Inhibition of breathing after surfactant depletion is achieved at a higher arterial PCO(2 )during ventilation with liquid than with gas

BACKGROUND: Inhibition of phrenic nerve activity (PNA) can be achieved when alveolar ventilation is adequate and when stretching of lung tissue stimulates mechanoreceptors to inhibit inspiratory activity. During mechanical ventilation under different lung conditions, inhibition of PNA can provide a physiological setting at which ventilatory parameters can be compared and related to arterial blood gases and pH. OBJECTIVE: To study lung mechanics and gas exchange at inhibition of PNA during controlled gas ventilation (GV) and during partial liquid ventilation (PLV) before and after lung lavage. METHODS: Nine anaesthetised, mechanically ventilated young cats (age 3.8 ± 0.5 months, weight 2.3 ± 0.1 kg) (mean ± SD) were studied with stepwise increases in peak inspiratory pressure (PIP) until total inhibition of PNA was attained before lavage (with GV) and after lavage (GV and PLV). Tidal volume (V(t)), PIP, oesophageal pressure and arterial blood gases were measured at inhibition of PNA. One way repeated measures analysis of variance and Student Newman Keuls-tests were used for statistical analysis. RESULTS: During GV, inhibition of PNA occurred at lower PIP, transpulmonary pressure (Ptp) and Vt before than after lung lavage. After lavage, inhibition of inspiratory activity was achieved at the same PIP, Ptp and Vt during GV and PLV, but occurred at a higher PaCO(2 )during PLV. After lavage compliance at inhibition was almost the same during GV and PLV and resistance was lower during GV than during PLV. CONCLUSION: Inhibition of inspiratory activity occurs at a higher PaCO(2 )during PLV than during GV in cats with surfactant-depleted lungs. This could indicate that PLV induces better recruitment of mechanoreceptors than GV

The Herpesvirus Associated Ubiquitin Specific Protease, USP7, Is a Negative Regulator of PML Proteins and PML Nuclear Bodies

The PML tumor suppressor is the founding component of the multiprotein nuclear structures known as PML nuclear bodies (PML-NBs), which control several cellular functions including apoptosis and antiviral effects. The ubiquitin specific protease USP7 (also called HAUSP) is known to associate with PML-NBs and to be a tight binding partner of two herpesvirus proteins that disrupt PML NBs. Here we investigated whether USP7 itself regulates PML-NBs. Silencing of USP7 was found to increase the number of PML-NBs, to increase the levels of PML protein and to inhibit PML polyubiquitylation in nasopharyngeal carcinoma cells. This effect of USP7 was independent of p53 as PML loss was observed in p53-null cells. PML-NBs disruption was induced by USP7 overexpression independently of its catalytic activity and was induced by either of the protein interaction domains of USP7, each of which localized to PML-NBs. USP7 also disrupted NBs formed from some single PML isoforms, most notably isoforms I and IV. CK2α and RNF4, which are known regulators of PML, were dispensable for USP7-associated PML-NB disruption. The results are consistent with a novel model of PML regulation where a deubiquitylase disrupts PML-NBs through recruitment of another cellular protein(s) to PML NBs, independently of its catalytic activity

Role of the tachykinin NK1 receptor in a murine model of cigarette smoke-induced pulmonary inflammation

<p>Abstract</p> <p>Background</p> <p>The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK₁receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD.</p> <p>Methods</p> <p>Tachykinin NK₁receptor knockout (NK₁-R^-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were evaluated.</p> <p>Results</p> <p>Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK₁-R^-/-mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK₁-R^-/-mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK₁-R^-/-mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK₁-R^-/-mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK₁receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK₁receptor on CS-induced pulmonary inflammation.</p> <p>Conclusion</p> <p>These data suggest that the tachykinin NK₁receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease.</p

A Kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury

© 2020, The Author(s). Renal tubular epithelial cells (RTECs) perform the essential function of maintaining the constancy of body fluid composition and volume. Toxic, inflammatory, or hypoxic-insults to RTECs can cause systemic fluid imbalance, electrolyte abnormalities and metabolic waste accumulation- manifesting as acute kidney injury (AKI), a common disorder associated with adverse long-term sequelae and high mortality. Here we report the results of a kinome-wide RNAi screen for cellular pathways involved in AKI-associated RTEC-dysfunction and cell death. Our screen and validation studies reveal an essential role of Cdkl5-kinase in RTEC cell death. In mouse models, genetic or pharmacological Cdkl5 inhibition mitigates nephrotoxic and ischemia-associated AKI. We propose that Cdkl5 is a stress-responsive kinase that promotes renal injury in part through phosphorylation-dependent suppression of pro-survival transcription regulator Sox9. These findings reveal a surprising non-neuronal function of Cdkl5, identify a pathogenic Cdkl5-Sox9 axis in epithelial cell-death, and support CDKL5 antagonism as a therapeutic approach for AKI

