6-161.7 vs +44.9 mL/kg; interquartile range 10.0-111.3; p = 0.008) and also had higher prevalence of acute kidney injury on day 3 of acute respiratory distress syndrome (50% vs 23%; p = 0.001). On stratified analysis, greater cumulative fluid balance on day 3 of acute respiratory distress syndrome was associated with mortality among patients with concomitant acute kidney injury (+111.5 mL/kg for nonsurvivors; interquartile range 82.6-236.8 vs +58.5 mL/kg for survivors; interquartile range 0.9-176.2; p = 0.041) but not among patients without acute kidney injury (p = 0.308). The presence of acute kidney injury on acute respiratory distress syndrome day 3 was associated with mortality among patients with positive cumulative fluid balance (29.1% vs 10.4% mortality; p = 0.001) but not among patients with even or negative cumulative fluid balance (p = 0.430). Day 1 plasma interleukin-6 levels were associated with the development of day 3 positive cumulative fluid balance, day 3 acute kidney injury, and PICU mortality and the association between elevated day 1 interleukin-6 and PICU mortality was partially mediated by the interval development of day 3 positive cumulative fluid balance and day 3 acute kidney injury (p < 0.001). In pediatric acute respiratory distress syndrome, elevated cumulative fluid balance on day 3 of acute respiratory distress syndrome is associated with mortality specifically in patients with concomitant acute kidney injury. Plasma interleukin-6 levels are associated with the development of positive cumulative fluid balance and acute kidney injury, suggesting a potential mechanism by which inflammation might predispose to mortality.


A new pipeline for structural characterization and classification of RNA-Seq microbiome data.
High-throughput sequencing enables the analysis of the composition of numerous biological systems, such as microbial communities. The identification of dependencies within these systems requires the analysis and assimilation of the underlying interaction patterns between all the variables that make up that system. However, this task poses a challenge when considering the compositional nature of the data coming from DNA-sequencing experiments because traditional interaction metrics (e.g., correlation) produce unreliable results when analyzing relative fractions instead of absolute abundances. The compositionality-associated challenges extend to the classification task, as it usually involves the characterization of the interactions between the principal descriptive variables of the datasets. The classification of new samples/patients into binary categories corresponding to dissimilar biological settings or phenotypes (e.g., control and cases) could help researchers in the development of treatments/drugs. Here, we develop and exemplify a new approach, applicable to compositional data, for the classification of new samples into two groups with different biological settings. We propose a new metric to characterize and quantify the overall correlation structure deviation between these groups and a technique for dimensionality reduction to facilitate graphical representation. We conduct simulation experiments with synthetic data to assess the proposed method's classification accuracy. Moreover, we illustrate the performance of the proposed approach using Operational Taxonomic Unit (OTU) count tables obtained through 16S rRNA gene sequencing data from two microbiota experiments. Also, compare our method's performance with that of two state-of-the-art methods. Simulation experiments show that our method achieves a classification accuracy equal to or greater than 98% when using synthetic data. Finally, our method outperforms the other classification methods with real datasets from gene sequencing experiments.


Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation.
Incidence rates of follicular lymphoma (FL) inexplicably vary markedly between Western and Asian countries. A hallmark of FL is the bcl-2 translocation, characterized by 1 of 2 common breakpoints known as major breakpoint region (MBR) and minor cluster region (mcr). We analyzed previously published data to compare rates of bcl-2 translocation in FL across geographic regions. Available data from the literature suggest that the incidence of bcl-2 in healthy persons in the absence of FL may be as high as 50% in Western and Asian populations. However, in FL our results show that the frequency of bcl-2 positivity was significantly higher for US than for Asian populations (P <.0001). This pattern persisted for MBR and mcr subgroups. We conclude that a significant gradient exists in the bcl-2 frequency between these FL populations. We therefore suggest that the relatively low incidence of FL in Asian populations is caused not by a lower frequency of bcl-2 rearrangements in healthy populations but by distinct molecular pathways developing in different geographic regions that nonetheless culminate in FL, which is morphologically similar but molecularly distinct. Studies demonstrating differences in clinical characteristics according to the presence or absence of bcl-2 rearrangements support this concept. Thus we hypothesize that FL may in fact be a heterogeneous malignancy encompassing entities with distinct molecular pathogenesis and potentially distinct clinical manifestations. If these findings were confirmed in prospective studies, it would imply that different etiologic or genetic factors might influence the development of FL across separate regions.


Pharmacokinetics of tolbutamide after oral administration in rabbits with folate-induced renal failure.
The pharmacokinetic changes of tolbutamide were studied after oral administration to normal rabbits and mild and medium folate-induced renal failure rabbits. Tolbutmide 50 mg/kg was orally administered to the rabbits. The plasma concentrations of tolbutamide were significantly increased (p<0.05) at 9 to 24 hr in mild and medium folate-induced renal failure rabbits compared with those in normal rabbits. Therefore, the area under the plasma concentration-time curves (AUC) was significantly higher (p<0.05 and p<0.01 respectively) in mild and medium folate-induced renal failure rabbits (2906 microg/ml x hr and 4074 microg/ml x hr) than that in normal rabbits (2295 microg/ml x hr). The cumulative urinary excretion of tolbutamide was significantly decreased (p<0.05) in medium folate-induced renal failure rabbits (3.3 mg) compared with the normal rabbits (5.9 mg). The elimination rate constant (Kel) of tolbutamide was significantly slower in medium folate-induced renal failure rabbits (0.027 hr(-1)) than that in normal rabbits(0.044 hr(-1)). The terminal half-life of tolbutamide in medium folate-induced renal failure rabbits (25.5 hr) was significantly longer (p<0.01) than in normal rabbits (15.7 hr). These results could be considered as possibly due to inhibited excretion of tolbutamide metabolites or retarded metabolism of tolbutamide.


Microbial cycling of volatile organic sulfur compounds.
Microbial cycling of volatile organic sulfur compounds (VOSCs), especially dimethyl sulfide (DMS) and methanethiol (MT), is intensively studied because these compounds play an important role in the processes of global warming, acid precipitation, and the global sulfur cycle. VOSC concentrations in freshwater sediments are low due to the balance between the formation and degradation of these compounds. These reactions occur for the greater part at the oxic/anoxic interphase of sediment and water column. In contrast to marine ecosystems, where dimethylsulfoniopropionate is the main precursor of MT and DMS, in freshwater ecosystems, VOSCs are formed mainly by methylation of sulfide and to a lesser extent from the degradation of S-containing amino acids. One of the major routes for DMS and MT formation through sulfide methylation is anaerobic O-demethylation of methoxylated aromatic compounds. Inhibition studies have revealed that the major part of the endogenously produced MT and DMS is degraded anaerobically by methanogens. The major bacterial groups involved in formation and consumption of VOSCs are described.


Diagnostic MicroRNA Biomarker Discovery for Non-Small-Cell Lung Cancer Adenocarcinoma by Integrative Bioinformatics Analysis.
Lung cancer is the leading cause of cancer death and its incidence is ranked high in men and women worldwide. Non-small-cell lung cancer (NSCLC) adenocarcinoma is one of the most frequent histological subtypes of lung cancer. The aberration profile and the molecular mechanism driving its progression are the key for precision therapy of lung cancer, while the screening of biomarkers is essential to the precision early diagnosis and treatment of the cancer. In this work, we applied a bioinformatics method to analyze the dysregulated interaction network of microRNA-mRNA in NSCLC, based on both the gene expression data and the microRNA-gene regulation network. Considering the properties of the substructure and their biological functions, we identified the putative diagnostic biomarker microRNAs, some of which have been reported on the PubMed citations while the rest, that is, miR-204-5p, miR-567, miR-454-3p, miR-338-3p, and miR-139-5p, were predicted as the putative novel microRNA biomarker for the diagnosis of NSCLC adenocarcinoma. They were further validated by functional enrichment analysis of their target genes. These findings deserve further experimental validations for future clinical application.


The lysine-49 phospholipase A2 from the venom of Agkistrodon piscivorus piscivorus. Relation of structure and function to other phospholipases A2.
A new class of phospholipases A2 that have a lysine at position 49 differ from the more conventional Asp-49 enzymes with respect to the sequential binding of the essential cofactor, calcium, and the substrate, phospholipid, in the formation of the catalytic complex (Maraganore, J.M., Merutka, G., Cho, W., Welches, W., Kézdy, F.J., and Heinrikson, R.L. (1984) J. Biol. Chem. 259, 13839-13843). We report here the complete amino acid sequence of the Lys-49 enzyme from Agkistrodon piscivorus piscivorus. The sequence was determined by automated Edman degradation of the intact, S-carboxymethylcysteinyl protein and of peptides derived therefrom by cleavage with cyanogen bromide, chymotrypsin, trypsin, and endoproteinase Lys-C. Despite several changes at amino acid residues previously considered to be invariant, the Lys-49 enzymes are homologous to the Asp-49 phospholipases. Homology is especially apparent in the following: 1) the pattern of 14 half-cystine residues, 2) conservation of hydrophobic residues which have been shown to encircle the active site, and 3) conservation of Asp-99 and His-48 which have been implicated in the catalytic reaction itself. These observations together with kinetic and binding data imply that the Lys-49 phospholipases have a catalytic mechanism and a three-dimensional architecture similar to those of the Asp-49 enzymes. Modeling of the Lys-49 enzyme based upon the structure of bovine pancreatic phospholipase reveals that the epsilon-amino group of Lys-49 can fit easily in the calcium-binding site and, moreover, that this orientation of a cationic side chain at position 49 could account for the characteristic and novel feature of the Lys-49 phospholipases, i.e. that they are able to form complexes with phospholipid in the absence of calcium.


