Relevance of measuring substances in bronchoalveolar lavage fluid for detecting aspiration-associated extraesophageal reflux disease

We read with great interest the paper by Ozdemir et al (1) on the assay of lipid-laden macrophages (LLMs) in broncho-alveolar lavage (BAL) fluid of patients with chronic cough as a marker of micro-aspiration of refluxate into airways. The Authors found that patients with abnormal extra-esophageal reflux as measured by 24-hour impedance-pH monitoring had higher LLM positivity in BAL specimens than those with normal reflux and accordingly, they suggested that this BAL finding should be used to diagnose aspiration in reflux-related chronic cough. The measurement of LLMs from BAL specimens is one of the most widely used tests to identify aspiration-associated extra-esophageal reflux disease (AERD), particularly in children (2). This test is based on the hypothesis that refluxate is phagocytosed by alveolar macrophages and that staining for those in the BAL fluid would verify the presence of AERD. However, previous studies have demonstrated conflicting results, because an increase in LLMs has been observed not only in reflux patients, but also in those without reflux and in any disorder leading to pulmonary inflammation (3,4). On the other hand, search for pepsin and bile acids in BAL has been shown to represent a more valid and specific biomarker of micro-aspiration in patients with objective evidence of abnormal reflux burden since, up to now, no studies measured their presence in BAL of healthy volunteers or patient-controls without evidence of reflux disease (5). Thus, the detection of the above substances in BAL has been overall considered as a strong confirmation of gastric contents coming up from the stomach into the airways. Ozdemir et al stated that BAL pepsin levels have been studied very poorly to diagnose gastro-esophageal reflux (GERD) in patients with respiratory symptoms and quote the only investigation by Decalmer et al (6), in which the Authors found in controls lower levels of pepsin than those detected in chronic cough patients. However, it must be emphasized that in this study various respiratory conditions beyond GERD were considered to elucidate the presence of unexplained chronic cough and this may have been an important confounding factor. In our laboratory the detection of pepsin and bile acids in BAL of patients with GERD was also performed in a recent study (7) using impedance-pH monitoring, which is nowadays considered to be the best test for measuring gastro-esophageal reflux, also in case of atypical manifestations of GERD (8-10). We found that patients with idiopathic pulmonary fibrosis (IPF) had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased. Moreover, more bile acids and pepsin were measured in BAL as a sound marker of gastric aspiration in the upper airways of these patients. Further studies carried out in patients with various pulmonary conditions corroborated our findings (11,12). So far, we would like to emphasize that the detection of various substances in BAL can be of great help in the diagnosis of micro-aspiration of refluxate which is able to induce chronic cough and other respiratory symptoms, but the assay of bile acids or pepsin levels seems to provide us with a more valid and reliable marker of contents reaching the larynx and pharynx from the stomach

Progetto di ristrutturazione della Casa-Albergo dello Sportivo a Pievepelago

Con la presente Tesi di Laurea ho affrontato la fase programmatica e la stesura degli elaborati preliminari del progetto di ristrutturazione della Casa-Albergo dello Sportivo a Pievepelago, costruito nel 1962 ed oggi di proprietà del Comune, mantenendo la sua funzione ricettiva per giovani allievi che partecipano ai Centri Estivi della F.I.T. , e al contempo ampliandola anche alla stagione invernale per i partecipanti alla scuola di sci. L’intervento è mirato ad aumentare le potenzialità (anche per un utilizzo finalizzato a nuove destinazioni d’uso) del complesso che rappresenta un punto d’interesse per gli sportivi di tutta la regione e di conseguenza un importante ritorno d’immagine per il paese di Pievepelago. Lo studio effettuato è iniziato con un’ indagine dello stato attuale, raccogliendo dati inerenti l’inquadramento territoriale (quali ad esempio la viabilità e disponibilità di parcheggi) e con la ricerca di notizie storiche. Dopodiché si è passati all’analisi delle attività e funzioni attraverso le classi di esigenza. Dopo questa prima fase denominata “conoscitiva” si è passati alla stesura del Documento preliminare all’avvio della progettazione (Dpp): un documento che contiene gli obiettivi che si in- tende raggiungere con l’opera programmata e le classi di esigenza, al fine di garantire l’adeguatezza dell’opera progettata a soddisfare le esigenze del committente, nel rispetto della normativa vigente. Nel rispetto della normativa vigente le tematiche affrontate sono state: - l’introduzione di nuove funzioni; - lo studio dell’accessibilità e della fruibilità; - lo studio delle norme di prevenzione incendi; - la valorizzazione architettonica; - l’analisi degli aspetti energetici. In ultima analisi è stato affrontato lo sviluppo di una proposta progettuale preliminare attraverso elaborati grafici. L’innalzamento dell’ala sud garantisce uno sfruttamento migliore dei posti let- to, mentre la disposizione planimetrica ai piani seminterrato e piano terra opera suddivisioni funzionali marcate e allo stesso tempo ipotizza la flessibilità degli spazi. Il nuovo vano scala visibile sul fronte principale rappresenta uno spazio centrale di cerniera e il fulcro visivo dell’insieme. Allo stesso tempo sono state selezionate nuove soluzioni tecniche per cercare di ridurre i consumi energetici e contenere le dispersioni termiche attraverso l’involucro. Questa esperienza è stata un primo approccio alla professione, permettendomi di acquisire ulteriori conoscenze circa la ricerca storica e archivistica, la verifica dei vincoli architettonici ed urbanistici, l’indagine sulle caratteristiche degli edifici esistenti, la progettazione della sicurezza e della accessibilità, nonché lo studio degli aspetti energetici dell’edificio nel rispetto delle normative vigenti in materia di risparmio energetico

