Plasma membrane disruptions with different modes of injurious mechanical ventilation in normal rat lungs

Plasma membrane disruptions are caused by excessive mechanical stress and thought to be involved in inflammatory mediator upregulation. Presently, plasma membrane disruption formation has been studied only during mechanical ventilation with large tidal volumes and limitedly to subpleural alveoli. No information is available concerning the distribution of plasma membrane disruptions within the lung or the development of plasma membrane disruptions during another modality of injurious mechanical ventilation, i.e., mechanical ventilation with eupneic tidal volume (7 mL[middle dot]kg-1) at low end-expiratory lung volume. The aim of this study is to assess whether 1) mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume causes plasma membrane disruptions; and 2) the distribution of plasma membrane disruptions differs from that of mechanical ventilation with large tidal volume at normal end-expiratory lung volume. Design: Experimental animal model. Subjects: Sprague-Dawley rats. Interventions: Plasma membrane disruptions have been detected as red spots in gelatin-included slices of rat lungs stained with ethidium homodimer-1 shortly after anesthesia (control) after prolonged mechanical ventilation with eupneic tidal volume at low end-expiratory lung volume followed or not by the restoration of physiological end-expiratory lung volume and after prolonged mechanical ventilation with large tidal volumes and normal end-expiratory lung volume. Measurements and Main Results: Plasma membrane disruptions increased during mechanical ventilation at low end-expiratory lung volume, mainly at the bronchiolar level. Resealing of most plasma membrane disruptions occurred on restoration of normal end-expiratory lung volume. Mechanical ventilation with large tidal volume caused the appearance of plasma membrane disruptions, both bronchiolar and parenchymal, the latter to a much greater extent than with mechanical ventilation at low end-expiratory lung volume. The increase of plasma membrane disruptions correlated with the concomitant increase of airway resistance with both modes of mechanical ventilation. Conclusions: Amount and distribution of plasma membrane disruptions between small airways and lung parenchyma depends on the type of injurious mechanical ventilation. This could be relevant to the release of inflammatory mediators

Formalising Mathematics – in Praxis; A Mathematician’s First Experiences with Isabelle/HOL and the Why and How of Getting Started

AbstractThis is an account of a mathematician’s first experiences with the proof assistant (interactive theorem prover) Isabelle/HOL, including a discussion on the rationale behind formalising mathematics and the choice of Isabelle/HOL in particular, some instructions for new users, some technical and conceptual observations focussing on some of the first difficulties encountered, and some thoughts on the use and potential of proof assistants for mathematics.</jats:p

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production

Effects of mechanical ventilation at low lung volume on respiratory mechanics and nitric oxide exhalation in normal rabbits

Lung mechanics, exhaled NO (NOe), and TNF-(alpha) in serum and bronchoalveolar lavage fluid were assessed in eight closed and eight open chest, normal anesthetized rabbits undergoing prolonged (3-4 h) mechanical ventilation (MV) at low volume with physiological tidal volumes (10 ml/kg). Relative to initial MV on positive end-expiratory pressure (PEEP), MV at low volume increased lung quasi-static elastance (+267 and +281%), airway (+471 and +382%) and viscolelastic resistance (+480 and +294%), and decreased NOe (-42 and -25%) in closed and open chest rabbits, respectively. After restoration of PEEP, viscoelastic resistance returned to control, whereas airway resistance remained elevated (+120 and +31%) and NOe low (-25 and -20%) in both groups of rabbits. Elastance remained elevated (+23%) only in closed-chest animals, being associated with interstitial pulmonary edema, as reflected by increased lung wet-to-dry weight ratio with normal albumin concentration in bronchoalveolar lavage fluid. In contrast, in 16 additional closed- and open-chest rabbits, there were no changes of lung mechanics or NOe after prolonged MV on PEEP only. At the end of prolonged MV, TNF-(alpha) was practically undetectable in serum, whereas its concentration in bronchoalveolar lavage fluid was low and similar in animals subjected or not subjected to ventilation at low volume (62 vs. 43 pg/ml). These results indicate that mechanical injury of peripheral airways due to their cyclic opening and closing during ventilation at low volume results in changes in lung mechanics and reduction in NOe and that these alterations are not mediated by a proinflammatory process, since this is expressed by TNF-(alpha) levels