Unsteady dynamics of a classical particle-wave entity.
A droplet bouncing on the surface of a vertically vibrating liquid bath can walk horizontally, guided by the waves it generates on each impact. This results in a self-propelled classical particle-wave entity. By using a one-dimensional theoretical pilot-wave model with a generalized wave form, we investigate the dynamics of this particle-wave entity. We employ different spatial wave forms to understand the role played by both wave oscillations and spatial wave decay in the walking dynamics. We observe steady walking motion as well as unsteady motions such as oscillating walking, self-trapped oscillations, and irregular walking. We explore the dynamical and statistical aspects of irregular walking and show an equivalence between the droplet dynamics and the Lorenz system, as well as making connections with the Langevin equation and deterministic diffusion.


Cytotoxicity evaluation of sodium lauryl sulfate in a paper-based 3D cell culture system.
Because three-dimensional (3D) cell culture is more similar to in vivo cell microenvironments than two-dimensional (2D) cell culture, various 3D cell culture systems have been developed. Recently, paper has been used as a promising material for 3D cell culture and tissue models due to its flexibility, ease of manufacture, low cost, and widespread accessibility. In this study, we fabricated a paper-based 3D cell culture platform consisting of a hydrophilic region for cell attachment and a hydrophobic region printed with wax. Using this paper platform for 3D culture of L929 cells, we evaluated the cytotoxicity of a model substance, sodium lauryl sulfate (SLS), using water-soluble tetrazolium salt, Live/Dead, and luminescence assays. Then we compared those cytotoxicity results with results from a conventional 3D cell culture kit and 2D cell culture. We found that 3D cultured cells on paper responded more sensitively to SLS than 2D cultured cells, and the cytotoxicity of SLS to cells grown on the paper-based 3D cell culture platform was similar to that of cells grown using a commercially available 3D cell culture kit. Therefore, we expect that our paper-based 3D cell culture platform can be applied as a simple and facile tool for cell viability evaluation.


Contribution of functional and quantitative genetic variants of Complement Factor H and Factor H-Related (FHR) proteins on renal pathology.
The complement system is a first line of defence against infectious, tumoral or autoimmune processes, and it is constitutively regulated to avoid excessive or unspecific activation. Factor H (FH), a most relevant complement regulator, controls complement activation in plasma and on the cellular surfaces of autologous tissues. FH shares evolutionary origin and structural features with a group of plasma proteins known as FH-Related Proteins (FHRs), which could act as FH functional antagonists. Studies in patient cohorts of atypical Haemolytic-Uraemic Syndrome (aHUS), C3 Glomerulopathy (C3G), and IgA nephropathy (IgAN), have identified rare genetic variants that give rise to severe FH and FHRs dysfunctions, and are major genetic predisposing factors. These patients also have a higher frequency of a few polymorphisms whose relevance as disease risk factors is incompletely understood. In the last years, the availability of specific reagents has allowed a more precise quantitation of FH and FHRs in plasma samples from patients and controls. These studies have revealed that some aHUS, C3G or IgAN risk polymorphisms determine mild changes in FH or FHRs levels that could somehow perturb complement regulation and favour disease pathogenesis.


The Use of External Fixation for the Management of the Unstable Anterior Pelvic Ring.
The objective of this article was to highlight the indications and various methods of external fixation for management of the unstable anterior pelvic ring. Although most often used temporarily in the setting of significant hemorrhage from a pelvic ring fracture, external fixation remains an option for definitive stabilization of select pelvic ring injuries. Classically, the iliac crest frame has been used, although use of the supra-acetabular frame has gained favor due to its superior bone purchase and improved biomechanics. Common complications from external fixation include pin site infections, loss of reduction, and the "external fixator deformity."


A prospective observational study of falling before and after knee replacement surgery.
knee arthritis is a risk factor for falling. Increasing numbers of people are receiving total knee arthroplasty (TKA) but the natural history of falling before and after TKA is unknown. to prospectively monitor falls in pre- and post-operative TKA patients and to identify independent risk factors for post-operative falling. a prospective observational study with a 1-year follow-up. community-dwelling older people recruited from a regional orthopaedic centre. consecutive patients added to the TKA waiting list who completed monthly falls diaries, pre-operatively and 1 year post-operatively. Data on knee status (WOMAC: pain, stiffness and function), balance confidence (the Activities Balance Confidence Scale-UK-ABC-UK) and mood (Geriatric Depression Scale-GDS) were collected at quarterly intervals. ninety-nine patients received a primary TKA. 24.2% fell in the last pre-operative quarter (24 patients reported 44 falls) and this decreased to 11.7-11.8% in the first four post-operative quarters. 45.8% of people who fell pre-operatively fell again in the first post-operative year. Higher pre-operative GDS scores and a history of falling were significant independent predictors of post-operative falling. a recent history of falling is common in people undergoing TKA and approximately 45% of patients fall again in the year following surgery. Patients being considered for TKA should be asked about falls history and undergo falls risk assessment and intervention.


Endometrial Tuberculosis: Hysteroscopic Findings of a Clinical Case.
Endometrial tuberculosis is a rare diagnosis in the postmenopausal period, and it can mimic a carcinoma. The present article describes the case of a 54-year-old female patient with weight loss, abdominal pain, and ascites. An ultrasonography showed endometrial thickening, and a video hysteroscopy revealed a uterine cavity with formations with cotton aspect covering the entire endometrial surface and the tubal ostia. An anatomopathological evaluation diagnosed endometrial tuberculosis. The treatment was with a standardized therapeutic scheme (ethambutol, isoniazid, pyrazinamide and rifampicin), and the patient evolved with clinical improvement and normal uterine cavity at hysteroscopy. Considering the lack of pathognomonic hysteroscopic findings of the disorder, it is important to disclose the images of the case.


Viewpoint: Challenges in Colloidal Photocatalysis and Some Strategies for Addressing Them.
Colloidal semiconductor nanocrystals, or "quantum dots" (QDs), have several optical and chemical properties that give them the potential to enable nonincremental increases in the efficiencies of many types of photocatalytic reactions relevant for energy conversion and organic synthesis. Colloidal photocatalysts have many desirable characteristics of both heterogeneous and homogeneous catalysts but come with their own particular set of challenges. This viewpoint outlines some of the obstacles one first encounters when driving reactions with these colloids and offers some strategies for overcoming these obstacles, including ways to extend their excited state lifetimes, prevent corrosion by photogenerated holes, and choose a surface chemistry and buffering system for maximum colloidal stability over a range of environmental conditions.


Testosterone in females: mediator of adaptive traits, constraint on sexual dimorphism, or both?
When selection on males and females differs, the sexes may diverge in phenotype. Hormones serve as a proximate regulator of sex differences by mediating sex-biased trait expression. To integrate these perspectives, we consider how suites of traits mediated by the same hormone in both sexes might respond to selection. In male birds, plasma testosterone (T) varies seasonally and among species according to mating system. When elevated experimentally, it is known to enhance some components of fitness and to decrease others. We report that female T also varies seasonally and co-varies with male T. Female T is higher in relation to male T in sexually monomorphic species and is higher absolutely in females of species with socially monogamous mating systems, which suggests adaptation. We also consider the effect of experimentally elevated T on females and whether traits are sensitive to altered T. We hypothesize that sensitive traits could become subject to selection after a natural change in T and that traits with opposing fitness consequences in males and females could constrain dimorphism. Results from birds, including the dark-eyed junco (Junco hyemalis), reveal many sensitive traits, some of which appear costly and may help to account for observed levels of sexual dimorphism.


[A trial of combination chemotherapy. Cis-platinum, peplomycin and adriamycin for advanced prostatic cancer].
Between September 1982 and May 1984, combination chemotherapy with cis-platinum, peplomycin and adriamycin was administered to 12 patients with histologically confirmed adenocarcinoma of the prostate and progressive disease with evaluable parameters. Cis-platinum (CDDP) 20 mg/sqm was administered intravenously on Days 1-5, peplomycin 5 mg/sqm by 24-hour continuous drip infusion on day 1-5 and adriamycin 25 mg/sqm on Day 1. This course was repeated every 28 days. The dose and schedule were modified by hematologic toxicity or other side effects. One patient refused therapy because of severe nausea and vomiting; therefore 11 patients were eligible for response evaluation. Of the 11 patients, two had a documented PR, five had SD and four had PD. Ten patients whose disease eventually progressed received a second line of therapy consisting either of estramustine or estrogen. Of these ten patients, 6 had a documented PR, one had SD and three had PD. It is concluded that this combination chemotherapy regimen may prime advanced prostatic cancer to respond to hormonal therapy, even though it has only a limited effect on advanced prostatic cancer.


Intravital microscopy in historic and contemporary immunology.
In this review, we discuss intravital microscopy of immune cells, starting from its historic origins to current applications in diverse organs. It is clear from a quantitative review of the literature that intravital microscopy is a key tool in both historic and contemporary immunological research, providing unique advances in our understanding of immune responses. We have chosen to focus this review on how intravital microscopy methodologies are used to image specific organs or systems and we present recent descriptions of fundamental immunological processes that could not have been achieved by other methods. The following target organs/systems are discussed in more detail: cremaster muscle, skin (ear and dorsal skin fold chamber), lymph node, liver, lung, mesenteric vessels, carotid artery, bone marrow, brain, spleen, foetus and lastly vessels of the knee joint.


Antithrombin Oslo: type Ib classification of the first reported antithrombin-deficient family, with a review of hereditary antithrombin variants.
Patients with classical antithrombin deficiency (Type I) from seven unrelated kindreds were studied by crossed immunoelectrophoresis of plasma in the presence and absence of heparin. The only abnormal pattern was found in the kindred first reported by Egeberg in 1965. An abnormal cathodal peak of antithrombin antigen was found in the presence, but not the absence, of heparin in the first dimension gel. We have named this variant antithrombin Oslo. Such evidence of an abnormal protein, despite equivalent low levels of antithrombin antigen and activity, has been denoted previously by Sas as Type Ib deficiency. In the context of this new report, we review the literature to date on 33 other variants of the Types Ib, II and III subclassifications with a discussion of the value of the classification scheme.


