BMI can influence adult males' and females' airway hyperresponsiveness differently

BACKGROUND: Epidemiological data indicate that obesity is a risk factor for asthma, but scientific literature is still debating the association between changes in body mass index (BMI) and airway hyperresponsiveness (AHR). METHODS: This study aimed at evaluating the influence of BMI on AHR, in outpatients with symptoms suggestive of asthma. 4,217 consecutive adult subjects (2,439 M; mean age: 38.2±14.9 yrs; median FEV(1) % predicted: 100 [IQR:91.88-107.97] and FEV(1)/FVC % predicted: 85.77% [IQR:81.1-90.05]), performed a methacholine challenge test for suspected asthma. Subjects with PD(20) < 200 or 200 < PD(20) < 800 or PD(20) > 800 were considered affected by severe, moderate or mild AHR, respectively. RESULTS: A total of 2,520 subjects (60% of all cases) had a PD(20) < 3,200 μg, with a median PD(20) of 366 μg [IQR:168–1010.5]; 759, 997 and 764 patients were affected by mild, moderate and severe AHR, respectively. BMI was not associated with increasing AHR in males. On the contrary, obese females were at risk for AHR only when those with moderate AHR were considered (OR: 1.772 [1.250-2.512], p = 0.001). A significant reduction of FEV(1)/FVC for unit of BMI increase was found in moderate AHR, both in males (β = −0.255; p =0.023) and in females (β = −0.451; p =0.017). CONCLUSIONS: Our findings indicate that obesity influences AHR only in females with a moderate AHR level. This influence may be mediated by obesity-associated changes in baseline lung function

MOLECULAR CHARACTERISATION OF A NOVEL ADP-RIBOSYLATING PUTATIVE TOXIN OF NEISSERIA MENINGITIDIS

Molecular characterisation of a novel ADP-ribosylating putative toxin of Neisseria meningitidis VEGGIi D, *BALDUCCI E, MASIGNANI V, DI MARCELLO F, SAVINO S, ARICO’ B, COMANDUCCI M, PIZZA M, RAPPUOLI R IRIS, Chiron SpA, Via Fiorentina 1, 53100 Siena Italy; *Dipartimento Scienze morfologiche e Biochimiche Comparate, Università degli Studi di Camerino, Camerino, Italy Session: Surface antigens Introduction: By computer analysis on the Neisseria meningitidis (serogroup B, MC 58 strain) genome sequence, a protein with a feature similar to known bacterial ADP-ribosylating toxins (CT produced by Vibrio cholerae, LT by Escherichia coli and PT by Bordetella pertussis) has been identified. Enzymatic assay has shown that this protein (NM-ADPRT) possesses both NAD glycohydrolase and ADP-ribosyltransferase activity. In this study we describe the identification of the putative catalytic residues, their site-directed mutagenesis, and the resulting activity of the mutants. Materials and methods: The novel NM-ADPRT and the correspondent mutants, were expressed in E. coli as C-terminus His-tag protein fusions. Site-directed mutagenesis was performed using the Multi Site-Directed Mutagenesis Kit (QuikChange). Recombinant NM-ADPRT forms were purified from E. coli in their soluble form by metal chelate affinity chromatography. Both the wild-type and the mutants were assayed for their ADP-ribosylation and NAD-glycohydolase activites, using [adenine –U-14C] NAD and agmatine as ADP-ribose acceptor. Antisera against NM-ADPRT and the mutant derivatives were obtained by immunization of CD1 mice. 20μg of each recombinant protein were given i.p. together with CFA for the first dose and IFA for the second (day 21) and the third (day 35) booster doses. Blood sample were taken on days 34 and 49. Immune sera were used in western blot and tested in a bactericidal assay. Results and discussion: On the basis of sequence homology of NM-ADPRT with LT, CT and PT we have identified the putative residues involved in enzymatic activity. These residues have been changed by site-directed mutagenesis and the purified mutant toxins have been tested for both ADP-ribosylating and NAD-glycohydrolase activities. Interestingly, some of the mutants show reduced or abolished enzymatic activity indicating that the identified residues play a role in catalysis. Antisera against the wild-type and mutant toxins have bactericidal activity. The titers induced by two mutants were higher than those induced by the wild-type form. These data suggest that the mutations introduced could influence not only the enzymatic activity but also the in vivo stability of the toxin. Conclusion: A novel ADP-ribosyltransferase has been identified in meningococcus B. Catalytic residues have been predicted by sequence homology and their role in catalysis has been confirmed by site-directed mutagenesis. These molecules are also able to induce a bactericidal response