Family Communication in Inherited Cardiovascular Conditions in Ireland

Over 100,000 individuals living in Ireland carry a mutated gene for an inherited cardiac condition (ICC), most of which demonstrate an autosomal dominant pattern of inheritance. First-degree relatives of individuals with these mutations are at a 50 % risk of being a carrier: disclosing genetic information to family members can be complex. This study explored how families living in Ireland communicate genetic information about ICCs and looked at the challenges of communicating information, factors that may affect communication and what influence this had on family relationships. Face to face interviews were conducted with nine participants using an approved topic guide and results analysed using thematic analysis. The participants disclosed that responsibility to future generations, gender, proximity and lack of contact all played a role in family communication. The media was cited as a source of information about genetic information and knowledge of genetic information tended to have a positive effect on families. Results from this study indicate that individuals are willing to inform family members, particularly when there are children and grandchildren at risk, and different strategies are utilised. Furthermore, understanding of genetics is partially regulated not only by their families, but by the way society handles information. Therefore, genetic health professionals should take into account the familial influence on individuals and their decision to attend genetic services, and also that of the media.postprin

Papers presented to the AAEC Symposium on Uranium Processing, Lucas Heights, 20-21 July, 1972.

Review of nuclear fuel cycles and world trends; Conventional processes to produce yellow cake; Carbonate leaching of uranium ores, a review; The application of mineralogy to uranium ore processing; Extraction investigations with some Australian uranium ores; Planned changes in the Mary Kathleen treatment plant for future operations; Possible trends and methods for the production of high purity products; Review of methods and technology for the reproduction of high purity products; Review of methods and technology for the production of uranium hexafluoride; Capital and production costs for the production of uranium hexafluoride; The market for Australian conversion services

Análise da função respiratória na doença de Parkinson Analysis of breathing function in Parkinson's disease

Avaliou-se a função respiratória de 40 parkinsonianos (P), entre 50 e 80 anos, nos estágio I a III da Escala de Hoehn e Yahr e de 40 não parkinsonianos (NP), com características semelhantes. A amplitude torácica de 1,8±0,8 cm nos P foi menor que 4,3±1,0 cm nos NP (p=0,00001), assim como os percentuais das capacidades vital e vital forçada de 66,8±20,3% e 69,6±22,2% nos P e de 82,3±15,7% e 82,7±16,6% nos NP (p=0,00001 e p=0,0023). Apresentaram-se equivalentes as pressões inspiratória e expiratória máximas, de 33,5±12,7 cmH2O e 36, 3±17,8 cmH2O nos P e de 37,0±12,2 cmH2O e 43,1±16,6 cmH2O nos NP (p=0,1753 e 0,0398), o volume do 1º segundo da curva expiratória forçada de 71,3±25,6% nos P e 80,6±23,6% nos NP (p=0,0899) e o percentual da capacidade vital forçada expirada em um segundo, de 104,5±19,9% nos P e 97,4±22,8% nos NP (p=0,1234). Os parkinsonianos evidenciaram restrição respiratória e diminuição de amplitude torácica, sem alteração da força muscular respiratória.<br>We studied 40 parkinsonian patients (P), mean age 50-80 years, with Hoehn and Yahr stages I-III and 40 no parkinsonian patients (NP), with similar characteristics. The results of the thoracic amplitude was 1,8±0,8cm of P that showed a reduction to 4,3±1,0 cm of NP (p=0,00001), the vital capacity and forced vital capacity, 66,8±20,3% and 69,6±22,2% of P was decreased that 82,3±15,7% and 82,7±16,6% of NP (p=0,00001 and p=0,0023). There was not difference among the maximal inspiratory and expiratory mouth pressures, 33,5±12,7 cmH2O and 36,3±17,8 cmH2O of P and 37,0±12,2 cmH2O and 43,1±16,6 cmH2O of NP (p=0,1753 and p=0,0398), the forced expiratory volume in 1 second, 71,3±25,6% of P and 80,6±23,6% of NP (p=0,0899), and the forced expiratory volume in 1 second/ forced vital capacity, 104,5±19,9% of P and 97,4±22,8% of NP (p=0,1234). The parkinsonian patients present restrictive pulmonary dysfunction, low chest wall compliance and the respiratory muscle strenght do not decreased