Formation of "Steady Size" State for Accurate Size Control of CdSe and CdS Quantum Dots.
We report on the formation of a "steady size" state for the growth of CdSe and CdS quantum dots (QDs), in which the size of the QDs remains constant and independent of reaction time. Kinetic study reveals that this state exists only when certain coordinating ligands are within a range between NS and NV + NS. NS and NV represent the number of atoms on the surface of the QDs and the total amount of atoms in the QDs, respectively. Under this condition, the size R of the QDs can be controlled solely by the reaction temperature T with a relationship of 1/R2 ∼ T. More importantly, a highly reproducible and accurate linear control of the emission wavelength of QDs on a subnanometer scale by the reaction temperature is achieved. The discovery enables large-scale synthesis of QDs with minimum size variation that meets critical demands on wavelength accuracy for QD-based optoelectronic applications.


Consequences of adolescent drug use and personality factors on adult drug use.
This study examined the stability of adolescent drug use into young adulthood and explored the possible influence of personality on adolescent and adult drug use. Participants in this longitudinal study (N = 640) completed questionnaires which assessed multiple indicators for latent constructs of tobacco, alcohol, cannabis, and hard drugs, and also for the personality constructs of Socialization. In addition, the effects of obedience and extraversion were examined. Results showed that a general drug use factor in adolescence significantly predicted young adult drug use. A particular effect of adolescent obedience on adult drug use was noted. Within adolescence, obedience, extraversion, and the construct of Socialization were significant predictors of drug use. Early onset of smoking predicted adolescent drug use. The implications of these findings for early drug use education and intervention are discussed. Additional analysis explored the possibility of treating obedience as another indicator of Socialization. This model could not provide as good a fit as the original model. The measure of obedience acted as a better predictor of drug use than an overall factor of Socialization. Gender differences are discussed.


The tissue content and turnover rates of intermediates in the biosynthesis of glycosaminoglycans in young rat skin.
1. The tissue contents of hexose monophosphate, N-acetylglucosamine 6-phosphate, UDP-glucose, UDP-galactose, UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine and UDP-glucuronic acid were determined in the skin of young rats less than 1 day post partum. Tissue-space determinations were used to calculate their average cellular concentrations. 2. The incorporation of [U-(14)C]-glucose into the intermediates was recorded with time and their rates of turnover were calculated. The results demonstrated product-precursor relationships along the pathway of hexosamine synthesis and that of hexuronic acid synthesis. The rates of synthesis of UDP-N-acetylhexosamine and UDP-glucuronic acid were 1.5+/-0.3 and 0.24+/-0.03mmumoles/min./g. of tissue respectively. These results indicated the average turnover time of the total tissue glycosaminoglycans to be about 5 days.


Ethanol-like effects of thiopental and ketamine in healthy humans.
The gamma-aminobutyric acid-A (GABA(A)) and N-methyl-D-aspartate (NMDA) receptors mediate aspects of the behavioural effects of alcohol. Prior studies reported drugs that block NMDA receptors or facilitate GABA(A) receptor function produce ethanol-like effects in humans. The purpose of this study was to compare the ethanol-related effects of two pharmacological agents with known NMDA and GABA(A) receptor activity. As part of an ongoing, larger study, 28 subjects (age, 21-30) with no personal or family histories of alcoholism were administered subanesthetic doses of the GABA(A) receptor agonist thiopental, the NMDA receptor antagonist, ketamine and placebo on three separate test days. Various ethanol-related measures were administered. At doses of thiopental and ketamine that produced similar levels of sedation and cognitive effects, both agents produced significant ethanol-like effects and subjective intoxication. However, the intensity of the ethanol-like effects of ketamine was greater than that of thiopental. In addition, ketamine produced alterations in perception that were not produced by thiopental. These data provide further support for a model where GABA(A) receptor facilitation may contribute significantly to ethanol effects associated with social drinking, whereas NMDA receptor antagonism may contribute to relatively greater extent to features of ethanol 'intoxication'.


Effect of the phenotype of the M1-middle cerebral artery occlusion on the recanalization rates in the ASTER trial.
An adequate recanalization grade is an independent predictor of a good clinical outcome in patients with acute ischemic stroke. It can be obtained with stent retrievers (SR) and contact aspiration (CA). The aim of this ancillary study of the ASTER trial was to investigate the effect of the regular and irregular phenotype of the M1-middle cerebral artery (M1-MCA) segment occlusion on the procedural and clinical outcomes in the ASTER trial population. The predetermined occlusion phenotype assessment was performed by the core laboratory of the ASTER trial and patients with M1-MCA occlusion were included in this study. Clinical and procedural outcomes were analyzed according to the technique used and to the occlusion phenotype. 188 patients were included in the analysis (95 received SR, 93 CA as first-line treatment). The occlusion phenotypes were graded as irregular in 52.7% of cases (n=99, 95% CI 45.5% to 59.8%). In patients with an irregular occlusion phenotype, complete or adequate recanalization at the end of the first-line strategy was more often achieved with SR than CA (TICI 3: SR 44.1% vs CA 22.5%, OR 0.35, 95% CI 0.14 to 0.89, p=0.027), with a shorter procedure time, a lower number of passes (>2 passes: SR 32.2% vs CA 57.5%, OR 3.31, 95% CI 1.36 to 8.03, p=0.009), and higher rates of favorable clinical outcome (SR 55.2% vs CA 31.6%, OR 0.40, 95% CI 0.16 to 0.97, p=0.042). Irregular M1-MCA occlusion phenotypes treated with SR as first-line approach were associated with better procedural and clinical outcomes in the ASTER trial population.


Relations and dependencies between morphological characters.
In biological classification, a character is a property of a taxon that can distinguish it from other taxa. Characters are not independent, and the relations between characters can arise from structural constraints, developmental pathways or functional constraints. That has lead to famous controversies in the history of biology. In addition, a character as a tool of data analysis has some subjective aspects. In this contribution, I develop algebraic and geometric schemes to address these issues in a mathematical framework.


Properties of primary motor cortex output to hindlimb muscles in the macaque monkey.
The cortical control of forelimb motor function has been studied extensively, especially in the primate. In contrast, cortical control of the hindlimb has been relatively neglected. This study assessed the output properties of the primary motor cortex (M1) hindlimb representation in terms of the sign, latency, magnitude, and distribution of effects in stimulus-triggered averages (StTAs) of electromyography (EMG) activity recorded from 19 muscles, including hip, knee, ankle, digit, and intrinsic foot muscles, during a push-pull task compared with data reported previously on the forelimb. StTAs (15, 30, and 60 μA at 15 Hz) of EMG activity were computed at 317 putative layer V sites in two rhesus macaques. Poststimulus facilitation (PStF) was distributed equally between distal and proximal muscles, whereas poststimulus suppression (PStS) was more common in distal muscles than proximal muscles (51/49%, respectively, for PStF; 72/28%, respectively, for PStS) at 30 μA. Mean PStF and PStS onset latency generally increased the more distal the joint of a muscle's action. Most significantly, the average magnitude of hindlimb poststimulus effects was considerably weaker than the average magnitude of effects from forelimb M1. In addition, forelimb PStF magnitude increased consistently from proximal to distal joints, whereas hindlimb PStF magnitude was similar at all joints except the intrinsic foot muscles, which had a magnitude of approximately double that of all of the other muscles. The results suggest a greater monosynaptic input to forelimb compared with hindlimb motoneurons, as well as a more direct synaptic linkage for the intrinsic foot muscles compared with the other hindlimb muscles.


The efficacy of an iterative "sequence of prevention" approach to injury prevention by a multidisciplinary team in professional rugby union.
Due to the complex systems nature of injuries, the responsibility for injury risk management cannot lie solely within a single domain of professional practice. Interdisciplinary collaboration between technical/tactical coaches, strength and conditioning coaches, team doctors, physical therapists and sport scientists is likely to have a meaningful impact on injury risk. This study describes the application and efficacy of a multidisciplinary approach to reducing team injury risk in professional rugby union. Observational longitudinal cohort study. Epidemiological injury data was collected from a professional rugby union team for 5 consecutive seasons. Following each season, these data informed multidisciplinary intervention strategies to reduce injury risk. The effectiveness of these strategies was iteratively assessed to inform future interventions. Specific examples of intervention strategies are provided. Overall team injury burden displayed a likely beneficial decrease (-8%; injury rate ratio (IRR) 0.9, 95%CI 0.9-1.0) from 2012 to 2016. This was achieved through a most likely beneficial improvement in non-contact injury burden (-39%; IRR 0.6, 95%CI 0.6-0.7). Contact injury burden was increased, but to a lesser extent (+18%; IRR 1.2, 95%CI 1.1-1.3, most likely harmful) during the same period. The range of skills required to effectively manage complex injury phenomena in professional collision sport crosses disciplinary boundaries. The evidence presented here points to the effectiveness of a multidisciplinary approach to reducing injury risk. This model will likely be applicable across a range of team and individual sports.


Stem cells and progenitor cells in renal disease.
Stem cells and progenitor cells are necessary for repair and regeneration of injured renal tissue. Infiltrating or resident stem cells can contribute to the replacement of lost or damaged tissue. However, the regulation of circulating progenitor cells is not well understood. We have analyzed the effects of erythropoietin on circulating progenitor cells and found that low levels of erythropoietin induce mobilization and differentiation of endothelial progenitor cells. In an animal model of 5/6 nephrectomy we could demonstrate that erythropoietin ameliorates tissue injury. Full regeneration of renal tissue demands the existence of stem cells and an adequate local "milieu," a so-called stem cell niche. We have previously described a stem cell niche in the kidneys of the dogfish, Squalus acanthus. Further analysis revealed that in the regenerating zone of the shark kidney, stem cells exist that can be induced by loss of renal tissue to form new glomeruli. Such animal models improve our understanding of stem cell behavior in the kidney and may eventually contribute to novel therapies.