The Pictet-Spengler reaction updates its habits

The Pictet-Spengler reaction (P-S) is one of the most direct, efficient, and variable synthetic method for the construction of privileged pharmacophores such as tetrahydroisoquinolines (THIQs), tetrahydro-β-carbolines (THBCs), and polyheterocyclic frameworks. In the lustro (five-year period) following its centenary birthday, the P-S reaction did not exit the stage but it came up again on limelight with new features. This review focuses on the interesting results achieved in this period (2011–2015), analyzing the versatility of this reaction. Classic P-S was reported in the total synthesis of complex alkaloids, in combination with chiral catalysts as well as for the generation of libraries of compounds in medicinal chemistry. The P-S has been used also in tandem reactions, with the sequences including ring closing metathesis, isomerization, Michael addition, and Gold- or Brønsted acid-catalyzed N-acyliminium cyclization. Moreover, the combination of P-S reaction with Ugi multicomponent reaction has been exploited for the construction of highly complex polycyclic architectures in few steps and high yields. The P-S reaction has also been successfully employed in solid-phase synthesis, affording products with different structures, including peptidomimetics, synthetic heterocycles, and natural compounds. Finally, the enzymatic version of P-S has been reported for biosynthesis, biotransformations, and bioconjugations

Robotic versus open oncological gastric surgery in the elderly. a propensity score-matched analysis

Although there is no agreement on a definition of elderly, commonly an age cutoff of ≥ 65 or 75&nbsp;years is used. Even if robot-assisted surgery is a validated option for the elderly population, there are no specific indications for its application in the surgical treatment of gastric cancer. The aim of this study is to evaluate the safety and feasibility of robot-assisted gastrectomy and to compare the short and long-term outcomes of robot-assisted (RG) versus open gastrectomy (OG). Patients aged ≥ 70&nbsp;years old undergoing surgery for gastric cancer at the Department of Surgery of San Donato Hospital in Arezzo, between September 2012 and March 2017 were enrolled. A 1:1 propensity score matching was performed according to the following variables: age, Sex, BMI, ASA score, comorbidity, T stage and type of resection performed. 43 OG were matched to 43 RG. The mean operative time was significantly longer in the RG group (273.8 vs. 193.5&nbsp;min, p &lt; 0.01). No differences were observed in terms of intraoperative blood loss, an average number of lymph nodes removed, mean hospital stay, morbidity and mortality. OG had higher rate of major complications (6.9 vs. 16.3%, OR 2.592, 95% CI 0.623–10.785, p = 0.313) and a significantly higher postoperative pain (0.95 vs. 1.24, p = 0.042). Overall survival (p = 0.263) and disease-free survival (p = 0.474) were comparable between groups. Robotic-assisted surgery for oncological gastrectomy in elderly patients is safe and effective showing non-inferiority comparing to the open technique in terms of perioperative outcomes and overall 5-year survival

Decision Making on Vestibular Schwannoma: Lessons from a Multidisciplinary Board

Background: Management of vestibular schwannoma (VS) is a complex process aimed at identifying a clinical indication for fractionated stereotactic radiotherapy (sRT) or radiosurgery, microsurgical resection, or wait and scan (WS). We describe the experience of our VS multidisciplinary team (MDT) at a tertiary university referral center created for diagnosis, treatment, and follow-up of VS patients. Methods: We conducted a retrospective study on 132 consecutive patients referred to the MDT and managed by observation (WS), microsurgery, or fractionated sRT. The analysis included patient age, tumor size, hearing level, facial nerve function, tumor control, complications, and quality of life questionnaires. Results: Among the patients, 21% were subjected to microsurgery, 10% to sRT, and 69% to WS. The median follow-up time was 30 months. Outcomes based on different management modalities are described. Statistically significant differences among groups were detected in terms of quality of life (physical domain). Conclusions: MDT may provide the best individualized therapy for VS patients compared with a single gold-standard strategy

Investigating regional differences in short-term effects of air pollution on daily mortality in the APHEA project: a sensitivity analysis for controlling long-term trends and seasonality.

Short-term effects of air pollution on daily mortality in eight western and five central-eastern European countries have been reported previously, as part of the APHEA project. One intriguing finding was that the effects were lower in central-eastern European cities. The analysis used sinusoidal terms for seasonal control and polynomial terms for meteorologic variables, but this is a more rigid approach than the currently accepted method, which uses generalized additive models (GAM). We therefore reanalyzed the original data to examine the sensitivity of the results to the statistical model. The data were identical to those used in the earlier analyses. The outcome was the daily total number of deaths, and the pollutants analyzed were black smoke (BS) and sulfur dioxide (SO(2)). The analyses were restricted to days with pollutant concentration < 200 microg/m(3) and < 150 microg/m(3) alternately. We used Poisson regression in a GAM model, and combined individual city regression coefficients using fixed and random-effect models. An increase in BS by 50 microg/m(3) was associated with a 2.2% and 3.1% increase in mortality when analysis was restricted to days < 200 microg/m(3) and < 150 microg/m(3), respectively. The corresponding figures were 5.0% and 5.6% for a similar increase in SO(2). These estimates are larger than the ones published previously: by 69% for BS and 55% for SO(2). The increase occurred only in central-eastern European cities. The ratio of western to central-eastern cities for estimates was reduced to 1.3 for BS (previously 4.8) and 2.6 for SO(2) (previously 4.4). We conclude that part of the heterogeneity in the estimates of air pollution effects between western and central-eastern cities reported in previous publications was caused by the statistical approach used and the inclusion of days with pollutant levels above 150 microg/m(3). However, these results must be investigated further