LIMITS AND POSSIBILITIES OF MORAL ENHANCEMENT

How to be Good is not a book against moral enhancement, but a book against a specific form of moral enhancement that is moral bio-enhancement. However, How to be Good is also a book in favour of another specific form: cognitive enhancement which is, or at least in certain cases can also be, a form of moral enhancement. This paper discuss the limits and possibilities of Moral Enhancement in Harris\u2019 perspective

Pathophysiological studies are mandatory to understand the benefit of proton pump inhibitors in patients with idiopathic pulmonary fibrosis

none4noWe read with great interest the paper by Lee et al on the protective effect of proton pump inhibitors (PPIs) for survival in patients with GERD and idiopathic pulmonary fibrosis (IPF). The Authors reviewed a very large number of consecutive adult patients with IPF (n=786) and concluded that the prevalence of GERD is lower in Korean patients than in other countries and that PPI use for at least 4 months may have a protective effect against IPF-related mortality. Although these data appear interesting, relevant limitations of this study were its retrospective nature and the fact that the diagnosis of GERD was not based on sound methods, in that only 18 out of 107 patients had erosive esophagitis at endoscopy, while the remaining ones had NERD (n=66) or typical reflux symptoms without EGD (n=23). Moreover, no functional tests were performed (or described) in them. This is particularly relevant since it has been shown in previous series that a large number of IPF patients lack of GERD symptoms despite objective evidence of GERD at endoscopy or reflux monitoring. Indeed, in IPF patients a phenomenon so called “silent reflux” has been described and the consequent microaspiration into the lungs has been mainly implicated in the pathogenesis of this condition. In contrast with the paper of Lee et al (1), many previous studies have reported a higher prevalence of GERD in patients with IPF, and this important relationship has been sustained by pathophysiological investigations which allowed to detect objectively the presence of an abnormal reflux. For instance, Lee et al did not mention a study in IPF individuals performed with 24-hour impedance pH monitoring, which is nowadays considered to be the best test for measuring gastroesophageal reflux, also in case of atypical manifestations. In this study, patients with IPF had significantly higher esophageal acid exposure and greater number of acid refluxes than controls, but also weakly acidic refluxes were remarkably increased (9). Furthermore, more bile acids and pepsin were detected in both broncheoalveolar lavage fluid and saliva as strong confirmation of the risk of gastric aspiration in upper airways of these patients. Similarly, in an earlier pathophysiological study in a group of scleroderma patients with various degrees of pulmonary fibrosis based on high resolution computed tomography, not only acid but also weakly acidic refluxes were found much higher in patients with more severe than in those with mild or moderate pulmonary fibrosis (10). In conclusion, we would like to emphasize that reflux monitoring plays a fundamental role in confirming the presence of GERD in IPF patients and, therefore, the benefit of PPI use in them should be evaluated in carefully investigated subjects in order to provide stronger evidence that PPI may be helpful for their well being and survivalnoneSavarino, Edoardo; Zentilin, Patrizia; Marabotto, Elisa; Savarino, VincenzoSavarino, EDOARDO VINCENZO; Zentilin, Patrizia; Marabotto, Elisa; Savarino, Vincenz

Variational Approaches for Image Labeling on the Assignment Manifold

The image labeling problem refers to the task of assigning to each pixel a single element from a finite predefined set of labels. In classical approaches the labeling task is formulated as a minimization problem of specifically structured objective functions. Assignment flows for contextual image labeling are a recently proposed alternative formulation via spatially coupled replicator equations. In this work, the classical and dynamical viewpoint of image labeling are combined into a variational formulation. This is accomplished by following the induced Riemannian gradient descent flow on an elementary statistical manifold with respect to the underlying information geometry. Convergence and stability behavior of this approach are investigated using the log-barrier method. A novel parameterization of the assignment flow by its dominant component is derived, revealing a Riemannian gradient flow structure that clearly identifies the two governing processes of the flow: spatial regularization of assignments and gradual enforcement of unambiguous label decisions. Also, a continuous-domain formulation of the corresponding potential is presented and well-posedness of the related optimization problem is established. Furthermore, an alternative smooth variational approach to maximum a-posteriori inference based on discrete graphical models is derived by utilizing local Wasserstein distances. Following the resulting Riemannian gradient flow leads to an inference process which always satisfies the local marginalization constraints and incorporates a smooth rounding mechanism towards unambiguous assignments