Antiarthritic Effect of Polar Extract of Curcuma longa on Monosodium Iodoacetate Induced Osteoarthritis in Rats.
Curcuma longa Linn, "the golden spice" is a common spice used in Southern Asia and Middle East countries. It has a history of ethnopharmacological use for its various activities like anti-septic, anti-inflammatory, anti-oxidant, anti-microbial, anti-cancer and so on. To investigate the effects of polar extract of C. longa (PCL) against monosodium iodoacetate (MIA) induced osteoarthritis in rat and to compare with curcuminoids, which are contemporarily believed to be the only active phytochemicals of C. longa for relieving pain in osteoarthritis. Osteoarthritis in rats was induced by intra-articular injection of monosodium iodoacetate (MIA) in right knee. PCL or curcuminoids or tramadol was administered orally as single dose on the 5th day post MIA injection to rats. Weight bearing capacity and percentage inhibition of nociception of PCL treated groups were determined and compared with curcuminoids and tramadol (reference drug). In addition, gene expression levels of type II collagen and matrix metalloproteinases (MMP) in joint cartilage was measured by Reverse transcription polymerase chain reaction. PCL significantly decreased the difference in weight distribution between left and right limb in a dose dependent manner. Anti-arthritic activity of PCL is evident from significant up regulation of type II collagen gene (COL2A1) and down regulation of MMP-3 and MMP-7. Polar extract of C. longa showed beneficial effects on joints by exhibiting antiosteoarthritic effects via maintaining equilibrium between anabolic and catabolic factors of joint cartilage.


Haloperidol-Midazolam vs. Haloperidol-Ketamine in Controlling the Agitation of Delirious Patients; a Randomized Clinical Trial.
Agitation management in delirious patients is crucial in a crowded emergency department (ED) for both patient and personnel safety. Benzodiazepines, antipsychotics, and newly derived ketamine are among the most commonly used drugs in controlling these cases. This study aimed to compare the effectiveness of haloperidol-midazolam with haloperidol-ketamine combination in this regard. In this double-blind randomized clinical trial, delirious patients with agitation in ED were randomly assigned to a group: group A: haloperidol 2.5 mg IV and midazolam 0.05 mg/kg IV or group B: haloperidol 2.5 mg IV and ketamine 0.5 mg/kg IV. Sedative effects as well as side effects at 0, 5, 10, 15, 30 minutes and 1, 2, 4 hours after the intervention were compared between the 2 groups. We enrolled 140 cases with Altered Mental Status Score (AMSS)≥+2 and mean age of 52.819.4 years (78.5% male). Agitation was significantly controlled in both groups (p<0.05). In group B, AMSS score was more significantly and rapidly reduced 5 (p = 0.021), 10 (p = 0.009), and 15 (p = 0.034) minutes after drug administration. After intervention, oxygen saturation was significantly decreased in group A 5 (p = 0.031) and 10 (p = 0.019) minutes after baseline. Time required to the maximum effect was significantly lower in group B versus group A (p=0.014). Less patients in group B had major side effects (p=0.018) and needed physical restraint (p=0.001). Haloperidol-ketamine can control agitation in delirium more rapidly than haloperidol-midazolam. This combination had lower adverse events with lower need for physical restraint.


Concurrent versus terminal feedback: The effect of feedback delivery on lumbar puncture skills in simulation training.
Simulation-based medical education (SBME) is widely used to teach bedside procedural skills. Feedback is crucial to SBME but research on optimal timing to support novice learners' skill development has produced conflicting results. We randomly assigned 32 novice medical students to receive feedback either during (concurrent) or after (terminal) trialing lumbar puncture (LP). Participants completed pre- and post-acquisition tests, as well as retention and transfer tests, graded on a LP checklist by two blinded expert raters. Cognitive load and anxiety were also assessed, as well as learners' perceptions of feedback. Participants who received concurrent feedback demonstrated significantly higher LP checklist scores (M = 91.54, SE = 1.90) after controlling for baseline levels, than those who received terminal feedback (M = 85.64, SE = 1.90), collapsed across post, retention, and transfer tests. There was no difference in cognitive load and anxiety between groups. In open-ended responses, participants who received concurrent feedback more often expressed satisfaction with their learning experience compared to those who received terminal feedback. Concurrent may be superior to terminal feedback when teaching novice learners complex procedures and has the potential to improve learning if incorporated into SBME and clinical teaching. Further research is needed to elucidate underlying cognitive processes to explain this finding.


[Consequences of short term fluctuations of the environmental temperatures in calves--Part 2: Effects on the health status of animals within three weeks after exposure].
The aim of the present study was to examine consequences of sudden changes in ambient temperature over a 4-hour period (see part 1 [ELMER & REINHOLD, 2002]) on respiratory health in clinically healthy calves. Therefore, the relationship between short-term changes in ambient temperature and the occurrence of clinical respiratory disease was checked over a period of 3 weeks after exposure in 10 calves exposed to 5 degrees C, in 9 calves exposed to 35 degrees C and in 8 control calves (kept at 18-20 degrees C). Within the period beginning 3 days before exposure and lasting until up to 21 days after exposure, each calf was examined clinically. Rectal temperature and respiratory rate were measured daily. All calves were euthanised on day 21 after exposure. Macroscopically visible pneumonic lesions were evaluated using a semiquantitative system. Tissue samples from tonsils, bronchi, trachea, lung and mediastinal lymph nodes were examined bacteriologically. In contrast to non-exposed control calves, severe respiratory illness was observed in individual calves of both exposed groups (5 degrees C, 35 degrees C). Significant increases in body temperature, respiratory rate and animal losses (2 calves died in the group exposed to 5 degrees C, one calf died in the group exposed to 35 degrees C) were the main clinical findings. At necropsy (3 weeks after exposure), no pneumonic lesions were observed in control calves--despite the fact that this group had the highest microbiological colonisation rates in tonsils and in large airways, i.e. trachea and bronchi, within all groups. However, variable pneumonic lung lesions were seen in remaining calves exposed to cold or warm air (5 degrees C, 35 degrees C). The microbiological examination confirmed that mainly Mycoplasma spp. were identified in the lung tissue of calves exposed to 5 degrees C while Pasteurella multocida and/or Mannheimia haemolytica were the only germs found in the lung tissue of calves exposed to 35 degrees C. The results of parts 1 and 2 of the present study related to health issues of calves should be taken into account for future legislation on animal welfare.


A CCAAT/enhancer-binding protein site at -87 is required for the activation of a novel murine melanocortin 2-receptor promoter at late stages during adipogenesis.
The peptide hormone ACTH stimulates lipolysis and suppresses leptin production in adipocytes via the G protein-coupled receptor, melanocortin 2 receptor (MC2-R). We have shown previously that peroxisome proliferator-activated receptor-gamma2 is the primary factor responsible for transactivation of the already identified murine MC2-R promoter in the differentiating 3T3-L1 adipocyte cell line. In this study we show that despite the activity of this promoter being transient during differentiation, MC2-R message remains elevated at later time points during adipogenesis. Analysis of the late transcripts reveals that they initiate from a transcriptional start site in the first intron of the murine MC2-R. The genomic sequence upstream of this start site acts as an adipocyte-specific promoter whose activation is delayed in differentiation, compared with the upstream promoter. A CCAAT/enhancer-binding protein binding site, 87 bp upstream of the transcriptional initiation site, is necessary for the activity of this promoter, and protein binding analyses reveal that this site is bound by CCAAT/enhancer-binding protein factors. Real-time PCR analysis of mRNA initiating from the two start sites shows that there is a switch in promoter usage from the 5' to the 3' promoter around d 5, indicating the complex regulation of the murine MC2-R during adipogenesis.


Human-resource professionals' perceptions of organizational politics as a function of experience, organizational size, and perceived independence.
The author examined human-resource professionals' occupation-related and general work experience, socialization from participation in professional activities, organizational size, and perceived independence as predictors of perceptions of organizational politics (POPS). Results varied with the author's use of the overall POPS scale (K. M. Kacmar & G. R. Ferris, 1991) vs. a more specific subscale that measured perceptions related to such issues as pay- and promotion-related politics. It was most notable that work experience appeared to have an inverse relationship with POPS among human-resource professionals in the area of pay and promotions. The author discussed results in relation to the implications and directions for future research.


The Impact of Cocaine Use and the Obesity Paradox in Patients With Heart Failure With Reduced Ejection Fraction Due to Non-ischemic Cardiomyopathy.
Background Obesity and illicit drugs are independent risk factors for developing heart failure (HF). However, recent studies have suggested that patients who already have HF and are obese have better clinical outcomes. We aim to study the effect of cocaine use on this obesity paradox phenomenon as it pertains to HF readmissions. Methodology In a retrospective chart analysis, we reviewed patients with a diagnosis of HF with reduced ejection fraction (HFrEF) admitted to Metropolitan Hospital in New York. We studied the association between body mass index (BMI) categories, namely, non-obese (<30 kg/m2) and obese (≥30 kg/m2), cocaine use, and the primary outcome (time to readmission for HF within 30 days after discharge). The interaction between cocaine and obesity status and its association with the primary outcome was also assessed. Results A total of 261 patients were identified. Non-obese status and cocaine use were associated with an increased hazard of readmission in 30 days (hazard ratio (HR) = 2.28, p = 0.049 and HR = 3.12, p = 0.004, respectively). Furthermore, cocaine users who were non-obese were over six times more likely to be re-admitted in 30 days compared to non-cocaine users who were obese (HR = 6.45, p = 0.0002). Conclusions Non-obese status and continued use of cocaine have a negative additive effect in impacting HF readmissions.