Polypyrrole-Fe2O3 nanohybrid materials for electrochemical storage

We report on the synthesis and electrochemical characterization of nanohybrid polypyrrole (PPy) (PPy/Fe2O3) materials for electrochemical storage applications. We have shown that the incorporation of nanoparticles inside the PPy notably increases the charge storage capability in comparison to the “pure” conducting polymer. Incorporation of large anions, i.e., paratoluenesulfonate, allows a further improvement in the capacity. These charge storage modifications have been attributed to the morphology of the composite in which the particle sizes and the specific surface area are modified with the incorporation of nanoparticles. High capacity and stability have been obtained in PC/NEt4BF4 (at 20 mV/s), i.e., 47 mAh/g, with only a 3% charge loss after one thousand cyles. The kinetics of charge–discharge is also improved by the hybrid nanocomposite morphology modifications, which increase the rate of insertion–expulsion of counter anions in the bulk of the film. A room temperature ionic liquid such as imidazolium trifluoromethanesulfonimide seems to be a promising electrolyte because it further increases the capacity up to 53 mAh/g with a high stability during charge–discharge processes

Guidance on guidelines: Understanding the evidence on the uptake of health care guidelines

Rationale Regardless of health issue, health sector, patient condition, or treatment modality, the chances are that provision is supported by “a guideline” making professionally endorsed recommendations on best practice. Against this background, research has proliferated seeking to evaluate how effectively such guidance is followed. These investigations paint a gloomy picture with many a guideline prompting lip service, inattention, and even opposition. This predicament has prompted a further literature on how to improve the uptake of guidelines, and this paper considers how to draw together lessons from these inquiries. Methods This huge body of material presents a considerable challenge for research synthesis, and this paper produces a critical, methodological comparison of 2 types of review attempting to meet that task. Firstly, it provides an overview of the current orthodoxy, namely, “thematic reviews,” which aggregate and enumerate the “barriers and facilitators” to guideline implementation. It then outlines a “realist synthesis,” focussing on testing the “programme theories” that practitioners have devised to improve guideline uptake. Results Thematic reviews aim to provide a definitive, comprehensive catalogue of the facilitators and barriers to guideline implementation. As such, they present a restatement of the underlying problems rather than an improvement strategy. The realist approach assumes that the incorporation of any guideline into current practice will produce unintended system strains as different stakeholders wrestle over responsibilities. These distortions will prompt supplementary revisions to guidelines, which in turn beget further strains. Realist reviews follow this dynamic understanding of organisational change. Conclusions Health care decision makers operate in systems that are awash with guidelines. But guidelines only have paper authority. Managers do not need a checklist of their pros and cons, because the fate of guidelines depends on their reception rather than their production. They do need decision support on how to engineer and reengineer guidelines so they dovetail with evolving systems of health care delivery

NarE: a novel ADP-ribosyltransferase from Neisseria meningitidis.

Mono ADP-ribosyltransferases (ADPRTs) are a class of functionally conserved enzymes present in prokaryotic and eukaryotic organisms. In bacteria, these enzymes often act as potent toxins and play an important role in pathogenesis. Here we report a profile-based computational approach that, assisted by secondary structure predictions, has allowed the identification of a previously undiscovered ADP-ribosyltransferase in Neisseria meningitidis (NarE). NarE shows structural homologies with E. coli heat-labile enterotoxin (LT) and cholera toxin (CT) and possesses ADP-ribosylating and NAD-glycohydrolase activities. As in the case of LT and CT, NarE catalyses the transfer of the ADP-ribose moiety to arginine residues. Despite the absence of a signal peptide, the protein is efficiently exported into the periplasm of Neisseria. The narE gene is present in 25 out of 43 strains analysed, is always present in ET-5 and Lineage 3 but absent in ET-37 and Cluster A4 hypervirulent lineages. When present, the gene is 100% conserved in sequence and is inserted upstream of and co-transcribed with the lipoamide dehydrogenase E3 gene. Possible roles in the pathogenesis of N. meningitidis are discussed