In-Silico docking of HIV-1 integrase inhibitors reveals a novel drug type acting on an enzyme/DNA reaction intermediate

BACKGROUND: HIV-1 integrase (IN) is an emerging drug target, as IN strand transfer inhibitors (INSTIs) are proving potent antiretroviral agents in clinical trials. One credible theory sees INSTIs as docking at the cellular (acceptor) DNA-binding site after IN forms a transitional complex with viral (donor) DNA. However, mapping of the DNA and INSTI binding sites within the IN catalytic core domain (CCD) has been uncertain. METHODS: Structural superimpositions were conducted using the SWISS PDB and Cn3D free software. Docking simulations of INSTIs were run by a widely validated genetic algorithm (GOLD). RESULTS: Structural superimpositions suggested that a two-metal model for HIV-1 IN CCD in complex with small molecule, 1-(5-chloroindol-3-yl)-3-(tetrazoyl)-1,3-propandione-ene (5CITEP) could be used as a surrogate for an IN/viral DNA complex, because it allowed replication of contacts documented biochemically in viral DNA/IN complexes or displayed by a crystal structure of the IN-related enzyme Tn5 transposase in complex with transposable DNA. Docking simulations showed that the fitness of different compounds for the catalytic cavity of the IN/5CITEP complex significantly (P < 0.01) correlated with their 50% inhibitory concentrations (IC(50)s) in strand transfer assays in vitro. The amino acids involved in inhibitor binding matched those involved in drug resistance. Both metal binding and occupation of the putative viral DNA binding site by 5CITEP appeared to be important for optimal drug/ligand interactions. The docking site of INSTIs appeared to overlap with a putative acceptor DNA binding region adjacent to but distinct from the putative donor DNA binding site, and homologous to the nucleic acid binding site of RNAse H. Of note, some INSTIs such as 4,5-dihydroxypyrimidine carboxamides/N-Alkyl-5-hydroxypyrimidinone carboxamides, a highly promising drug class including raltegravir/MK-0518 (now in clinical trials), displayed interactions with IN reminiscent of those displayed by fungal molecules from Fusarium sp., shown in the 1990s to inhibit HIV-1 integration. CONCLUSION: The 3D model presented here supports the idea that INSTIs dock at the putative acceptor DNA-binding site in a IN/viral DNA complex. This mechanism of enzyme inhibition, likely to be exploited by some natural products, might disclose future strategies for inhibition of nucleic acid-manipulating enzymes

Moral pluralism and Christian Bioethics. On Tr. H. Engelhardt Jr. After God

This article retraces progression of Engelhardt’s work so as to place After God in broader context. In The Foundations of Bioethics, Engelhardt argues that given the moral pluralism that is at the core of postmodernity, only a merely formal morality of permission can bind moral strangers in peaceful coexistence. In The Foundations of Christian Bioethics, Engelhardt presents a bioethics that binds Orthodox Christian moral friends. After God shows itself more pessimistic about the possibility of a merely formal morality of moral friends and calls traditional Christians to wage a culture war. These reflections close with some criticisms of Engelhardt’s philosophical-theological project

Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn’s disease

Background Crohn’s disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear. Objectives The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD. Search methods We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register).We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language. Selection criteria Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. Data collection and analysis Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi2 and I2 statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria. Main results Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA).One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I2 = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to high risk of bias (open-label study) and very sparse data (26 events). There was a reduction in endoscopic relapse at 24 months favouring 6-mercaptopurine over 5-ASA patients. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse compared to 48% of 5-ASA patients (RR 0.36, 95% CI 0.18 to 0.72; 1 study, 91 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (29 events). Adverse events that required withdrawal were more common in the purine analogue group compared to 5-ASA. Twenty per cent of patients in the purine analogue group withdrew due to adverse events compared to 10% of 5-ASA patients (RR 2.07, 95% CI 1.26 to 3.39; 5 studies, 423 patients).The results for withdrawal due to adverse events between purine analogues and placebo or for other comparisons were uncertain. Commonly reported adverse events across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, exacerbation of Crohn’s disease, nasopharyngitis, and flatulence. Authors’ conclusions Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted

Therapeutic imprinting of the immune system: towards a remission of AIDS in primates?

Our inability to cure HIV/AIDS is related to the ability of the virus to establish reservoirs during treatment. In order to develop new strategies, it is certainly essential that a suitable animal model be implemented. In the recent work of Shytaj et al., it has been possible to inhibit viral replication to levels below the assay detection limit in the macaque AIDS model. Moreover, different therapeutic regimens applied to the rhesus macaque AIDS model (herein reviewed), including ours, are starting to show the potential to induce, following therapy suspension, conditions reminiscent of a drug-free control of the infection