Pregabalin and Persistent Postoperative Pain Following Posterior Spinal Fusion in Children and Adolescents: A Randomized Clinical Trial.
Surgical correction of spinal deformity requires major surgical intervention with extensive manipulation of the spine and neural elements. Persistent postoperative pain affects patient quality of life and can also cause financial burden for patient families and for society. We aimed to investigate the effect of perioperative pregabalin on the incidence of persistent pain following instrumented spinal fusion. We conducted a randomized, double-blinded, and placebo-controlled single-center clinical trial. Adolescents and children 10 to 21 years old with a spinal deformity who were scheduled for pedicle screw instrumentation and fusion were randomized into either the pregabalin or placebo group. Patients received 2 mg/kg of pregabalin or a placebo twice daily preoperatively and for 5 days postoperatively. The duration of follow-up was 2 years. The primary outcomes were cumulative opioid consumption during the first 48 hours postoperatively and the incidence of persistent postoperative pain over the course of the 2-year follow-up. Sixty-four of 77 eligible patients were enrolled in the study, with all patients completing the 2-year follow-up. Thirty-three patients were randomized into the pregabalin group and 31 into the placebo group. There was no significant difference in cumulative 48-hour opioid consumption between the study groups. The Scoliosis Research Society 24-Item Questionnaire pain domain score improved significantly, from a mean value of 3.8 in both groups to 4.3 in the pregabalin and 4.0 in the placebo group at 2 years postoperatively, with no differences between the study groups at any time point (p = 0.317). The Scoliosis Research Society total scores of the study groups were similar (p = 0.678). Back pain, as measured with use of a visual analogue scale, improved significantly (p = 0.001) with no significant differences at any time point (preoperatively and 6 months, 1 year, and 2 years postoperatively). Perioperative pregabalin does not reduce postoperative opioid consumption or the incidence of persistent postoperative pain following instrumented posterior spinal fusion for spinal deformities in an adolescent population. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.


Synthesis of heterocycles by formal cycloadditions of isocyanides.
Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one-pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes.


Basidiospore homoplasy and variation in the Inocybe chelanensis group in North America.
We present a morphological and phylogenetic study of Inocybe chelanensis and other North American species of Inocybe that have unusually elongated nodulose spores. Taxonomy and illustrations of these species are provided, along with a key to these and similar species found in Europe and North America. The species concept of I. chelanensis is broadened to include the range of variation occurring for the species in North America. Despite similar basidiospore morphologies, I. chelanensis and I. candidipes are not closely related. Inocybe chelanensis is related more closely to I. stellatospora and I. candidipes is related to I. glabrodisca based on RPB1 and nLSU-rDNA nucleotide sequences. Distal enlongation of Inocybe basidiospores was achieved independently in at least two separate lineages of Inocybe. Inocybe candidipes and I. sierraensis are described as new.


'Special units for common problems': the birth of alcohol treatment units in England.
In 1962 the Ministry of Health issued a memorandum entitled The Hospital Treatment of Alcoholism. The memorandum was the first official statement specifically regarding the treatment of alcoholism within the National Health Service. It marked the end of an era characterized by Ministry of Health rejection of the need to review policies regarding alcohol consumption and alcoholism treatment and the entry of the Ministry into the emerging alcohol arena. This paper uses documentary sources and interview material to examine the events leading up to the memorandum and its recommendation to Regional Health Authorities to establish specialist alcoholism treatment units. The development of such units was not supported by everyone in the alcohol field at that time and the paper discusses the pressures on Department of Health officials which appear to have influenced policy choices. The fact that pressures come from different sources, some advocating different policy options, raises the question: did medical perspectives and evidence for the specialist treatment approach influence policy or did policy makers select the option best fitted to existing Departmental interests?


In vitro activity against Staphylococcus aureus of a novel antimicrobial agent, PRF-119, a recombinant chimeric bacteriophage endolysin.
Antistaphylococcal activity of the novel chimeric endolysin PRF-119 was evaluated with the microdilution method. The MIC(50) and MIC(90) of 398 methicillin-susceptible Staphylococcus aureus isolates were 0.098 μg/ml and 0.391 μg/ml, respectively (range, 0.024 to 0.780 μg/ml). Both the MIC(50) and MIC(90) values of 776 methicillin-resistant S. aureus isolates were 0.391 μg/ml (range, 0.024 to 1.563 μg/ml). All 192 clinical isolates of coagulase-negative staphylococci exhibited MIC values of >50 μg/ml. In conclusion, PRF-119 exhibited very good activity specifically against S. aureus.


Structural deformations of two-dimensional planar structures under uniaxial strain: the case of graphene.
In the present work, a method for the study of the structural deformations of two dimensional planar structures under uniaxial strain is presented. The method is based on molecular mechanics using the original stick and spiral model and a modified one which includes second nearest neighbor interactions for bond stretching. As we show, the method allows an accurate prediction of the structural deformations of any two dimensional planar structure as a function of strain, along any strain direction in the elastic regime, if structural deformations are known along specific strain directions, which are used to calculate the stick and spiral model parameters. Our method can be generalized including other strain conditions and not only uniaxial strain. We apply this method to graphene and we test its validity, using results obtained from ab initio density functional theory calculations. What we find is that the original stick and spiral model is not appropriate to describe accurately the structural deformations of graphene in the elastic regime. However, the introduction of second nearest neighbor interactions provides a very accurate description.


In vitro computer analysis of crown discolouration from commonly used endodontic sealers.
The aim of this study was to assess the degree of staining of tooth crowns by commonly used endodontic sealers using a computer analysis method. Crown discolouration by root canal sealers AH26, Endofill, Tubliseal, Zinc oxide eugenol (ZnOE), Apatite root canal sealer III as well as gutta-percha and Cavizol (a filling material containing ZnOE) were tested on extracted human premolar teeth. The roots of the teeth were resected 3 mm below the cemento-enamel junction. The pulp chambers were then cleaned and irrigated. The samples were divided into nine groups of five samples each and filled with test materials. Ten teeth were used as control groups: five positive (amalgam) and five negative (distilled water). The degree of tooth discolouration was analysed at 3, 6 and 9 months. The crown discolouration was assessed by computer analysis of digital images taken from the samples using the CIE Lab colour system. Statistical analysis was carried out using anova, repeated measure anova and Tukey's HSD tests. All sealers caused a degree of tooth discolouration, which increased with time. Endofill and ZnOE caused the greatest discolouration and Apatite root canal sealer III caused the least discolouration after 9 months. The most discolouration during the test periods occurred in the cervical third of the crown.


Isolation of DNA sequences preferentially expressed during sporulation in Saccharomyces cerevisiae.
A differential hybridization screen has been used to identify genes cloned from the yeast Saccharomyces cerevisiae that are expressed preferentially during sporulation. Duplicate copies of a partial Sau3A yeast DNA library prepared in the vector pBR322 were hybridized with radioactive cDNA probes representing the mRNA populations of sporulating a alpha cells and asporogenous alpha alpha cells at various times after transfer to sporulation medium. Thirty-eight clones showed an enhanced hybridization signal with the a alpha sporulation probe relative to the alpha alpha control cDNA probe. A comparison of the array of fragments produced by restriction endonuclease digestion of these plasmids suggested that 15 different sequences had been cloned. An RNA blot analysis using these cloned DNAs to probe RNAs purified from aa, a alpha, and alpha alpha cells harvested either during vegetative growth or at 10 h after transfer to sporulation medium indicated that 14 different sporulation-specific genes had been identified. Transcripts complementary to these genes are present only in a alpha cells after transfer to sporulation medium. Three of these clones contain two sporulation-specific genes. Three genes have been identified that are expressed in all cell types during vegetative growth and only in a alpha cells in sporulation medium.


Genome Mining and Assembly-Line Biosynthesis of the UCS1025A Pyrrolizidinone Family of Fungal Alkaloids.
UCS1025A is a fungal polyketide/alkaloid that displays strong inhibition of telomerase. The structures of UCS1025A and related natural products are featured by a tricyclic furopyrrolizidine connected to a trans-decalin fragment. We mined the genome of a thermophilic fungus and activated the ucs gene cluster to produce UCS1025A at a high titer. Genetic and biochemical analysis revealed a PKS-NRPS assembly line that activates 2S,3S-methylproline derived from l-isoleucine, followed by Knoevenagel condensation to construct the pyrrolizidine moiety. Oxidation of the 3S-methyl group to a carboxylate leads to an oxa-Michael cyclization and furnishes the furopyrrolizidine. Our work reveals a new strategy used by nature to construct heterocyclic alkaloid-like ring systems using assembly line logic.


Glutamine/glutamate (Glx) concentration in prefrontal cortex predicts reversal learning performance in the marmoset.
This study used Magnetic Resonance Spectroscopy (MRS) to identify potential neurometabolitic markers of cognitive performance in male (n = 7) and female (n = 8) middle-aged (∼5 years old) common marmosets (Callithrix jacchus). Anesthetized marmosets were scanned with a 4.7 T/40 cm horizontal magnet equipped with 450 mT/m magnetic field gradients and a 20 G/cm magnetic field gradient insert, within 3 months of completing the CANTAB serial Reversal Learning task. Neurometabolite concentrations of N-Acetyl Asparate, Myo-Inositol, Choline, Phosphocreatine + creatine, Glutamate and Glutamine were acquired from a 3 mm3 voxel positioned in the Prefrontal Cortex (PFC). Males acquired the reversals (but not simple discriminations) faster than the females. Higher PFC Glx (glutamate + glutamine) concentration was associated with faster acquisition of the reversals. Interestingly, the correlation between cognitive performance and Glx was significant in males, but not in females. These results suggest that MRS is a useful tool to identify biochemical markers of cognitive performance in the healthy nonhuman primate brain and that biological sex modulates the relationship between neurochemical composition and cognition.