Effect of heliox breathing on flow limitation in chronic heart failure patients

Patients with chronic heart failure (CHF) exhibit orthopnoea and tidal expiratory flow limitation in the supine position. It is not known whether the flow-limiting segment occurs in the peripheral or central part of the tracheobronchial tree. The location of the flow-limiting segment can be inferred from the effects of heliox (80% helium/20% oxygen) administration. If maximal expiratory flow increases with this low-density mixture, the choke point should be located in the central airways, where the wave-speed mechanism dominates. If the choke point were located in the peripheral airways, where maximal flow is limited by a viscous mechanism, heliox should have no effect on flow limitation and dynamic hyperinflation. Tidal expiratory flow limitation, dynamic hyperinflation and breathing pattern were assessed in 14 stable CHF patients during air and heliox breathing at rest in the sitting and supine position. No patient was flow-limited in the sitting position. In the supine posture, eight patients exhibited tidal expiratory flow limitation on air. Heliox had no effect on flow limitation and dynamic hyperinflation and only minor effects on the breathing pattern. The lack of density dependence of maximal expiratory flow implies that, in CHF patients, the choke point is located in the peripheral airways

A formalisation of the Balog–Szemerédi–Gowers theorem in Isabelle/HOL

We describe our formalisation in the interactive theorem prover Isabelle/HOL of the Balog–Szemerédi–Gowers Theorem, a profound result in additive combinatorics which played a central role in Gowers’s proof deriving the first effective bounds for Szemerédi’s Theorem. The proof is of great mathematical interest given that it involves an interplay between different mathematical areas, namely applications of graph theory and probability theory to additive combinatorics involving algebraic objects. This interplay is what made the process of the formalisation, for which we had to develop formalisations of new background material in the aforementioned areas, more rich and technically challenging. We demonstrate how locales, Isabelle’s module system, can be employed to handle such interplays in mathematical formalisations. To treat the graph-theoretic aspects of the proof, we make use of a new, more general undirected graph theory library developed by Edmonds, which is both flexible and extensible. In addition to the main theorem, which, following our source, is formulated for difference sets, we also give an alternative version for sumsets which required a formalisation of an auxiliary triangle inequality. We moreover formalise a few additional results in additive combinatorics that are not used in the proof of the main theorem. This is the first formalisation of the Balog–Szemerédi–Gowers Theorem in any proof assistant to our knowledge

Formalising Szemerédi’s regularity lemma and Roth’s theorem on arithmetic progressions in Isabelle/HOL

We have formalised Szemerédi’s Regularity Lemma and Roth’s Theorem on Arithmetic Progressions, two major results in extremal graph theory and additive combinatorics, using the proof assistant Isabelle/HOL. For the latter formalisation, we used the former to first show the Triangle Counting Lemma and the Triangle Removal Lemma: themselves important technical results. Here, in addition to showcasing the main formalised statements and definitions, we focus on sensitive points in the proofs, describing how we overcame the difficulties that we encountered

Lung Microbiome in Asthma : Current Perspectives

A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways. In this article, we specifically review current evidence on the characteristics of lung microbiome, and specifically the bacteriome, the modes of interaction between lung microbiota and host immune system, the role of the "lung-gut axis", and the functional effects thereof on asthma pathogenesis. We also attempt to explore the possibilities of therapeutic manipulation of the microbiome, aiming at the establishment of asthma prevention strategies and the optimization of asthma treatment

Primary choriocarcinoma of the renal pelvis presenting as intracerebral hemorrhage: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>A choriocarcinoma is a malignant neoplasm normally arising in the gestational trophoblast, gonads and, less frequently, the retroperitoneum, mediastinum and pineal gland. Primary choriocarcinomas of the renal pelvis are extremely rare.</p> <p>Case presentation</p> <p>We report a case of primary choriocarcinoma of the renal pelvis in a 38-year-old Greek woman of reproductive age, presenting with a sudden development of intracerebral hemorrhage due to metastatic lesions. The diagnosis was established with a renal biopsy, along with an elevated serum level of beta-human chorionic gonadotropin. An extensive diagnostic work up confirmed the origin of the choriocarcinoma to be the renal pelvis.</p> <p>Conclusion</p> <p>Extragonadal choriocarcinomas are rare neoplasms that require extensive laboratory and imaging studies to exclude a gonadal origin. Moreover, this is the first case of severe intracerebral hemorrhage as the initial presentation of primary choriocarcinoma of the renal pelvis. Nonetheless, choriocarcinomas should be considered in the differential diagnosis of women of reproductive age.</p