Stepwise association of hydrogen cyanide and acetonitrile with the benzene radical cation: structures and binding energies of (C6H6•+)(HCN)n, n = 1-6, and (C6H6•+)(CH3CN)n, n = 1-4, clusters.
Equilibrium thermochemical measurements using the ion mobility drift cell technique have been utilized to investigate the binding energies and entropy changes associated with the stepwise association of HCN and CH(3)CN molecules with the benzene radical cation in the C(6)H(6)(•+)(HCN)(n) and C(6)H(6)(•+)(CH(3)CN)(n) clusters with n = 1-6 and 1-4, respectively. The binding energy of CH(3)CN to the benzene cation (14 kcal/mol) is stronger than that of HCN (9 kcal/mol) mostly due to a stronger ion-dipole interaction because of the large dipole moment of acetonitrile (3.9 D). However, HCN can form hydrogen bonds with the hydrogen atoms of the benzene cation (CH(δ+)···NCH) and linear hydrogen bonding chains involving HCN···HCN interaction. HCN molecules tend to form externally solvated structures with the benzene cation where the ion is hydrogen bonded to the exterior of HCN chains. For the C(6)H(6)(•+)(CH(3)CN)(n) clusters, internally solvated structures are formed where the acetonitrile molecules are directly interacting with the benzene cation through ion-dipole and hydrogen bonding interactions. The lack of formation of higher clusters with n > 4, in contrast to HCN, suggests the formation of a solvent shell at n = 4, which is attributed to steric interactions among the acetonitrile molecules attached to the benzene cation and to the presence of the blocking CH(3) groups, both effects make the addition of more than four acetonitrile molecules less favorable.


Local fibrin glue and chitosan-based dressings in haemophilia surgery.
Fibrin glue and chitosan-based dressings (CBDs) could be useful local haemostatic agents for severe haemorrhage in persons with haemophilia undergoing surgical procedures. The aim of the present study was to clarify the role of fibrin glue and CBDs in persons with haemophilia. A review of the most recent literature on the topic was performed. Local fibrin glue and CBDs are not always necessary to achieve haemostasis in all surgical procedures performed in persons with haemophilia. However, they could be good adjunct therapies, mainly when a surgical field or a surgical wound potentially will bleed more than expected (i.e. patients with inhibitors), and also circumcisions, dental extractions, and some orthopaedic procedures (mainly the surgical removal of pseudotumours). Although a correct surgical haemostasis can be usually achieved by the infusion of factor concentrate at the right dose, my recommendation for surgeons is always to have fibrin glue and CBDs by their side. CBDs could be better haemostatic dressings for control of haemorrhage than current standards of care. To clarify the real value of fibrin glue and CBDs in surgery of haemophilia in specific situations new well designed prospective comparative studies should be carried out.


Evaluating the submission of digital images as a method of surveillance for Ixodes scapularis ticks.
Widespread access to the internet is offering new possibilities for data collection in surveillance. We explore, in this study, the possibility of using an electronic tool to monitor occurrence of the tick vector of Lyme disease, Ixodes scapularis. The study aimed to compare the capacity for ticks to be identified in web-based submissions of digital images/photographs, to the traditional specimen-based identification method used by the provincial public health laboratory in Quebec, Canada. Forty-one veterinary clinics participated in the study by submitting digital images of ticks collected from pets via a website for image-based identification by an entomologist. The tick specimens were then sent to the provincial public health laboratory to be identified by the 'gold standard' method using a microscope. Of the images submitted online, 74·3% (284/382) were considered of high-enough quality to allow identification. The laboratory identified 382 tick specimens from seven different species, with I. scapularis representing 76% of the total submissions. Of the 284 ticks suitable for image-based species identification, 276 (97·2%) were correctly identified (Kappa statistic of 0·92, Z = 15·46, P < 0·001). This study demonstrates that image-based tick identification may be an accurate and useful method of detecting ticks for surveillance when images are of suitable quality.


Quality in the Context of Value: Reliability of Quality Metrics in an Academic Health System Shifting Toward Value-Based Payments.
Quality metrics are fundamental to value-based payment reforms. Because metrics are key components used to drive performance, health care organizations participating in payment reforms should consider metric reliability-a measure of true performance versus statistical "noise." This cross-sectional study examined reliability, variation from patient and clinician characteristics, and volume thresholds for 9 ambulatory quality metrics in a health system engaged in value-based payment reforms. Hierarchical mixed models were used to analyze data from 276 316 patients attributed to 4373 clinicians in 31 primary care clinics from 2015 to 2017. Reliability was lower for all metrics at the clinician level (range 6%-64%) than at the clinic level (84%-99%), with little variation related to patient or clinician characteristics. Few clinicians, but the majority of clinics, contributed sufficient volumes of patient encounters to meet a 70% reliability threshold. These findings suggest that clinic-level performance measurement may be more appropriate than individual clinician-level measurement, particularly in low-volume contexts.


Investigation of correlation between bony pelvis dimensions and pelvic organ prolapse in different compartments.
To investigate the association between bony pelvis dimensions and anterior, apical, and posterior compartment pelvic organ prolapse (POP) and explore the mechanism of different types of POP from an anatomical point of view. A total of 253 patients with POP were selected as the experimental group (138 patients with anterior compartment defect, 86 with apical compartment defect, and 29 with posterior compartment defect); 253 patients with uterine myoma constituted the control group. Their demographics were recorded, and anteroposterior diameters of the pelvic inlet, intertuberous diameter, and interspinous diameter were measured. One-way analysis of variance, least significant difference t-test, and Student's t-test were used to evaluate the pelvic measurements among the four groups. The anteroposterior diameter of the pelvic inlet in the apical compartment POP group was smaller than that in the other groups (P < 0.05). Interspinous diameters in the anterior and apical groups were larger than those in the posterior POP and control groups (P < 0.05). Intertuberous diameter in the control group was smaller than that in the anterior and apical POP groups and larger than that in the posterior POP group (P < 0.05). Women with apical compartment POP are more likely to have a smaller anteroposterior diameter. Larger interspinous and intertuberous diameters were associated with anterior and apical POP, and smaller intertuberous diameter was associated with posterior POP.


Photocatalytic Conversion of Nitrogen to Ammonia with Water on Surface Oxygen Vacancies of Titanium Dioxide.
Ammonia (NH3) is an essential chemical in modern society. It is currently manufactured by the Haber-Bosch process using H2 and N2 under extremely high-pressure (>200 bar) and high-temperature (>673 K) conditions. Photocatalytic NH3 production from water and N2 at atmospheric pressure and room temperature is ideal. Several semiconductor photocatalysts have been proposed, but all suffer from low efficiency. Here we report that a commercially available TiO2 with a large number of surface oxygen vacancies, when photoirradiated by UV light in pure water with N2, successfully produces NH3. The active sites for N2 reduction are the Ti3+ species on the oxygen vacancies. These species act as adsorption sites for N2 and trapping sites for the photoformed conduction band electrons. These properties therefore promote efficient reduction of N2 to NH3. The solar-to-chemical energy conversion efficiency is 0.02%, which is the highest efficiency among the early reported photocatalytic systems. This noble-metal-free TiO2 system therefore shows a potential as a new artificial photosynthesis for green NH3 production.


A hybrid agent-based model of the developing mammary terminal end bud.
Mammary gland ductal elongation is spearheaded by terminal end buds (TEBs), where populations of highly proliferative cells are maintained throughout post-pubertal organogenesis in virgin mice until the mammary fat pad is filled by a mature ductal tree. We have developed a hybrid multiscale agent-based model to study how cellular differentiation pathways, cellular proliferation capacity, and endocrine and paracrine signaling play a role during development of the mammary gland. A simplified cellular phenotypic hierarchy that includes stem, progenitor, and fully differentiated cells within the TEB was implemented. Model analysis finds that mammary gland development was highly sensitive to proliferation events within the TEB, with progenitors likely undergoing 2-3 proliferation cycles before transitioning to a non-proliferative phenotype, and this result is in agreement with our previous experimental work. Endocrine and paracrine signaling were found to provide reliable ductal elongation rate regulation, while variations in the probability a new daughter cell will be of a proliferative phenotype were seen to have minimal effects on ductal elongation rates. Moreover, the distribution of cellular phenotypes within the TEB was highly heterogeneous, demonstrating significant allowable plasticity in possible phenotypic distributions while maintaining biologically relevant growth behavior. Finally, simulation results indicate ductal elongation rates due to cellular proliferation within the TEB may have a greater sensitivity to upstream endocrine signaling than endothelial to stromal paracrine signaling within the TEB. This model provides a useful tool to gain quantitative insights into cellular population dynamics and the effects of endocrine and paracrine signaling within the pubertal terminal end bud.


A two-stage impression technique for distal-extension removable partial dentures.
Partially edentulous mouths with distal-extension ridges present the challenge of correctly registering two tissues as dissimilar as teeth and edentulous ridges. A technique is described that makes it possible to make impressions with a combination of different impression materials within the same tray and have a firm support that assures even distribution of the impression material and faithfulness of reproduction.


[Cytochrome system of myocardial mitochondria in patients with mitral valve insufficiency].
The content of cytochromes in the mytochondria of the papillary muscles and auricles of the left atria was studied by means of differentiated spectrophotometry in patients operated on for mitral valve insufficiency. A significant reduction of all cytochromes was noted in the papillary muscles of the left ventricle that depended on the stage of circulatory insufficiency. In cases of a protracted course of the disease a tendency towards a reduction in the content of all cytochromes, especially the a + a3 cytochrome, was noted in the papillary muscle. When the content of cytochromes in the myocardium was reduced, the number of cardiac complications in the postoperative period was much higher. A moderately expressed activity of the rheumatic process had no significant effect upon the content of cytochromes in the heart muscle.


Time-dependent configuration-interaction calculations of laser-pulse-driven many-electron dynamics: controlled dipole switching in lithium cyanide.
We report simulations of laser-driven many-electron dynamics by means of the time-dependent configuration interaction singles (doubles) approach. The method accounts for the correlation of ground and excited states, is capable of describing explicitly time-dependent, nonlinear phenomena, and is systematically improvable. Lithium cyanide serves as a molecular test system in which the charge distribution and hence the dipole moment are shown to be switchable, in a controlled fashion, by (a series of) laser pulses which induce selective, state-to-state electronic transitions. One focus of our time-dependent calculations is the question of how fast the transition from the ionic ground state to a specific excited state that is embedded in a multitude of other states can be made, without creating an electronic wave packet.


Targeting microRNA-122: walking on cutting edge of hepatitis C virus infection therapy.
Hepatitis C virus (HCV) infection, with an estimated 170 million carriers worldwide, remains a major cause of chronic liver disease. Current anti-HCV treatments have significant side effects and have met with only partial success. Therefore, a more effective therapeutic modality for HCV infection is needed. The stability and propagation of HCV is dependent on the interaction between its genome and a highly abundant liver microRNA (miRNA), known as microRNA-122 (miR-122). As a conserved host factor that would not be expected to evolve resistance mutations, miR-122 makes an attractive antiviral target. In this review we will discuss how targeting miR-122, using antisense oligonucleotides (ASOs), can be a new anti-HCV treatment.


Symptom Levels in Care-Seeking Bangladeshi and Nepalese Adults With Advanced Cancer.
Three-fourths of patients with advanced cancer are reported to suffer from pain. A primary barrier to provision of adequate symptom treatment is failure to appreciate the intensity of the symptoms patients are experiencing. Because data on Bangladeshi and Nepalese patients' perceptions of their symptomatic status are limited, we sought such information using a cell phone questionnaire. At tertiary care centers in Dhaka and Kathmandu, we recruited 640 and 383 adult patients, respectively, with incurable malignancy presenting for outpatient visits and instructed them for that single visit on one-time completion of a cell phone platform 15-item survey of questions about common cancer-associated symptoms and their magnitudes using Likert scales of 0 to 10. The questions were taken from the Edmonton Symptom Assessment System and the Brief Pain Inventory instruments. All but two Bangladeshi patients recruited agreed to study participation. Two-thirds of Bangladeshi patients reported usual pain levels ≥ 5, and 50% of Nepalese patients reported usual pain levels ≥ 4 (population differences significant at P < .001). Bangladeshi and Nepalese adults with advanced cancer are comfortable with cell phone questionnaires about their symptoms and report high levels of pain. Greater attention to the suffering of these patients is warranted.


In situ monitoring by quantitative Raman spectroscopy of alcoholic fermentation by Saccharomyces cerevisiae under high pressure.
We monitored alcoholic fermentation in Saccharomyces cerevisiae as a function of high hydrostatic pressure. Ethanol production from 0.15 M glucose was measured by Raman spectroscopy in situ in a diamond-anvil cell. At 10 MPa, fermentation proceeds three times faster than at ambient pressure and the fermentation yield is enhanced by 5% after 24 h. Above 20 MPa, the reaction kinetics slows down with increasing pressure. The pressure above which no more ethanol is produced is calculated to be 87 +/- 7 MPa. These results indicate that the activity of one or several enzymes of the glycolytic pathway is enhanced at low pressure up to 10 MPa. At higher pressures, they become progressively repressed, and they are completely inhibited above 87 MPa. Although fermentation was predicted to stop at ca. 50 MPa, due to the loss of activity of phosphofructokinase, the present study demonstrates that there is still an activity of ca. 30% of that measured at ambient pressure at 65 MPa. This study also validates the use of Raman spectroscopy for monitoring the metabolism of living microorganisms.


2a-[4-(Tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole derivatives: new selective antagonists of the 5-hydroxytryptamine7 receptor.
A series of tetrahydrobenzindoles was prepared, and the affinity of these compounds for the 5-hydroxytryptamine7 (5-HT7) receptor and other receptors was evaluated. Most of the compounds showed high affinity for the 5-HT7 receptor, and 2a-[4-(tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole derivatives (26a-j) exhibited high selectivity for this receptor. The nature of the substituent at the 9-position of the tetrahydropyridindole ring affected the affinity for the 5-HT7 receptor, and the 9-carbamoyl moiety afforded increased selectivity. Compound 26j exhibited high affinity for the 5-HT7 receptor, with at least 280-fold selectivity over the 5-HT2 receptor. In a functional model of 5-HT7 receptor activation, this compound was confirmed to have 5-HT7 receptor antagonist activity. It should be a useful tool for clarifying the biological role of the 5-HT7 receptor.


[Triglycerides and phospholipids - relation to fertility].
Searching for further characteristics of sperm in the diagnosis of male infertility it was examined if ejaculates with "normo-, oligo-, astheno-, terato-" and "azoospermia" showed typical modifications in their triglyceride- and phospholipid contents. The examination was conveyed in spermatozoa and seminal plasma. In its results the examination of triglycerides showed no connection between concentration and diagnosis. In relation to its phospholipid contents the seminal plasma of "oligo-" and "azoospermia" was richer while it was diminished in the seminal plasma of "terato-" and "asthenozoospermia". The examination of spermatozoa taken from terato- and oligozoosperm ejaculates showed as well diminished concentrations in their phospholipid contents.


Conscious sedation guidance.
This guidance is intended to promote good clinical practice for the provision in dentistry of conscious sedation that is both safe and effective. It is not a recipe book for sedation and therefore does not include details of drug dosages. The recommendations are applicable to all patients receiving conscious sedation, to facilitate the provision of any type of dental treatment whether it is delivered in a dental practice, a community dental service clinic or a hospital setting. It also covers the provision of conscious sedation for dental treatment provided on a domiciliary basis. Specifically excluded from this guidance, however, are patients who require assisted ventilation, intensive care sedation, premedication for general anaesthesia, postoperative analgesia, sedation in palliative care, night sedation and sedation in the home setting other than for the provision of dental treatment on a domiciliary basis. Existing guidelines, relevant systematic reviews, policy documents, legislation or other recommendations were reviewed and appraised for their quality of development, evidence base and applicability to the remit of the guidance under development. To supplement this information, key questions were formulated by the Guidance Development Group and used as the basis for designing systematic literature search strategies to identify further research evidence that may address these questions, including unpublished work where relevant.The following internet sites were searched for guidelines: New Zealand Guidelines Group, Canadian Collaboration on Clinical Practice Guidelines in Dentistry, National Guidelines Clearinghouse, FDI World Dental Federation, National Electronic Library for Health Guideline Finder, and Medline. The Cochrane Library was searched for systematic reviews and Medline, Embase and the Cochrane Library for studies to address key questions. The searches were supplemented by material already known to members of the Guidance Development Group. Titles and abstracts of the identified references were screened for relevance independently by two researchers who were not members of the Guidance Development Group. Disagreement about the inclusion of specific individual references for further consideration was resolved by discussion and if necessary the opinion of a third researcher was sought. Included references were appraised and data was abstracted independently by two researchers using a specifically designed data-abstraction form. This information was then checked for inconsistencies, which were resolved by discussion, and used to construct evidence tables. The evidence tables were presented to the Guidance Development Group to inform their decision-making and their recommendations related to the key question under consideration. Levels of evidence were assigned by two researchers who were not members of the Guidance Development Group. Formulation of each recommendation was achieved by consensus reached through discussion, drawing on the broad range of interest and experience of sedation related to dentistry within the membership of the Guidance Development Group. Consultation and peer review were conducted prior to publication. A draft of the guidance was the subject of discussion at the Dental Sedation Teachers Group annual symposium in April 2004. Subsequently, approximately 100 copies were distributed throughout the UK to a range of professional organisations and individuals who have an interest in dental sedation, and comments were requested. In addition, all dentists in Scotland who recently claimed the National Health Service allowance for treatment with sedation were invited to comment. The consultation draft was also made available on the group's website (www.scottishdental.org/cep). All comments received through this consultation were considered and the guidance was amended accordingly prior to peer review. Further amendments were made in response to feedback from peer reviewers before publication. The guidance will be reviewed in 2 years' time (2008) and if there have been significant changes it will be updated accordingly. The detailed guidance make 48 recommendations in a range of areas: Discuss alternative methods of anxiety management with patient and ensure that dental care with sedation meets agreed definition of conscious sedation. As part of a thorough assessment, discuss with patient all aspects of their conscious sedation treatment and also provide written instructions. Obtain patient's written consent; maintain comprehensive and contemporaneous patient records. Ensure that environment for sedation is safe and that correct equipment and drugs are provided for each sedation technique used. Ensure that equipment and drugs for dealing with medical emergencies or complications related to sedation are immediately available. Ensure all members of dental team are correctly trained in sedation techniques used, including monitoring of patient during treatment and management of any sedation-related complications. For oral and transmucosal sedation, ensure that sedationist is trained in other titratable techniques and skilled in performing venous cannulation. Ensure that teams giving conscious sedation provide treatment for patient groups they are experienced in managing. For inhalation sedation, ensure that a titrated dose of nitrous oxide is administered using dedicated purpose-designed equipment. Oral, transmucosal and intravenous sedation require pulse oximetry and blood-pressure monitoring. A titrated dose of midazolam is recommended for intravenous sedation. Monitor patients throughout the recovery period until discharge by sedationist into the care of responsible adult escort who has also been given written postoperative instructions. An escort might not be required after nitrous oxide inhalation sedation. A number of recommendations were made regarding the future conduct and reporting of clinical trials. The following areas were highlighted as requiring further high-quality research: Fasting before conscious sedation. Conscious sedation of paediatric dental patients. Dental conscious sedation using combinations of drugs. Dental conscious sedation using continuous infusion. The choice of sedation method for dental patients. Cognitive and behavioural effects of conscious sedation. The interaction of pharmacological and nonpharmacological anxiety management techniques. The complete guidance is available for download at www.scottishdental.org/cep/guidance/dentalsedation.htm.


A stationary wavelet transform and a time-frequency based spike detection algorithm for extracellular recorded data.
Spike detection from extracellular recordings is a crucial preprocessing step when analyzing neuronal activity. The decision whether a specific part of the signal is a spike or not is important for any kind of other subsequent preprocessing steps, like spike sorting or burst detection in order to reduce the classification of erroneously identified spikes. Many spike detection algorithms have already been suggested, all working reasonably well whenever the signal-to-noise ratio is large enough. When the noise level is high, however, these algorithms have a poor performance. In this paper we present two new spike detection algorithms. The first is based on a stationary wavelet energy operator and the second is based on the time-frequency representation of spikes. Both algorithms are more reliable than all of the most commonly used methods. The performance of the algorithms is confirmed by using simulated data, resembling original data recorded from cortical neurons with multielectrode arrays. In order to demonstrate that the performance of the algorithms is not restricted to only one specific set of data, we also verify the performance using a simulated publicly available data set. We show that both proposed algorithms have the best performance under all tested methods, regardless of the signal-to-noise ratio in both data sets. This contribution will redound to the benefit of electrophysiological investigations of human cells. Especially the spatial and temporal analysis of neural network communications is improved by using the proposed spike detection algorithms.


The complex scenario of obesity, diabetes and hypertension in the area of influence of primary healthcare facilities in Mexico.
Among non-communicable chronic diseases (NCCD), diabetes and hypertension are the main cause of adult mortality worldwide. Among the members of the Organization for Economic Cooperation and Development, Mexico is first in prevalence of diabetes and second in obesity. To face this problematic situation of NCCDs the Ministry of Health declared a national epidemiological alert against the overweight, obesity and diabetes. The target of this study is to characterize the status of obesity, diabetes and hypertension in the adult population in the area of influence of primary health facilities located in high social marginality areas. We conducted a cross-sectional observational study and used a convenience sample. A survey was conducted on a population of 18 years old and above in four primary health facilities in four Mexican States. The survey explored sociodemographic characteristics, the presence of chronic diseases, the access to healthcare services, risk factors and life styles. We also applied a complementary questionnaire to 20% of the participants, in order to explore food consumption during the last week and physical activity (International Physical Activity Questionnaire). We based our analysis on descriptive statistics and logistic multivariate regression to analyze factors associated with diabetes and hypertension. 73% (n = 7531, CI 0.72-0.74) percent of the population reported being diabetic, hypertensive and/or overweight. The majority of them receive healthcare in public health services. People over 40 years old, are 11 times more probable of living with diabetes and 8.7 times more probable of living with hypertension. Both conditions affect mostly women, whose main activity is to be a housewife. People who have lunch and dinner out of home are more likely to develop diabetes. People who perform intense physical activity are less likely to live with hypertension. According to the self-report, more than 70% of adult population living in areas with high social marginality suffer diabetes, hypertension and obesity. However, the percentage of people who live with these chronic conditions and are not aware of them, is unknown. The Mexican health system needs a primary healthcare that emphasizes on health promotion, timely detection of risk factors of Non Communicable Diseases and prevention of their complications.


Glutamine Deprivation Causes Hydrogen Peroxide-induced Interleukin-8 Expression via Jak1/Stat3 Activation in Gastric Epithelial AGS Cells.
The Janus kinase (Jak)/Signal transducers of activated transcription (Stat) pathway is an upstream signaling pathway for NF-κB activation in Helicobacter pylori-induced interleukin (IL)-8 production in gastric epithelial AGS cells. H. pylori activates NADPH oxidase and produces hydrogen peroxide, which activates Jak1/Stat3 in AGS cells. Therefore, hydrogen peroxide may be critical for IL-8 production via Jak/Stat activation in gastric epithelial cells. Glutamine is depleted during severe injury and stress and contributes to the formation of glutathione (GSH), which is involved in conversion of hydrogen peroxide into water as a cofactor for GSH peroxidase. We investigated whether glutamine deprivation induces hydrogen peroxide-mediated IL-8 production and whether hydrogen peroxide activates Jak1/Stat3 to induce IL-8 in AGS cells. Cells were cultured in the presence or absence of glutamine or hydrogen peroxide, with or without GSH or a the Jak/Stat specific inhibitor AG490. Glutamine deprivation decreased GSH levels, but increased levels of hydrogen peroxide and IL-8, an effect that was inhibited by treatment with GSH. Hydrogen peroxide induced the activation of Jak1/Stat3 time-dependently. AG490 suppressed hydrogen peroxide- induced activation of Jak1/Stat3 and IL-8 expression in AGS cells, but did not affect levels of reactive oxygen species in AGS cells. In gastric epithelial AGS cells, glutamine deprivation increases hydrogen peroxide levels and IL-8 expression, which may be mediated by Jak1/Stat3 activation. Glutamine supplementation may be beneficial for preventing gastric inflammation by suppressing hydrogen peroxide-mediated Jak1/Stat3 activation and therefore, reducing IL-8 production. Scavenging hydrogen peroxide or targeting Jak1/Stat3 may also prevent oxidant-mediated gastric inflammation.


Ethical Dilemmas in Global Plastic Surgery: Divergent Perspectives of Local and Visiting Surgeons.
As more of the world's resources are directed toward improving patient access to safe surgical and anesthesia care, there is a growing concern that volunteer surgeons' "desire to help" has numerous unintended consequences. The purpose of this study was to ask in-country, local surgeons and visiting volunteer plastic surgeons about the frequency of ethical dilemmas for different types of global surgery collaborations and to assess their perception of compliance with the concepts of autonomy, beneficence, nonmaleficence, and justice. A cross-sectional email survey tool was sent to a representative sample of domestic American Society of Plastic Surgeons members, all international members of the American Society of Plastic Surgeons, and international partners of the Volunteers in Plastic Surgery committee of the Plastic Surgery Foundation. The survey response rate was 7.7 percent, with 356 respondents from 65 countries. This survey data showed a statistically significant divergence of perspectives between local and visiting surgeons in regard to scope of practice, quality of patient care, impact on local health care systems, perception of the quality of care by local providers, the integrity of the informed consent process, and photography in global plastic surgery collaborations. Though the short-term mission trip model was particularly polarizing when comparing the responses of local and visiting surgeons, educational and research exchanges may also significantly interrupt local health care and incite ethical lapses. This survey provides quantitative insight into the impact of current global plastic surgery collaborations and highlights ethical areas of disagreement between local and visiting surgeons.


The physiological consequences of different distributions of diffuse pleural thickening on CT imaging.
Diffuse pleural thickening (DPT) refers to extensive visceral pleural fibrosis with adhesion formation to the parietal pleura obliterating the pleural space. The radiological definition of DPT remains controversial with most of the literature requiring the presence of an obliterated costophrenic angle (CPA) for defining DPT. We conducted a study to investigate the variable distributions of DPT and associated lung function deficit. 85 patients referred to a pleural clinic with suspected pleural thickening were screened for our study. Data were collected from 37 patients with DPT confirmed on CT by size criteria (≥3 mm thick, ≥5 cm wide and ≥8 cm in length), and 21 controls with pleural plaques but no other pleuroparenchymal pathology. 27 patients were excluded. Groups were matched to age, body mass index and smoking history. The percentage of predicted forced vital capacity showed a gradual decline from 98.9% for the control group to 83.5% in the DPT without CPA obliteration group (p < 0.05), to 79.5% in the unilateral DPT group (p < 0.001) and 66.7% in the bilateral group (p < 0.001). Similar reductions were seen in the percentage of predicted total lung capacity in the DPT with no CPA obliteration group and the bilateral DPT group. Our study shows an incremental reduction in the forced vital capacity and total lung capacity in DPT without CPA obliteration, unilateral and bilateral DPT when compared with a matched control group. Advances in knowledge: Different distributions of DPT including no CPA obliteration can cause respiratory impairment, with bilateral DPT being the worst affected.


Sustained intermittent release of gonadotropin-releasing hormone in the prepubertal male rhesus monkey induced by N-methyl-DL-aspartic acid.
The purpose of the present study was to determine whether gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus of the prepubertal monkey may be prematurely provoked into producing a sustained train of intermittent GnRH release N-methyl-DL-aspartic acid (NMA), an analog of the putative excitatory neurotransmitter aspartate, was used to stimulate the hypothalamus. In order to utilize pituitary luteinizing hormone (LH) secretion as a bioassay of hypothalamic GnRH release, juvenile males were castrated and the responsiveness of their gonadotrophs to GnRH was enhanced prior to the study with a chronic intermittent intravenous infusion of the synthetic decapeptide (0.1 microgram/min for 3 min every hour). Treatment with this regimen of GnRH, which appears to provide the pituitary gonadotrophs with a hypophysiotropic stimulus similar to that produced by the hypothalamus of castrated adults, elicited a pattern of pulsatile LH secretion in prepubertal animals similar to that observed in the open-loop situation in adults. This episodic pattern of LH release was sustained without decrement following termination of GnRH priming and initiation of an intermittent intravenous infusion of NMA (4.5-6.5 mg NMA/kg body weight/pulse, administered over 1 min) delivered at a frequency of 1 pulse/1 h for 50 h. In contrast, an intermittent infusion of the vehicle employed to administer NMA (saline) failed to maintain LH secretion. Administration of the same dose of NMA at a slower frequency of 1 pulse/2 h for 52 h, while also sustaining LH secretion without decrement, resulted in an exaggeration in the LH response.(ABSTRACT TRUNCATED AT 250 WORDS)


A long-reach ultra-dense 10 Gbit/s WDM-PON using a digital coherent receiver.
We investigate the impact of channel spacing and nonlinear transmission over 120 km of standard single mode fiber for a 10 Gbit/s long-reach wavelength division multiplexed passive optical network (WDM-PON). We employed polarization division multiplexed quadrature phase shift keying (PDM-QPSK), which allowed data transmission at 3.125 GBaud, including a 25% overhead for forward error correction. To receive this spectrally efficient modulation format, a digital coherent receiver was employed, allowing for both frequency selectivity and an increased sensitivity of -45 dBm (25 photons/bit).We investigated a channel spacing as low as 5 GHz, for which the loss budget was 48.6 dB, increasing to 54.0 dB for a 50 GHz grid.